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Sample records for scandium 53

  1. Scandium recovery from slags after oxidized nickel ore processing

    Science.gov (United States)

    Smyshlyaev, Denis; Botalov, Maxim; Bunkov, Grigory; Rychkov, Vladimir; Kirillov, Evgeny; Kirillov, Sergey; Semenishchev, Vladimir

    2017-09-01

    One of the possible sources of scandium production - waste (slags) from processing of oxidized nickel ores, has been considered in present research work. The hydrometallurgical method has been selected as the primary for scandium extraction. Different reagents for leaching of scandium, such as sulfuric acid, various carbonate salts and fluorides, have been tested. Sulfuric acid has been recognized as an optimal leaching reagent. Sulfuric acid concentration of 100 g L-1 allowed recovering up to 97 % of scandium.

  2. Influence of scandium concentration on power generation figure of merit of scandium aluminum nitride thin films

    Energy Technology Data Exchange (ETDEWEB)

    Akiyama, Morito; Nagase, Toshimi [Measurement Solution Research Center, National Institute of Advanced Industrials Science and Technology, Tosu, Saga 841-0052 (Japan); Umeda, Keiichi; Honda, Atsushi [Murata Manufacturing Co., Ltd., Nagaokakyo, Kyoto 617-8555 (Japan)

    2013-01-14

    The authors have investigated the influence of scandium concentration on the power generation figure of merit (FOM) of scandium aluminum nitride (Sc{sub x}Al{sub 1-x}N) films prepared by cosputtering. The power generation FOM strongly depends on the scandium concentration. The FOM of Sc{sub 0.41}Al{sub 0.59}N film was 67 GPa, indicating that the FOM is five times larger than that of AlN. The FOM of Sc{sub 0.41}Al{sub 0.59}N film is higher than those of lead zirconate titanate and Pb(Mg{sub 1/3}Nb{sub 2/3})O{sub 3}-PbTiO{sub 3} films, which is the highest reported for any piezoelectric thin films. The high FOM of Sc{sub 0.41}Al{sub 0.59}N film is due to the high d{sub 31} and the low relative permittivity.

  3. Lifetime measurements and oscillator strengths in singly ionized scandium and the solar abundance of scandium

    Science.gov (United States)

    Pehlivan Rhodin, A.; Belmonte, M. T.; Engström, L.; Lundberg, H.; Nilsson, H.; Hartman, H.; Pickering, J. C.; Clear, C.; Quinet, P.; Fivet, V.; Palmeri, P.

    2017-12-01

    The lifetimes of 17 even-parity levels (3d5s, 3d4d, 3d6s and 4p2) in the region 57 743-77 837 cm-1 of singly ionized scandium (Sc II) were measured by two-step time-resolved laser induced fluorescence spectroscopy. Oscillator strengths of 57 lines from these highly excited upper levels were derived using a hollow cathode discharge lamp and a Fourier transform spectrometer. In addition, Hartree-Fock calculations where both the main relativistic and core-polarization effects were taken into account were carried out for both low- and high-excitation levels. There is a good agreement for most of the lines between our calculated branching fractions and the measurements of Lawler & Dakin in the region 9000-45 000 cm-1 for low excitation levels and with our measurements for high excitation levels in the region 23 500-63 100 cm-1. This, in turn, allowed us to combine the calculated branching fractions with the available experimental lifetimes to determine semi-empirical oscillator strengths for a set of 380 E1 transitions in Sc II. These oscillator strengths include the weak lines that were used previously to derive the solar abundance of scandium. The solar abundance of scandium is now estimated to logε⊙ = 3.04 ± 0.13 using these semi-empirical oscillator strengths to shift the values determined by Scott et al. The new estimated abundance value is in agreement with the meteoritic value (logεmet = 3.05 ± 0.02) of Lodders, Palme & Gail.

  4. Smelting of Scandium by Microwave Irradiation.

    Science.gov (United States)

    Fujii, Satoshi; Tsubaki, Shuntaro; Inazu, Naomi; Suzuki, Eiichi; Wada, Yuji

    2017-09-27

    Scandium is being explored as an alloying element for aluminum alloys, which are gaining importance as high-performance lightweight structural alloys in the transportation industry. A few years ago, Sc was also found to be suitable for use in electrical devices. High-Sc-content ScAlN thin films have attracted significant attention because of their strong piezoelectricity. The piezoelectric response of ScAlN suggests that ScAlN thin films formed on a hard substrate would be suitable surface acoustic wave wideband filters for next-generation wireless communication systems. However, it is often difficult to use ScAlN thin films in MEMS devices-including acoustic ones-because of the extremely high price of metallic Sc, given the difficulty associated with smelting it. Here, we propose a novel process for smelting Sc metal by microwave irradiation. Sc metal was able to be obtained successfully from ScF₃ through a microwave-irradiation-based carbon reduction reaction. The reaction temperature for this reduction process was approximately 880°C, which is half of that for the conventional smelting process involving reduction with Ca. Thus, the proposed microwave irradiation process has significant potential for use in the smelting of Sc metal.

  5. Smelting of Scandium by Microwave Irradiation

    Directory of Open Access Journals (Sweden)

    Satoshi Fujii

    2017-09-01

    Full Text Available Scandium is being explored as an alloying element for aluminum alloys, which are gaining importance as high-performance lightweight structural alloys in the transportation industry. A few years ago, Sc was also found to be suitable for use in electrical devices. High-Sc-content ScAlN thin films have attracted significant attention because of their strong piezoelectricity. The piezoelectric response of ScAlN suggests that ScAlN thin films formed on a hard substrate would be suitable surface acoustic wave wideband filters for next-generation wireless communication systems. However, it is often difficult to use ScAlN thin films in MEMS devices—including acoustic ones—because of the extremely high price of metallic Sc, given the difficulty associated with smelting it. Here, we propose a novel process for smelting Sc metal by microwave irradiation. Sc metal was able to be obtained successfully from ScF3 through a microwave-irradiation-based carbon reduction reaction. The reaction temperature for this reduction process was approximately 880°C, which is half of that for the conventional smelting process involving reduction with Ca. Thus, the proposed microwave irradiation process has significant potential for use in the smelting of Sc metal.

  6. Hydrometallurgical methods of recovery of scandium from the wastes of various technologies

    Science.gov (United States)

    Molchanova, T. V.; Akimova, I. D.; Smirnov, K. M.; Krylova, O. K.; Zharova, E. V.

    2017-03-01

    The recovery of scandium from the wastes of the production of uranium, titanium, iron-vanadium, and alumina is studied. The applied acid schemes of scandium transfer to a solution followed by ion-exchange recovery and extraction concentration of scandium ensure the precipitation of crude scandium oxides containing up to 5% Sc2O3. Scandium oxides of 99.96-99.99% purity are formed after additional refining of these crude oxides according to an extraction technology using a mixture 15% multiradical phosphine oxide or Cyanex-925 + 15% tributyl phosphate in kerosene.

  7. Synthesis and Reactivity of a Scandium Terminal Hydride: H2  Activation by a Scandium Terminal Imido Complex.

    Science.gov (United States)

    Han, Xianghao; Xiang, Li; Lamsfus, Carlos A; Mao, Weiqing; Lu, Erli; Maron, Laurent; Leng, Xuebing; Chen, Yaofeng

    2017-10-20

    Dihydrogen is easily activated by a scandium terminal imido complex containing the weakly coordinated THF. The reaction proceeds through a 1,2-addition mechanism, which is distinct from the σ-bond metathesis mechanism reported to date for rare-earth metal-mediated H2 activation. This reaction yields a scandium terminal hydride, which is structurally well-characterized, being the first one to date. The reactivity of this hydride is reported with unsaturated substrates, further shedding light on the existence of the terminal hydride complex. Interestingly, the H2 activation can be reversible. DFT investigations further eludciate the mechanistic aspects of the reactivity of the scandium anilido-terminal hydride complex with PhNCS but also on the reversible H2 activation process. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. Thermoelectric material comprising scandium doped zinc cadmium oxide

    DEFF Research Database (Denmark)

    2016-01-01

    There is presented a composition of scandium doped Zinc Cadmium Oxide with the general formula ZnzCdxScyO which the inventors have prepared, and for which material the inventors have made the insight that it is particularly advantageous as an n-type oxide material, such as particularly advantageous...

  9. Scandium/carbon filters for soft x rays

    NARCIS (Netherlands)

    Artioukov, IA; Kasyanov, YS; Kopylets, IA; Pershin, YP; Romanova, SA

    2003-01-01

    This Note deals with thin-film soft x-ray filters for operation at the wavelengths near carbon K edge (similar to4.5 nm). The filters were fabricated by magnetron sputtering deposition of thin layers of scandium (total thickness 0.1-0.2 mum) onto films of polypropylene (thickness 1.5 mum) and

  10. Solvent extraction of scandium from lateritic nickel- cobalt ores using different organic reagents

    OpenAIRE

    Ferizoğlu Ece; Kaya Şerif; Topkaya Yavuz A.

    2016-01-01

    Scandium is the most important and strategic metal that can be recovered as a by-product from lateritic nickel-cobalt ores. In this research, different extractants were investigated in order to extract scandium from a sulfate medium by a using a solvent extraction method. Generally, the organic extractants are classified as acidic, neutral and basic organophosphorus compounds. However, in solvent extraction of scandium, the acidic and neutral organophosphorus compounds are preferred due to th...

  11. BASIC RESEARCH ON THE SEPARATION OF SCANDIUM YTTRIUM, AND THE RARE EARTHS BY SOLVENT EXTRACTION.

    Science.gov (United States)

    RARE EARTH ELEMENTS, * SOLVENT EXTRACTION ), (*CHELATE COMPOUNDS, RARE EARTH ELEMENTS), PURIFICATION, ATOMIC SPECTROSCOPY, SCANDIUM, YTTRIUM, PRASEODYMIUM, SAMARIUM, EUROPIUM, GADOLINIUM, TERBIUM, FLUORINE COMPOUNDS, KETONES

  12. Determination of scandium concentrate composition by WD-XRF and ICP-MS methods

    Science.gov (United States)

    Sarkisova, A. S.; Shibitko, A. O.; Abramov, A. V.; Rebrin, O. I.; Bunkov, G. M.; Lisienko, D. G.

    2017-09-01

    WD-XRF spectroscopy was applied for determining composition of scandium concentrate (ScC) containing 70 % scandium fluoride. Determination of ScC composition was performed using 6 glass beads reference materials produced by fusing synthesized mixture of analyte compounds with the lithium-borate flux in the ratio of 1:10. ScC powder with the known composition was then used as a powder pellet reference material to analyze scandium concentrate from technological line by external standard method. ICP-MS method was employed to control the ScC composition. The statistical data processing and metrological parameters evaluation of the analytical technique developed were carried out.

  13. Tin etching from metallic and oxidized scandium thin films

    Science.gov (United States)

    Pachecka, M.; Lee, C. J.; Sturm, J. M.; Bijkerk, F.

    2017-08-01

    The role of oxide on Sn adhesion to Sc surfaces was studied with in-situ ellipsometry, X-ray photoelectron spectroscopy and secondary electron microscopy. Sn etching with hydrogen radicals was performed on metallic Sc, metallic Sc with a native oxide, and a fully oxidized Sc layer. The results show that Sn adsorbs rather weakly to a non-oxidized Sc surface, and is etched relatively easily by atomic hydrogen. In contrast, the presence of native oxide on Sc allows Sn to adsorb more strongly to the surface, slowing the etching. Furthermore, thinner layers of scandium oxide result in weaker Sn adsorption, indicating that the layer beneath the oxide plays a significant role in determining the adsorption strength. Unexpectedly, for Sn on Sc2O3, and, to a lesser extent, for Sn on Sc, the etch rate shows a variation over time, which is explained by surface restructuring, temperature change, and hydrogen adsorption saturation.

  14. Tin etching from metallic and oxidized scandium thin films

    Directory of Open Access Journals (Sweden)

    M. Pachecka

    2017-08-01

    Full Text Available The role of oxide on Sn adhesion to Sc surfaces was studied with in-situ ellipsometry, X-ray photoelectron spectroscopy and secondary electron microscopy. Sn etching with hydrogen radicals was performed on metallic Sc, metallic Sc with a native oxide, and a fully oxidized Sc layer. The results show that Sn adsorbs rather weakly to a non-oxidized Sc surface, and is etched relatively easily by atomic hydrogen. In contrast, the presence of native oxide on Sc allows Sn to adsorb more strongly to the surface, slowing the etching. Furthermore, thinner layers of scandium oxide result in weaker Sn adsorption, indicating that the layer beneath the oxide plays a significant role in determining the adsorption strength. Unexpectedly, for Sn on Sc2O3, and, to a lesser extent, for Sn on Sc, the etch rate shows a variation over time, which is explained by surface restructuring, temperature change, and hydrogen adsorption saturation.

  15. Extraction of scandium by liquid di-2-ethylhexylphosphoric acid in fusible diluents

    Directory of Open Access Journals (Sweden)

    Ainur Isatayeva

    2015-03-01

    Full Text Available Currently widespread distribution of extraction methods using fusible reagents can be explained by a number of advantages, such as high kinetic characteristics of the process, the ease separation of two phases, high selectivity of many extractants, relatively complete regeneration. For the extraction of scandium in technological order, neutral and cation exchange extractants can be used. Several extraction reagents melt easily at high temperatures, and such melts can be used for extraction. Efficiency of the extraction of metal by cation reagents depends on many factors. Extraction of scandium by melt mixtures of di-2-ethylhexylphosphoric acid - higher carboxylic acid - paraffin and the effect of acidity of the aqueous phase, the concentration of scandium and the aqueous extractant in the organic phase, the volume ratio of organic and aqueous phases on the extraction of metal were studied. It was found that the extraction of scandium proceeds through the cation exchange mechanism. Scandium was extracted quantitatively (> 99.0% from acid solutions. The optimal concentration of di-2-ethylhexylphosphoric acid in the extractant was 0,250 M, quantitative extraction of scandium was observed in the range of its concentrations of 10-3-10-6 M and the volume ratio of organic phases to aqueous phases of 1:5 - 1:20.

  16. Thermodynamic and kinetic study of scandium(III) complexes of DTPA and DOTA: a step toward scandium radiopharmaceuticals.

    Science.gov (United States)

    Pniok, Miroslav; Kubíček, Vojtěch; Havlíčková, Jana; Kotek, Jan; Sabatie-Gogová, Andrea; Plutnar, Jan; Huclier-Markai, Sandrine; Hermann, Petr

    2014-06-23

    Diethylenetriamine-N,N,N',N'',N''-pentaacetic acid (DTPA) and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) scandium(III) complexes were investigated in the solution and solid state. Three (45)Sc NMR spectroscopic references suitable for aqueous solutions were suggested: 0.1 M Sc(ClO4)3 in 1 M aq. HClO4 (δSc =0.0 ppm), 0.1 M ScCl3 in 1 M aq. HCl (δSc =1.75 ppm) and 0.01 M [Sc(ox)4](5-) (ox(2-) = oxalato) in 1 M aq. K2C2O4 (δSc =8.31 ppm). In solution, [Sc(dtpa)](2-) complex (δSc = 83 ppm, Δν = 770 Hz) has a rather symmetric ligand field unlike highly unsymmetrical donor atom arrangement in [Sc(dota)](-) anion (δSc = 100 ppm, Δν = 4300 Hz). The solid-state structure of K8[Sc2(ox)7]⋅13 H2O contains two [Sc(ox)3](3-) units bridged by twice "side-on" coordinated oxalate anion with Sc(3+) ion in a dodecahedral O8 arrangement. Structures of [Sc(dtpa)](2-) and [Sc(dota)](-) in [(Hguanidine)]2[Sc(dtpa)]⋅3 H2O and K[Sc(dota)][H6 dota]Cl2⋅4 H2O, respectively, are analogous to those of trivalent lanthanide complexes with the same ligands. The [Sc(dota)](-) unit exhibits twisted square-antiprismatic arrangement without an axial ligand (TSA' isomer) and [Sc(dota)](-) and (H6 dota)(2+) units are bridged by a K(+) cation. A surprisingly high value of the last DOTA dissociation constant (pKa =12.9) was determined by potentiometry and confirmed by using NMR spectroscopy. Stability constants of scandium(III) complexes (log KScL 27.43 and 30.79 for DTPA and DOTA, respectively) were determined from potentiometric and (45)Sc NMR spectroscopic data. Both complexes are fully formed even below pH 2. Complexation of DOTA with the Sc(3+) ion is much faster than with trivalent lanthanides. Proton-assisted decomplexation of the [Sc(dota)](-) complex (τ1/2 =45 h; 1 M aq. HCl, 25 °C) is much slower than that for [Ln(dota)](-) complexes. Therefore, DOTA and its derivatives seem to be very suitable ligands for scandium

  17. Effects of iron on intermetallic compound formation in scandium modified Al–Si–Mg Alloys

    Energy Technology Data Exchange (ETDEWEB)

    Patakham, Ussadawut [National Metal and Materials Technology Center, National Science and Technology Development Agency, 114 Thailand Science Park, Klong Nueng, Klong Luang, Pathumthani 12120 (Thailand); Limmaneevichitr, Chaowalit, E-mail: chaowalit.lim@mail.kmutt.ac.th [Production Engineering Department, Faculty of Engineering, King Mongkut’s University of Technology Thonburi, 126 Pracha-Utid Rd., Bangmod, Tungkhru, Bangkok 10140 (Thailand)

    2014-12-15

    Highlights: • Iron reduces the modification effects of scandium in Al–Si–Mg alloys. • Morphologies of Sc-rich intermetallic phases vary with Fe and Sc contents and the cooling rates. • Sc neutralizes effects of Fe by changing Fe-rich intermetallic phases from platelets to more cubic. - Abstract: In general, iron has a strong tendency to dissolve in molten aluminum. Iron has very low solid solubility in aluminum–silicon casting alloys, so it will form intermetallic compounds that cause detrimental effects on mechanical properties. In this work, the effects of iron on intermetallic compound formations in scandium modified Al–Si–Mg alloys were studied. There were two levels of iron addition (0.2 and 0.4 wt.%) and two levels of scandium addition (0.2 and 0.4 wt.%). We found that the effects of scandium modification decreased with increasing iron addition. The morphologies of the complex intermetallic compounds were characterized by scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS) and electron backscatter diffraction (EBSD) techniques. It was found that scandium changes the morphology of Fe-rich intermetallic compounds from β-phase (plate-like) to α-phase, which reduces the harmful effects of β-phase.

  18. Solvent extraction of scandium from lateritic nickel- cobalt ores using different organic reagents

    Directory of Open Access Journals (Sweden)

    Ferizoğlu Ece

    2016-01-01

    Full Text Available Scandium is the most important and strategic metal that can be recovered as a by-product from lateritic nickel-cobalt ores. In this research, different extractants were investigated in order to extract scandium from a sulfate medium by a using a solvent extraction method. Generally, the organic extractants are classified as acidic, neutral and basic organophosphorus compounds. However, in solvent extraction of scandium, the acidic and neutral organophosphorus compounds are preferred due to their higher extraction efficiencies. Thus, the aim of the present study was to compare the scandium extraction efficiencies of some acidic and neutral organic reagents. For this reason, Ionquest 290 (Bis(2,4,4-trimethylpenthyl phosphonic acid, DEHPA (Di(2-ethylhexyl phosphoric acid, Cyanex 272 ((Bis(2,4,4-trimethylpentyl phosphinic acid which are acidic organophosphorus compounds, and Cyanex 923 (Trialkylphosphine oxide, which is a neutral organophosphorus compound, were used. The extraction capacities of these organics were studied with respect to the extractant concentration at same pH and phase ratio. As a result of the study, DEHPA was found to have higher scandium extraction efficiency with lower iron extraction at pH = 0.55 at a phase ratio of 10:1 = A:O.

  19. Correlation between stoichiometry and properties of scandium oxide films prepared by reactive magnetron sputtering

    Science.gov (United States)

    Belosludtsev, Alexandr; Juškevičius, Kęstutis; Ceizaris, Lukas; Samuilovas, Romanas; Stanionytė, Sandra; Jasulaitienė, Vitalija; Kičas, Simonas

    2018-01-01

    Scandium oxide films were deposited on fused silica substrates by reactive pulsed DC magnetron sputtering. The use of feed-back optical emission monitoring enabled high-rate reactive deposition of films with tunable stoichiometry and properties. The under-stoichiometric, stoichiometric and over-stoichiometric scandium oxide films were prepared. The compressive stress in films was between 235 and 530 MPa. We showed that phase structure, density, surface roughness and optical properties of the scandium oxide are affected by the film stoichiometry and deposition conditions. Transparent scandium oxide films were slightly hydrophobic (94 ± 3°), homogeneous with a crystallite size of 20 ± 5 nm. The lowest extinction coefficient 0.7 × 10-3, the highest refractive index 2.08 (both quantities at the wavelength of 355 nm) and the highest density 4.1 ± 0.1 g cm-3 exhibited film prepared with the stoichiometric composition. Stoichiometric scandium oxide can be used in various optical applications as high refractive index and wide bandgap material. Transitions to under- or over-stoichiometry lead to a decrease of film density, refractive index and increase of the extinction coefficient.

  20. Mossbauer investigation of scandium oxide-hematite nanoparticles

    Science.gov (United States)

    Allwes, Mark; Sorescu, Monica

    Scandium oxide-doped hematite, xSc2O3*(1-x)alpha-Fe2O3 with molar concentration x =0.1, 0.3, and 0.5 was prepared by using ball milling, taking samples at times 0, 2, 4, 8, and 12 hours. The resulting Mossbauer spectra of the nanoparticles systems were parameterized using NORMOS-90. For each concentration, the spectra at 0 hours only consisted of 1 sextet, as the substitution of Sc2O3into Fe2O3 did not appear until after 2 hours of ball milling time (BMT). Concentration x =0.1 at BMT 2hours consisted of 2 sextets while x =0.3 and 0.5 were fit with 1 sextet and 1 quadrupole-split doublet. Concentration x =0.1 at BMT 4 and 8 hours consisted of 3 sextets, and at BMT 12 hours consisted of 4 sextets. For concentrations x =0.3 and 0.5 at BMT 4, 8, and 12 hours the spectra were fit with 3 sextets and 1 quadrupole-split doublet. With increasing initial concentration, the appearance of the quadrupole-split doublet became more pronounced, indicating the substitution of Fe into Sc2O3 occurred. But for x =0.1, the BMT did influence the number of sextets needed, causing an increase in substitution of Sc2O3 into Fe2O3.

  1. Association between toenail scandium levels and risk of acute myocardial infarction in European men: The EURAMIC and Heavy Metals Study

    NARCIS (Netherlands)

    Gómez-Aracena, J.; Martin-Moreno, J.M.; Riemersma, R.A.; Bode, P.; Gutiérrez-Bedmar, M.; Gorgojo, L.; Kark, J.D.; Garcia-Rodríguez, A.; Gomez-Gracia, E.; Kardinaal, A.F.M.; Aro, A.; Veer, P. van 't; Wedel, H.; Kok, F.J.; Fernández-Crehuet, J.

    2002-01-01

    The association between scandium status and risk of acute myocardial infarction (MI) was examined in a multicentre case control study in 10 centres from Europe and Israel. Scandium in toenails was assessed in 684 cases and 724 controls less than 70 years of age. Mean concentrations of toenail

  2. In-source laser spectroscopy developments at TRILIS-towards spectroscopy on actinium and scandium

    Energy Technology Data Exchange (ETDEWEB)

    Raeder, Sebastian, E-mail: raeder@triumf.ca; Dombsky, Marik; Heggen, Henning; Lassen, Jens; Quenzel, Thomas [TRIUMF, Canada' s National Laboratory for Nuclear and Particle Physics (Canada); Sjoedin, Marica [GANIL (France); Teigelhoefer, Andrea [TRIUMF, Canada' s National Laboratory for Nuclear and Particle Physics (Canada); Wendt, Klaus [Johannes Gutenberg-Universitaet Mainz, Institut fuer Physik (Germany)

    2013-04-15

    Resonance Ionization Laser Ion Sources (RILIS) have become a versatile tool for production and study of exotic nuclides at Isotope Separator On-Line (ISOL) facilities such as ISAC at TRIUMF. The recent development and addition of a grating tuned spectroscopy laser to the TRIUMF RILIS solid state laser system allows for wide range spectral scans to investigate atomic structures on short lived isotopes, e.g., those from the element actinium, produced in uranium targets at ISAC. In addition, development of new and improved laser ionization schemes for rare isotope production at ISAC is ongoing. Here spectroscopic studies on bound states, Rydberg states and autoionizing (AI) resonances on scandium using the existing off-line capabilities are reported. These results allowed to identify a suitable ionization scheme for scandium via excitation into an autoionizing state at 58,104 cm{sup - 1} which has subsequently been used for ionization of on-line produced exotic scandium isotopes.

  3. Process and Mechanical Properties: Applicability of a Scandium modified Al-alloy for Laser Additive Manufacturing

    Science.gov (United States)

    Schmidtke, K.; Palm, F.; Hawkins, A.; Emmelmann, C.

    The applicability of an aluminium alloy containing scandium for laser additive manufacturing (LAM) is considered. Modified aluminium alloys with a scandium content beyond the eutectic point offer great potential to become a high prioritized aerospace material. Depending on other alloying elements like magnesium or zirconium, strongly required weight reduction, corrosion resistance and improved strength properties of metallic light weight alloys can be achieved. The development, production and testing of parts built up by a laser powder bed process will be presented with regard to the qualification of the new material concept "ScalmalloyRP®" for laser additive manufacturing.

  4. Synthesis and structural characterization of scandium SALEN complexes.

    Science.gov (United States)

    Meermann, Christian; Sirsch, Peter; Törnroos, Karl W; Anwander, Reiner

    2006-02-28

    A series of heteroleptic scandium SALEN complexes, [(SALEN)Sc(mu-Cl)]2 and (SALEN)Sc[N(SiHMe2)2] is obtained via amine elimination reactions using [Sc(N(i)Pr2)2(mu-Cl)(THF)]2 and Sc[N(SiHMe2)2]3(THF) as metal precursors, respectively. H(2)SALEN ligand precursors comprising H2Salen [(1,2-ethandiyl)bis(nitrilomethylidyne)bis(2,4-di-tert-butyl)phenol], H2Salpren [(2,2-dimethylpropanediyl)bis(nitrilomethylidyne)bis(2,4-di-tert-butyl)phenol], H2Salcyc [(1R,2R)-(-)-1,2-cyclohexanediyl)bis(nitrilomethylidyne)bis(2,4-di-tert-butyl)phenol] and H2Salphen [((1S,2S)-(-)-1,2-diphenylethandiyl)bis(nitrilomethylidyne)bis(2,4-di-tert-butyl)phenol] are selected according to solubility and ligand backbone variation ("=N-(R)-N=" bite angle) criteria. Consideration is given to the feasibility of [Cl --> NR2] and [N(SiHMe2)2--> OSiR3] secondary ligand exchange reactions. X-ray crystal structure analyses of donor-free (Salpren)Sc(N(i)Pr2), (R,R)-(Salcyc)Sc[N(SiHMe2)2], (Salen)Sc(OSi(t)BuPh2) and (Salphen)Sc(OSiH(t)Bu2) reveal (i) a very short Sc-N bond distance of 2.000(3) A, (ii) weak beta(Si-H)(amido)-Sc agostic interactions and (iii) an exclusive intramolecularly tetradentate and intrinsically bent coordination mode of the SALEN ligands with angle(Ph,Ph) dihedral angles and Sc-[N(2)O(2)] distances in the 124.27(9)-127.7(3) degrees and 0.638(1)-0.688(1) A range, respectively.

  5. Scandium SALEN complexes bearing chloro, aryloxo, and hydroxo ligands.

    Science.gov (United States)

    Meermann, Christian; Törnroos, Karl W; Anwander, Reiner

    2009-03-16

    Heteroleptic amide complexes (SALEN)Sc[N(SiHMe(2))(2)] (SALEN = Salen(tBu,tBu), Salcyc(tBu,tBu), or Salpren(tBu,tBu) if not stated differently) were examined as synthesis precursors according to silylamine elimination reactions. Treatment of (SALEN)Sc[N(SiHMe(2))(2)] with H(2)O or phenols (HOAr(R,R); R = tBu, iPr) afforded complexes [(SALEN)Sc(mu-OH)](2) and (SALEN)Sc(OAr(R,R)), while chloro exchange products were formed from the respective reactions with NH(4)Cl or AlMe(2)Cl. Such complexes [(SALEN)Sc(mu-Cl)](2) and (SALEN)ScCl(thf) were also obtained by utilizing alternative synthesis protocols, allowing for controlled donor absence and presence. Heteroleptic amide precursors [Sc(NiPr(2))(2)(mu-Cl)(thf)](2) and [Sc[N(SiHMe(2))(2)](2)(mu-Cl)(thf)](2) readily undergo amine elimination reactions with H(2)SALEN derivatives to form the corresponding chloride complexes. Spectroscopic and X-ray structural data of the heteroleptic scandium complexes revealed an exclusive intramolecular tetradentate coordination mode of the SALEN ligands independent of the SALEN ligand bite angle and the nature of the "second" ligand (chloro, amido, aryloxo, hydroxo). The coordination of the SALEN ligands is rationalized on the basis of (a) the displacement d of the metal center from the [N(2)O(2)] least-squares plane, (b) the dihedral angle alpha between the phenyl rings of the salicylidene moieties, and (c) the angle beta = Ct-Ln-Ct (Ct = centroid of the phenyl rings) in the case of strongly twisted ligands.

  6. Vertical distribution of scandium in the north central Pacific

    Science.gov (United States)

    Amakawa, Hiroshi; Nomura, Miho; Sasaki, Kazunori; Oura, Yasuji; Ebihara, Mitsuru

    2007-06-01

    The concentrations of scandium (Sc) in seawater, which have remained unreported since the early 1970s, were determined together with those of yttrium (Y) and lanthanides (Ln) with samples from the north central Pacific Ocean (St. BO-3). The Sc concentration shows a so-called nutrient-like profile: it increases gradually from the surface (about 2 pmol/kg) to the ocean floor (about 20 pmol/kg). That pattern closely resembles those of Y and Ln (correlation coefficient (r) > 0.92). Some light-to-middle Ln (Pr-Tb) exhibit a closer correlation with Sc than do Y, La, or heavy Ln (Ho-Lu). In contrast, Y/Sc and Ln/Sc ratios (elemental abundance ratios) indicate that Sc is depleted compared to either Y or Ln in seawater more than in loess, which represents chemical compositions of crustal material. These observations offer a conflicting view of chemical reactivity related Y, Ln, and Sc: r values show that the chemical reactivity of Sc resembles those of Y and Ln, but differences of Y/Sc and Ln/Sc ratios in seawater and in loess suggest that the chemical reactivity of Sc differs from those of Y and Ln. More Sc data for seawater are necessary to clarify the chemical reactivity of Sc in the ocean. We also propose that comparative studies of vertical profiles of Sc and such elements as Fe, Ti, Zr, and Hf showing so-called nutrient-like profiles at the same oceanic stations would be helpful and effective for clarifying the behavior of Sc in the ocean.

  7. In situ observation of the reaction of scandium and carbon by neutron diffraction

    Energy Technology Data Exchange (ETDEWEB)

    Juarez-Arellano, Erick A., E-mail: eajuarez@unpa.edu.m [Institut fuer Geowissenschaften, Universitaet Frankfurt, Altenhoeferallee 1, 60438 Frankfurt a.M. (Germany); Universidad del Papaloapan, Circuito Central 200, Parque Industrial, Tuxtepec 68301 (Mexico); Winkler, Bjorn [Institut fuer Geowissenschaften, Universitaet Frankfurt, Altenhoeferallee 1, 60438 Frankfurt a.M. (Germany); Vogel, Sven C. [Los Alamos National Laboratory, Lujan Center. Mail Stop H805, Los Alamos, NM 87545 (United States); Senyshyn, Anatoliy [Forschungsneutronenquelle Heinz Maier-Leibnitz (FRM II), Technische Universitaet Muenchen, Lichtenbergstr. 1, D-85747 Garching (Germany); Materialwissenschaft, TU Darmstadt, Petersensstr. 23, D-64287 Darmstadt (Germany); Kammler, Daniel R. [Sandia National Laboratories, Albuquerque, NM 87185 (United States); Avalos-Borja, Miguel [CNyN, UNAM, A. Postal 2681, Ensenada, B.C. (Mexico)

    2011-01-05

    Research highlights: {yields} Exist two ScC cubic phases with B1-structure type differing in site occupancy of C. {yields} A new orthorhombic scandium carbide phase is formed at 1473(50) K. {yields} The recrystallization of alpha-Sc occurs between 1000 and 1223 K. - Abstract: The formation of scandium carbides by reaction of the elements has been investigated by in situ neutron diffraction up to 1823 K. On heating, the recrystallization of {alpha}-Sc occurs between 1000 and 1223 K. The formation of Sc{sub 2}C and ScC (NaCl-B1 type structure) phases has been detected at 1323 and 1373 K, respectively. The formation of a new orthorhombic scandium carbide phase was observed at 1473(50) K. Once the scandium carbides are formed they are stable upon heating or cooling. No other phases were detected in the present study, in which the system was always carbon saturated. The thermal expansion coefficients of all phases have been determined, they are constant throughout the temperature interval studied.

  8. The effects of aluminum or scandium on the toughness, density and ...

    African Journals Online (AJOL)

    The effects of the substitution of aluminum or scandium on the density, toughness as well as the stability of the phases formed by such an addition on platinum, iridium, rhodium and palladium metals were evaluated with the density functional quantum mechanical calculation methods. All the metals had four atoms per ...

  9. Effects of erbium‑and chromium‑doped yttrium scandium gallium ...

    African Journals Online (AJOL)

    2014-08-21

    Aug 21, 2014 ... surfaces because of its high power, and the ablation was deeper for these samples. High‑magnification SEM ... Key words: Erbium chromium‑doped yttrium scandium gallium garnet, diode laser, restorative dental materials, scanning electron ... garnet (Nd: YAG) and carbon dioxide (CO2) lasers on indirect ...

  10. Chemical and biological evaluation of scandium(III)-polyaminopolycarboxylate complexes as potential PET agents and radiopharmaceuticals

    Energy Technology Data Exchange (ETDEWEB)

    Huclier-Markai, S.; Sabatie, A.; Ribet, S. [Univ. de Nantes (France). Lab. Subatech; Kubicek, V.; Hermann, P. [Charles Univ., Prague (Czech Republic). Dept. of Inorganic Chemistry; Paris, M. [Univ. de Nantes (France). Inst. des Materiaux; Vidaud, C. [CEA/DSV/iBEB/SBTN, Bagnols sur Ceze (France). Lab. d' Etude des Proteines Cibles; Cutler, C.S. [Univ. of Missouri, Columbia, MO (United States). Reserach Reactor Center

    2011-07-01

    Scandium isotopes ({sup 44}Sc, {sup 47}Sc) are more available and their properties are convenient for either PET imaging or radiotherapy. To use them in nuclear medicine, ligands forming complexes with a high stability are necessary. Available experimental data on stability constants for complexes of ligands such as EDTA, DTPA, DOTA, NOTA and TETA with various metal ions have been published. But scandium is the exception since scarce data is available in the literature. Values of stability constants of Sc(III) with the ligands were determined by free-ion selective radiotracer extraction, complemented by {sup 45}Sc NMR and potentiometry data. The thermodynamic stability of the Sc-complexes increases in the order TETA < NOTA < EDTA < DTPA < DOTA. The in vitro stability of the Sc(III) complexes was studied in the presence of hydroxyapatite and rat serum to estimate their in vivo stability. The most stable complex was shown to be Sc-DOTA.

  11. Precipitation behaviour and recrystallisation resistance in aluminum alloys with additions of hafnium, scandium and zirconium

    OpenAIRE

    Hallem, Håkon

    2005-01-01

    The overall objective of this work has been to develop aluminium alloys, which after hot and cold deformation are able to withstand high temperatures without recrystallising. This has been done by investigating aluminium alloys with various additions of hafnium, scandium and zirconium, with a main focus on Hf and to which extent it may partly substitute or replace Zr and/or Sc as a dispersoid forming elements in these alloys. What is the effect of hafnium, alone and in combination with Zr...

  12. Pilot-scale recovery of rare earths and scandium from phosphogypsum and uranium leachates

    Directory of Open Access Journals (Sweden)

    Mashkovtsev Maxim

    2016-01-01

    Full Text Available Ural Federal University (UrFU and VTT have performed joint research on development of industrial technologies for the extraction of REM and Scandium compounds from phosphogypsum and Uranium ISL leachate solutions. Leaching-absorption experiments at UrFU have been supported with multicomponent solution modelling by VTT. The simulations have been performed with VTT’s ChemSheet/Balas program and can be used for speciation calculations in the lixiviant solution. The experimental work combines solvent extraction with advanced ion exchange methodology in a pilot facility capable of treating 5 m3 solution per hour. Currently, the plant produces cerium carbonate, lanthanum oxide, neodymium oxide and concentrate of heavy rare earth metals. A batch of 45 t solids has been processed with the gain of 100 kg’s of REM concentrate. A mini-pilot plant with productivity above 50 liters per hour has been applied to recover scandium oxide and REE concentrates from the uranium ISL solution. As the preliminary product contains radioactivity (mainly strontium, an additional decontamination and cleaning of both concentrates by extraction has rendered a necessity. Finally a purified 99% concentrate of scandium oxide as well as 99% rare earth concentrate are received.

  13. Optimization of scandium oxide growth by high pressure sputtering on silicon

    Energy Technology Data Exchange (ETDEWEB)

    Feijoo, P.C., E-mail: pedronska@fis.ucm.es; Pampillon, M.A.; San Andres, E.; Lucia, M.L.

    2012-12-30

    This work demonstrates the viability of scandium oxide deposition on silicon by means of high pressure sputtering. Deposition pressure and radio frequency power are varied for optimization of the properties of the thin films and the ScO{sub x}/Si interface. The physical characterization was performed by ellipsometry, Fourier transform infrared spectroscopy, x-ray diffraction and transmission electron microscopy. Aluminum gate electrodes were evaporated for metal-insulator-semiconductor (MIS) fabrication. From the electrical characterization of the MIS devices, the density of interfacial defects is found to decrease with deposition pressure, showing a reduced plasma damage of the substrate surface for higher pressures. This is also supported by lower flatband voltage shifts in the capacitance versus voltage hysteresis curves. Sputtering at high pressures (above 100 Pa) reduces the interfacial SiO{sub x} formation, according to the infrared spectra. The growth rates decrease with deposition pressure, so a very accurate control of the layer thicknesses could be provided. - Highlights: Black-Right-Pointing-Pointer Scandium oxide is considered as a high permittivity dielectric. Black-Right-Pointing-Pointer Scandium oxide was deposited on Si by high pressure sputtering. Black-Right-Pointing-Pointer Characterization was performed for deposition condition optimization. Black-Right-Pointing-Pointer High deposition pressures showed higher film and interface quality.

  14. Recovery of Scandium from Leachate of Sulfation-Roasted Bayer Red Mud by Liquid-Liquid Extraction

    Science.gov (United States)

    Liu, Zhaobo; Li, Hongxu; Jing, Qiankun; Zhang, Mingming

    2017-11-01

    The leachate obtained from sulfation-roasted Bayer red mud is suitable for extraction of scandium by liquid-liquid solvent extraction because it contains trace amounts of Fe3+ and Si4+. In this study, a completely new metallurgical process for selective recovery of scandium from Bayer red mud was proposed. The extraction performances of Sc3+, Fe3+, Al3+, Si4+, Ca2+, and Na+ from synthetic leachate of sulfation-roasted red mud were first investigated using organophosphorus extractants (di-2-ethylhexyl phosphoric acid P204 and 2-ethylhexyl phosphoric acid mono-2-ethylhexyl ester P507) and carboxylic acid extractant (Versatic acid 10). It shows that P204 has an excellent extraction ability and that it can be applied to the scandium recovery. P507 and Versatic acid 10 are much poorer in performance for selective extraction of scandium. In the leachate of sulfation-roasted red mud, approximately 97% scandium can be recovered using a P204/sulfonated kerosene (1% v/v) extraction system under the condition of an organic-to-aqueous phase ratio of 10:1 and with an extraction temperature of 15°C.

  15. Scandium-doped zinc cadmium oxide as a new stable n-type oxide thermoelectric material

    DEFF Research Database (Denmark)

    Han, Li; Christensen, Dennis Valbjørn; Bhowmik, Arghya

    2016-01-01

    Scandium-doped zinc cadmium oxide (Sc-doped ZnCdO) is proposed as a new n-type oxide thermoelectric material. The material is sintered in air to maintain the oxygen stoichiometry and avoid instability issues. The successful alloying of CdO with ZnO at a molar ratio of 1 : 9 significantly reduced...... is a good candidate for improving the overall conversion efficiencies in oxide thermoelectric modules. Meanwhile, Sc-doped ZnCdO is robust in air at high temperatures, whereas other n-type materials, such as Al-doped ZnO, will experience rapid degradation of their electrical conductivity and ZT....

  16. Scandium and yttrium phosphasalen complexes as initiators for ring-opening polymerization of cyclic esters.

    Science.gov (United States)

    Bakewell, Clare; White, Andrew J P; Long, Nicholas J; Williams, Charlotte K

    2015-03-02

    The synthesis and characterization of novel scandium and yttrium phosphasalen complexes is reported, where phosphasalen refers to two different bis(iminophosphorane) derivatives of the more ubiquitous salen ligands. The activity of the complexes as initiators for the ring-opening polymerization of cyclic esters is presented. The scandium complexes are inactive for lactide polymerization but slow and controlled initiators for ε-caprolactone polymerization. The lack of activity toward lactide exhibited by these compounds is probed, and a rare example of single-monomer insertion product, unable to undergo further reactions with lactide, is identified. In contrast, the analogous yttrium phosphasalen complex is a very active initiator for the ring-opening polymerization of rac-lactide (kobs = 1.5 × 10(-3) s(-1) at 1:500 [yttrium initiator]:[rac-lactide], 1 M overall concentration of lactide in THF at 298 K). In addition to being a very fast initiator, the yttrium complex also maintains excellent levels of polymerization control and a high degree of isoselectivity, with the probability of isotactic enchainment being Pi = 0.78 at 298 K.

  17. Thermodynamic parameters of scandium trifluoride and triiodide in the condensed state

    Science.gov (United States)

    Aristova, N. M.; Belov, G. V.

    2015-06-01

    The thermodynamic properties of new classes of compounds, particularly scandium trihalides ScF3, ScCl3, ScBr3, and ScI3, are added to the IVTANTHERMO software package. A critical analysis and processing of the entire array of primary data available in the literature is performed. An equation approximating the temperature dependence of heat capacity in the temperature range 298.15- T m (K) is derived for each crystalline scandium trihalide. The resulting equations C {/p po}( T) for the solid state and the data for the liquid phase are used to calculate the thermodynamic functions of entropy, the reduced Gibbs free energies, and the enthalpy increments. Both the experimental data available in literature and the missing estimated thermodynamic data are used in calculations. The error of the recommended values is estimated in all cases. In the first part of this work, we describe the thermodynamic properties of ScF3 and ScI3 used as the reference data for calculating the thermodynamic functions of ScCl3 and ScBr3, for which experimental data are either very scarce or missing altogether. The resulting data are added to the database of the IVTANTHERMO software package.

  18. Recovery of Scandium(III) from Aqueous Solutions by Solvent Extraction with the Functionalized Ionic Liquid Betainium Bis(trifluoromethylsulfonyl)imide

    OpenAIRE

    Onghena, Bieke; Binnemans, Koen

    2015-01-01

    The ionic liquid betainium is(trifluoromethylsulfonyl)imide [Hbet][Tf2N] was used for the extraction of scandium from aqueous solutions. The influence of several extraction parameters on the extraction efficiency was investigated, including the initial metal concentration, phase ratio, and pH. The extraction kinetics was examined, and a comparison was made between conventional liquid−liquid extraction and homogeneous liquid−liquid extraction (HLLE). The stoichiometry of the extracted scandium...

  19. Modification mechanism of eutectic silicon in Al–6Si–0.3Mg alloy with scandium

    Energy Technology Data Exchange (ETDEWEB)

    Patakham, Ussadawut [Manufacturing and Systems Engineering Program, Department of Production Engineering, Faculty of Engineering, King Mongkut’s University of Technology Thonburi, 126 Pracha-Utid Rd., Bangmod, Tungkhru, Bangkok 10140 (Thailand); Kajornchaiyakul, Julathep [National Metal and Material Technology Center, National Science and Technology Development Agency, 114 Thailand Science Park, Klong Nueng, Klong Luang, Pathumthani 12120 (Thailand); Limmaneevichitr, Chaowalit, E-mail: chaowalit.lim@kmutt.ac.th [Manufacturing and Systems Engineering Program, Department of Production Engineering, Faculty of Engineering, King Mongkut’s University of Technology Thonburi, 126 Pracha-Utid Rd., Bangmod, Tungkhru, Bangkok 10140 (Thailand)

    2013-10-25

    Highlights: •Morphologies and growth of Sc and Sr-modified eutectic silicon resemble those of dendrites. •Crystal orientation of eutectic aluminum depends on growth characteristics of eutectic silicon. •We report strong evidence of the occurrence of an impurity-induced twinning mechanism. -- Abstract: The modification mechanism of eutectic silicon in Al–6Si–0.3Mg alloy with scandium was studied. The crystallographic orientation relationships between primary dendrites and the eutectic phase of unmodified and modified Al–6Si–0.3 Mg alloys were determined using electron backscatter diffraction (EBSD). The orientation of aluminum modified with scandium in the eutectic phase was different from that of the neighboring primary dendrites. This result implies that eutectic aluminum grows epitaxially from the surrounding primary aluminum dendrites in the unmodified alloy and that eutectic aluminum grows competitively from the surrounding primary aluminum dendrites in the modified alloy. The pole figure maps of eutectic Si in the [1 0 0], [1 1 0] and [1 1 1] axes of the unmodified and Sc-modified alloys were different, suggesting that the eutectic Al and Si crystals in modified alloy growth are more isotropic and cover a larger set of directions. The lattice fringes of Si of the alloys with and without Sc modification were different in the TEM results. The lattice fringes of Si in modified alloy were found to be multiple twins. However, this was not observed in the unmodified alloy. The growth characteristic of eutectic Si crystal in modified alloy suggests the occurrence of multiple twinning reactions and the formation of a high density of twins. This modification mechanism by Sc is explained by the results of scanning electron microscopy (SEM), electron backscatter diffraction (EBSD) and transmission electron microscopy (TEM) analysis, which provide strong evidence of the occurrence of the impurity-induced twinning (IIT) mechanism.

  20. Grain refinement mechanism in an Al-Si-Mg alloy with scandium

    Energy Technology Data Exchange (ETDEWEB)

    Patakham, Ussadawut [Department of Production Engineering, Faculty of Engineering, King Mongkut' s University of Technology Thonburi, 126 Pracha-Utid Rd., Bangmod, Tungkhru, Bangkok 10140 (Thailand); Kajornchaiyakul, Julathep [National Metal and Material Technology Center, National Science and Technology Development Agency, 114 Thailand Science Park, Klong Nueng, Klong Luang, Pathumthani 12120 (Thailand); Limmaneevichitr, Chaowalit, E-mail: chaowalit.lim@kmutt.ac.th [Department of Production Engineering, Faculty of Engineering, King Mongkut' s University of Technology Thonburi, 126 Pracha-Utid Rd., Bangmod, Tungkhru, Bangkok 10140 (Thailand)

    2012-11-25

    Highlights: Black-Right-Pointing-Pointer Scandium can be used to refine aluminum grains in an Al-Si-Mg aluminum alloy. Black-Right-Pointing-Pointer The effectiveness of Sc is lower than that of conventional Al-Ti grain refiners. Black-Right-Pointing-Pointer Al{sub 3}Sc particles can act as heterogeneous nuclei of aluminum phases. Black-Right-Pointing-Pointer Higher alloying elements cause more intermetallic compound phases. Black-Right-Pointing-Pointer Those phases cannot effectively act as heterogeneous nuclei compared with Al{sub 3}Sc particles. - Abstract: Grain refinement of the primary aluminum ({alpha}-Al) phase in a hypoeutectic Al-Si alloy using scandium (Sc) was studied to identify the grain refinement mechanism. Optical microscopy (OM), Scanning electron microscopy (SEM) with energy dispersive spectroscopy (EDS) and electron backscatter diffraction (EBSD) techniques were extensively used in this study. We found that Sc refined grains of primary aluminum. However, the grain refinement efficiency of Sc was considerably lower than that of titanium (Ti) in the Al-Si-Mg foundry alloy. It was evident that the precipitated Sc-containing phases acted as heterogeneous nucleation sites for the primary aluminum phase. The Sc-containing heterogeneous sites are irregular in shape with sizes between 3 and 5 {mu}m. At least three groups of nuclei based on their chemical composition were found, i.e., (i) Al and Sc, (ii) Al, Si, Mg, and Sc, and (iii) Al, Si, Mg, Sc, and Fe. Crystal orientation mapping showed primary aluminum dendrites with one orientation in each grain near Al{sub 3}Sc particles. The grain refinement mechanism of Sc for aluminum relies on heterogeneous nucleation of Al{sub 3}Sc particles, with less responsibly for grain growth restriction. Many intermetallic phases with Al, Si, Fe, Mg and Sc as their major components were found, and these phases could not effectively act as heterogeneous nuclei.

  1. Neutron and Charged-Particle Induced Cross Sections for Radiochemistry for Isotopes of Scandium, Titanium, Vanadium, Chromium, Manganese, and Iron

    Energy Technology Data Exchange (ETDEWEB)

    Kelley, K; Hoffman, R D; Dietrich, F S; Bauer, R; Mustafa, M

    2004-11-30

    We have developed a set of modeled nuclear reaction cross sections for use in radiochemical diagnostics. Local systematics for the input parameters required by the Hauser-Feshbach statistical model were developed and used to calculate neutron and proton induced nuclear reaction cross sections in the mass region of scandium, titanium, vanadium, chromium, manganese, and iron (21 {le} Z {le} 26, 20 {le} N {le} 32).

  2. A composite cathode based on scandium doped titanate with enhanced electrocatalytic activity towards direct carbon dioxide electrolysis.

    Science.gov (United States)

    Yang, Liming; Xie, Kui; Wu, Lan; Qin, Qingqing; Zhang, Jun; Zhang, Yong; Xie, Ting; Wu, Yucheng

    2014-10-21

    A composite cathode based on redox-stable La0.2Sr0.8TiO(3+δ) (LSTO) can perform direct carbon dioxide electrolysis; however, the insufficient electro-catalytic activity limits the electrode performances and current efficiencies. In this work, catalytically active scandium is doped into LSTO to enhance the electro-catalytic activity for CO2 electrolysis. The structures, electronic conductivities and ionic conductivities of La0.2Sr0.8Ti(1-x)Sc(x)O (LSTS(x)O) (x = 0, 0.05, 0.1, 0.15 and 0.2) are systematically studied and further correlated with electrode performances. The ionic conductivities of single-phase LSTS(x)O (x = 0, 0.05, 0.1 and 0.15) remarkably improve versus the scandium doping contents though the electrical conductivities gradually change in an adverse trend. Electrochemical measurements demonstrate promising electrode polarisation of LSTS(x)O electrodes and increasing scandium doping contents accordingly improve electrode performances. The Faradic efficiencies of carbon dioxide electrolysis are enhanced by 20% with LSTS0.15O in contrast to bare LSTO electrodes in a solid oxide electrolyser at 800 °C.

  3. Adsorption of hydrogen in Scandium/Titanium decorated nitrogen doped carbon nanotube

    Energy Technology Data Exchange (ETDEWEB)

    Mananghaya, Michael, E-mail: mikemananghaya@gmail.com [De La Salle University, 2401 Taft Ave, 0922, Manila (Philippines); DLSU STC Laguna Boulevard, LTI Spine Road Barangays Biñan and Malamig, Biñan City, Laguna (Philippines); DOST-ASTHRDP, PCIEERD, Gen. Santos Ave., Bicutan, Taguig City 1631 (Philippines); Belo, Lawrence Phoa; Beltran, Arnel [De La Salle University, 2401 Taft Ave, 0922, Manila (Philippines); DLSU STC Laguna Boulevard, LTI Spine Road Barangays Biñan and Malamig, Biñan City, Laguna (Philippines)

    2016-09-01

    Nitrogen doped Carbon Nanotube with divacancy (4ND-CN{sub x}NT) that is decorated with Scandium and Titanium as potential hydrogen storage medium using the pseudo potential density functional method was investigated. Highly localized states near the Fermi level, which are derived from the nitrogen defects, contribute to strong Sc and Ti bindings, which prevent metal aggregation and improve the material stability. A detailed Comparison of the Hydrogen adsorption capability with promising system-weight efficiency of Sc over Ti was elucidated when functionalized with 4ND-CN{sub x}NT. Finally, the (Sc/4ND){sub 10}-CN{sub x}CNT composite material has a thermodynamically favorable adsorption and consecutive adsorption energy for ideal reversible adsorption and desorption of hydrogen at room temperature such that it can hold at least 5.8 wt% hydrogen molecules at the LDA and GGA level. - Highlights: • Carbon Nanotube with divacancy (4ND-CN{sub x}NT) decorated with Sc and Ti. • Nitrogen defects, contribute to strong Sc and Ti bindings. • H{sub 2} and (Sc/4ND){sub 10}-CN{sub x}CNT has a favorable adsorption. • 5.8 wt% adsorption at the LDA and GGA level.

  4. Urinary monitoring of exposure to yttrium, scandium, and europium in male Wistar rats.

    Science.gov (United States)

    Kitamura, Yasuhiro; Usuda, Kan; Shimizu, Hiroyasu; Fujimoto, Keiichi; Kono, Rei; Fujita, Aiko; Kono, Koichi

    2012-12-01

    On the assumption that rare earth elements (REEs) are nontoxic, they are being utilized as replacements of toxic heavy metals in novel technological applications. However, REEs are not entirely innocuous, and their impact on health is still uncertain. In the past decade, our laboratory has studied the urinary excretion of REEs in male Wistar rats given chlorides of europium, scandium, and yttrium solutions by one-shot intraperitoneal injection or oral dose. The present paper describes three experiments for the suitability and appropriateness of a method to use urine for biological monitoring of exposure to these REEs. The concentrations of REEs were determined in cumulative urine samples taken at 0-24 h by inductively coupled plasma atomic emission spectroscopy, showing that the urinary excretion of REEs is <2 %. Rare earth elements form colloidal conjugates in the bloodstream, which make high REEs accumulation in the reticuloendothelial system and glomeruli and low urinary excretion. The high sensitivity of inductively coupled plasma-argon emission spectrometry analytical methods, with detection limits of <2 μg/L, makes urine a comprehensive assessment tool that reflects REE exposure. The analytical method and animal experimental model described in this study will be of great importance and encourage further discussion for future studies.

  5. Selective recovery of vanadium and scandium by ion exchange with D201 and solvent extraction using P507 from hydrochloric acid leaching solution of red mud.

    Science.gov (United States)

    Zhu, Xiaobo; Li, Wang; Tang, Sen; Zeng, Majian; Bai, Pengyuan; Chen, Lunjian

    2017-05-01

    D201 resin and P507 extractant diluted with sulfonated kerosene were used to respectively separate vanadium and scandium, and impurity ions from hydrochloric acid leaching solution of red mud. More than 99% of vanadium was selectively adsorbed from the hydrochloric acid leaching solution under the conditions of pH value of 1.8, volume ratio of leaching solution to resin of 10, and flow rate of 3.33 mL/min. Maximum extraction and separation of scandium was observed from the acid leaching solution at an aqueous pH value of 0.2. More than 99% of scandium can be selectively extracted using 15% P507, 5% TBP at the aqueous solution/organic phase (A/O) ratio of 10:1 for 6 min. The loaded organic phase was washed with 0.3 mol/L sulfuric acid, wherein most impurities were removed. After the process of desorption or stripping, precipitation, and roasting, high-purity V2O5 and Sc2O3 were obtained. Finally, a conceptual flow sheet was established to separate and recover vanadium and scandium from red mud hydrochloric acid leaching solution. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. p53 Isoforms

    Science.gov (United States)

    Khoury, Marie P.; Bourdon, Jean-Christophe

    2011-01-01

    Normal function of the p53 pathway is ubiquitously lost in cancers either through mutation or inactivating interaction with viral or cellular proteins. However, it is difficult in clinical studies to link p53 mutation status to cancer treatment and clinical outcome, suggesting that the p53 pathway is not fully understood. We have recently reported that the human p53 gene expresses not only 1 but 12 different p53 proteins (isoforms) due to alternative splicing, alternative initiation of translation, and alternative promoter usage. p53 isoform proteins thus contain distinct protein domains. They are expressed in normal human tissues but are abnormally expressed in a wide range of cancer types. We have recently reported that p53 isoform expression is associated with breast cancer prognosis, suggesting that they play a role in carcinogenesis. Indeed, the cellular response to damages can be switched from cell cycle arrest to apoptosis by only manipulating p53 isoform expression. This may provide an explanation to the hitherto inconsistent relationship between p53 mutation, treatment response, and outcome in breast cancer. However, the molecular mechanism is still unknown. Recent reports suggest that it involves modulation of gene expression in a p53-dependent and -independent manner. In this review, we summarize our current knowledge about the biological activities of p53 isoforms and propose a molecular mechanism conciliating our current knowledge on p53 and integrating p63 and p73 isoforms in the p53 pathway. PMID:21779513

  7. Random-field Potts model for the polar domains of lead magnesium niobate and lead scandium tantalate

    Energy Technology Data Exchange (ETDEWEB)

    Qian, H.; Bursill, L.A

    1997-06-01

    A random filed Potts model is used to establish the spatial relationship between the nanoscale distribution of charges chemical defects and nanoscale polar domains for the perovskite-based relaxor materials lead magnesium niobate (PMN) and lead scandium tantalate (PST). The random fields are not set stochastically but are determined initially by the distribution of B-site cations (Mg, Nb) or (Sc, Ta) generated by Monte Carlo NNNI-model simulations for the chemical defects. An appropriate random field Potts model is derived and algorithms developed for a 2D lattice. It is shown that the local fields are strongly correlated with the chemical domain walls and that polar domains as a function of decreasing temperature is simulated for the two cases of PMN and PST. The dynamics of the polar clusters is also discussed. 33 refs., 9 figs.

  8. Development of methods for the selective separation of scandium, zirconium and tin for radiopharmaceutical applications; Entwicklung von Methoden zur selektiven Trennung von Scandium, Zirkonium und Zinn fuer radiopharmazeutische Anwendungen

    Energy Technology Data Exchange (ETDEWEB)

    Dirks-Fandrei, Carina

    2014-07-01

    The subject of the present work is the development of fast and highly selective methods for the separation and purification of scandium, zirconium and tin radionuclides from potential target materials for use in nuclear medicine. A number of selected resins (TrisKem International) were first characterized with respect to their extraction behaviour towards a large number of cations. Characterization studies were performed in batch experiments by determination of weight distribution ratios D{sub w} and further the influence of interferences on the uptake of these elements was evaluated. Weight distribution ratios were determined in different acids and acid concentrations with main focus on scandium, tin or zirconium. The interference of macro amounts of Calcium and Ti on the Sc extraction was evaluated as well as the interference of macro amounts of Y on the Zr extraction. Best suited uptake conditions were found for Scandium on DGA were determined to be 2.5 M HNO{sub 3} for Ti-Targets and 0.1 M HNO{sub 3} for Calcium-Targets. Otherwise it is also possible to extract Sc with TRU Resin. High uptakes were obtained at 2.5 M HNO{sub 3} for simulated Ti- and Calcium-targets. Separation methods were developed using elution studies; employed conditions were chosen according to parameters evaluated in the batch-experiment. The developed methods allowed separating Sc very rapidly in high purity very rapidly from Ti- or Calcium-targets. For Zr a separation method based on UTEVA Resin has been developed. Following results of batch experiments simulated Y-target solution were loaded onto a UTEVA resin column from 6 M HNO{sub 3}; the elution of Zr could be performed in 0.01 M oxalic acid. Decontamination factors in the order of 10{sup 4}-10{sup 5} could be obtained applying the developed method; the method thus allowed separating Zr in a high purity. Initial testing of a method for the separation of Sn from Cd targets based on the use of TBP Resin showed that the TBP resin seems

  9. The impact of an erbium, chromium:yttrium-scandium-gallium-garnet laser with radial-firing tips on endodontic treatment.

    Science.gov (United States)

    Schoop, U; Barylyak, A; Goharkhay, K; Beer, F; Wernisch, J; Georgopoulos, A; Sperr, W; Moritz, A

    2009-01-01

    Radial-firing tips should allow a more homogeneous laser irradiation of root canal walls. The aim of the study was to assess the effects of erbium, chromium:yttrium-scandium-gallium-garnet (Er,Cr:YSGG) laser irradiation in conjunction with those newly designed tips. The investigation comprised bacteriology, morphological evaluations and temperature measurements. Root canals were inoculated with two test strains and laser irradiated with power settings of 0.6 W and 0.9 W and a repetition rate of 20 Hz. Subsequently, the samples were subjected to microbiological evaluation. The morphological changes of the canal walls were assessed by scanning electron microscopy. To reveal possible thermal side effects, we carried out temperature measurements. The bacteriological evaluation revealed a decisive disinfectant effect. Scanning electron microscopy showed the homogeneous removal of smear layer from the root canal walls. The temperature rise at the root surface during the irradiation was moderate, yielding 1.3 degrees C for the 0.6 W setting and 1.6 degrees C for the 0.9 W setting. The investigations indicated that the Er,Cr:YSGG laser, in conjunction with radial-firing tips, is a suitable tool for the elimination of bacteria in root canals and for the removal of smear layer.

  10. Effect of scandium addition on the microstructure, mechanical and wear properties of the spray formed hypereutectic aluminum–silicon alloys

    Energy Technology Data Exchange (ETDEWEB)

    Raghukiran, Nadimpalli; Kumar, Ravi, E-mail: nvrk@iitm.ac.in

    2015-08-12

    Hypereutectic Al–x%Si–0.8Sc alloys (x=13, 16, 19 and 22 wt%) were produced by spray forming. The microstructures of all the alloys exhibited very fine silicon phase with average size of about 5–10 µm irrespective of the silicon content of the alloy. Transmission electron microscopy revealed the presence of a nano-scale scandium rich phase, identified as AlSi{sub 2}Sc{sub 2} (V-phase) uniformly distributed in the alloy. The presence of V-phase resulted in higher matrix hardness (1.34 GPa) in contrast to 1.04 GPa observed in the case of binary Al–Si alloys by nanoindentation. Isothermal heat treatment at 375 °C revealed insignificant coarsening of silicon phase in both binary and ternary alloys. The Al–x%Si–0.8Sc alloys exhibited higher flow stress and tensile strength in contrast to their binary alloy counterparts which was attributed to the bi-modal size distribution of the strengthening phases in the form of nano-scale V-phase and sub-micron to 10 µm size silicon particles. The pin-on-disk wear tests exhibited appreciable improvement in the wear performance of the relatively low-silicon content ternary alloys over their binary counterparts while the high-silicon content binary and ternary alloys exhibited no much difference in the wear performance.

  11. Scandium and Titanium Containing Single-Walled Carbon Nanotubes for Hydrogen Storage: a Thermodynamic and First Principle Calculation.

    Science.gov (United States)

    Mananghaya, Michael; Yu, Dennis; Santos, Gil Nonato; Rodulfo, Emmanuel

    2016-06-15

    The generalized gradient approximation (GGA) to density functional theory (DFT) calculations indicate that the highly localized states derived from the defects of nitrogen doped carbon nanotube with divacancy (4ND-CNxNT) contribute to strong Sc and Ti bindings, which prevent metal aggregation. Comparison of the H2 adsorption capability of Sc over Ti-decorated 4ND-CNxNT shows that Ti cannot be used for reversible H2 storage due to its inherent high adsorption energy. The Sc/4ND-CNxNT possesses favorable adsorption and consecutive adsorption energy at the local-density approximation (LDA) and GGA level. Molecular dynamics (MD) study confirmed that the interaction between molecular hydrogen and 4ND-CNxNT decorated with scandium is indeed favorable. Simulations indicate that the total amount of adsorption is directly related to the operating temperature and pressure. The number of absorbed hydrogen molecules almost logarithmically increases as the pressure increases at a given temperature. The total excess adsorption of hydrogen on the (Sc/4ND)10-CNxNT arrays at 300 K is within the range set by the department of energy (DOE) with a value of at least 5.85 wt%.

  12. Effects of scandium addition on iron-bearing phases and tensile properties of Al–7Si–0.6Mg alloys

    Energy Technology Data Exchange (ETDEWEB)

    Tzeng, Yu-Chih [Department of Mechanical Engineering, National Central University, Jhongli, Taiwan (China); Wu, Chih-Ting [Department of Vehicle Engineering, Army Academy R.O.C., Jhongli, Taiwan (China); Bor, Hui-Yun; Horng, Jain-Long; Tsai, Mu-Lin [Department of Mechanical Engineering, National Central University, Jhongli, Taiwan (China); Institute of Materials Science and Engineering, National Central University, Jhongli, Taiwan (China); Lee, Sheng-Long, E-mail: shenglon@cc.ncu.edu.tw [Department of Mechanical Engineering, National Central University, Jhongli, Taiwan (China); Institute of Materials Science and Engineering, National Central University, Jhongli, Taiwan (China)

    2014-01-21

    Iron is the most deleterious impurity in aluminum alloys and can easily combine with aluminum to form an acicular β-Al{sub 5}FeSi phase that reduces ductility during the solidification of the molten metal. Adding scandium (Sc) to Al–7Si–0.6Mg alloys can transform the acicular β-Al{sub 5}FeSi phase into a comparatively harmless nodular Sc–Fe phase (Al{sub 12}Si{sub 6}Fe{sub 2}(Mg,Sc){sub 5}). This Sc–Fe phase has a lower hardness and elastic modulus than the β-Al{sub 5}FeSi phase; it is thus less likely to initiate cracks in the Al matrix. Moreover, the nodular Sc–Fe phase can improve the fluidity of Al during solidification, reducing interdendritic shrinkage. Tensile testing measurements showed that the elongation of Al–7Si–0.6Mg alloys with 0.04 and 0.12 wt% Sc can be respectively increased by 115% and 110% compared to Al–7Si–0.6Mg without Sc. The corresponding quality indices are increased by 17% and 19%, respectively, suggesting that the tensile properties of Al–7Si–0.6Mg alloys can be enhanced by adding scandium.

  13. Separation of (44)Ti from proton irradiated scandium by using solid-phase extraction chromatography and design of (44)Ti/(44)Sc generator system.

    Science.gov (United States)

    Radchenko, V; Meyer, C A L; Engle, J W; Naranjo, C M; Unc, G A; Mastren, T; Brugh, M; Birnbaum, E R; John, K D; Nortier, F M; Fassbender, M E

    2016-12-16

    Scandium-44g (half-life 3.97h [1]) shows promise for positron emission tomography (PET) imaging of longer biological processes than that of the current gold standard, (18)F, due to its favorable decay parameters. One source of (44g)Sc is the long-lived parent nuclide (44)Ti (half-life 60.0 a). A (44)Ti/(44g)Sc generator would have the ability to provide radionuclidically pure (44g)Sc on a daily basis. The production of (44)Ti via the (45)Sc(p,2n) reaction requires high proton beam currents and long irradiation times. Recovery and purification of no-carrier added (nca) (44)Ti from scandium metal targets involves complex separation chemistry. In this study, separation systems based on solid phase extraction chromatography were investigated, including branched diglycolamide (BDGA) resin and hydroxamate based ZR resin. Results indicate that ZR resin in HCl media represents an effective (44)Ti/(44g)Sc separation system. Copyright © 2016 Elsevier B.V. All rights reserved.

  14. Expression of TP53 isoforms p53β or p53γ enhances chemosensitivity in TP53(null cell lines.

    Directory of Open Access Journals (Sweden)

    Elisabeth Silden

    Full Text Available The carboxy-terminal truncated p53 alternative spliced isoforms, p53β and p53γ, are expressed at disparate levels in cancer and are suggested to influence treatment response and therapy outcome. However, their functional role in cancer remains to be elucidated. We investigated their individual functionality in the p53(null background of cell lines H1299 and SAOS-2 by stable retroviral transduction or transient transfection. Expression status of p53β and p53γ protein was found to correlate with increased response to camptothecin and doxorubicin chemotherapy. Decreased DNA synthesis and clonogenicity in p53β and p53γ congenic H1299 was accompanied by increased p21((CIP1/WAF1, Bax and Mdm2 proteins. Chemotherapy induced p53 isoform degradation, most prominent for p53γ. The proteasome inhibitor bortezomib substantially increased basal p53γ protein level, while the level of p53β protein was unaffected. Treatment with dicoumarol, a putative blocker of the proteasome-related NAD(PH quinone oxidoreductase NQO1, effectively attenuated basal p53γ protein level in spite of bortezomib treatment. Although in vitro proliferation and clonogenicity assays indicated a weak suppressive effect by p53β and p53γ expression, studies of in vivo subcutaneous H1299 tumor growth demonstrated a significantly increased growth by expression of either p53 isoforms. This study suggests that p53β and p53γ share functionality in chemosensitizing and tumor growth enhancement but comprise distinct regulation at the protein level.

  15. OTUD5 regulates p53 stability by deubiquitinating p53.

    Directory of Open Access Journals (Sweden)

    Judong Luo

    Full Text Available The p53 tumour suppressor protein is a transcription factor that prevents oncogenic progression by activating the expression of apoptosis and cell-cycle arrest genes in stressed cells. The stability of p53 is tightly regulated by ubiquitin-dependent degradation, driven mainly by its negative regulators ubiquitin ligase MDM2.In this study, we have identified OTUD5 as a DUB that interacts with and deubiquitinates p53. OTUD5 forms a direct complex with p53 and controls level of ubiquitination. The function of OTUD5 is required to allow the rapid activation of p53-dependent transcription and a p53-dependent apoptosis in response to DNA damage stress.As a novel deubiquitinating enzyme for p53, OTUD5 is required for the stabilization and the activation of a p53 response.

  16. p53-based Cancer Therapy

    Science.gov (United States)

    Lane, David P.; Cheok, Chit Fang; Lain, Sonia

    2010-01-01

    Inactivation of p53 functions is an almost universal feature of human cancer cells. This has spurred a tremendous effort to develop p53 based cancer therapies. Gene therapy using wild-type p53, delivered by adenovirus vectors, is now in widespread use in China. Other biologic approaches include the development of oncolytic viruses designed to replicate and kill only p53 defective cells and also the development of siRNA and antisense RNA's that activate p53 by inhibiting the function of the negative regulators Mdm2, MdmX, and HPV E6. The altered processing of p53 that occurs in tumor cells can elicit T-cell and B-cell responses to p53 that could be effective in eliminating cancer cells and p53 based vaccines are now in clinical trial. A number of small molecules that directly or indirectly activate the p53 response have also reached the clinic, of which the most advanced are the p53 mdm2 interaction inhibitors. Increased understanding of the p53 response is also allowing the development of powerful drug combinations that may increase the selectivity and safety of chemotherapy, by selective protection of normal cells and tissues. PMID:20463003

  17. Gd-Sc-based mixed-metal nitride cluster fullerenes: mutual influence of the cage and cluster size and the role of scandium in the electronic structure.

    Science.gov (United States)

    Svitova, Anna L; Popov, Alexey A; Dunsch, Lothar

    2013-03-18

    The influence of the cage as well as of the cluster size has been studied in Gd-Sc nitride cluster fullerenes, which have been synthesized and isolated for these studies. A series of carbon cages ranging from C78 to C88 have been synthesized, isolated, and characterized in detail using absorption and vibrational spectroscopy as well as electrochemistry and density functional theory calculations. Gd-Sc mixed-metal cluster fullerenes in carbon cages different from C80 were described for the first time. A review of their structures, properties, and stability is given. The synthesis was performed with melamine as an effective solid source of nitrogen, providing high fullerene yield and suppressing empty fullerene formation. Substitution of gadolinium by scandium imposes a noticeable influence on the electronic structure of nitride cluster fullerenes as revealed by electrochemical, spectroscopic, and computational methods.

  18. Copper scandium zirconium phosphate

    DEFF Research Database (Denmark)

    Bond, Andrew David; Warner, Terence Edwin

    2013-01-01

    components. The [Sc(III)Zr(IV)(PO(4))(3)](2-) framework is composed of corner-sharing Sc/ZrO(6) octahedra and PO(4) tetrahedra. The Sc and Zr atoms are disordered on one atomic site on a crystallographic threefold axis. The P atom of the phosphate group lies on a crystallographic twofold axis. Nonframework...

  19. 48 CFR 6101.53 - Accelerated procedure [Rule 53].

    Science.gov (United States)

    2010-10-01

    ... 48 Federal Acquisition Regulations System 7 2010-10-01 2010-10-01 false Accelerated procedure . 6101.53 Section 6101.53 Federal Acquisition Regulations System CIVILIAN BOARD OF CONTRACT APPEALS... monetary amount in dispute and that amount is $100,000 or less. Such election shall be made no later than...

  20. CH-53K Heavy Lift Replacement Helicopter (CH-53K)

    Science.gov (United States)

    2015-12-01

    Selected Acquisition Report (SAR) RCS: DD-A&T(Q&A)823-390 CH-53K Heavy Lift Replacement Helicopter (CH-53K) As of FY 2017 President’s Budget...December 2015 SAR March 4, 2016 10:04:18 UNCLASSIFIED 4 Col Henry Vanderborght PMA-261 Heavy Lift Helicopters Program Executive Office - Air, Anti...757-5780 Fax: 301-757-5109 DSN Phone: 757-5780 DSN Fax: 757-5109 Date Assigned: May 29, 2014 Program Information Program Name CH-53K Heavy Lift

  1. Synthesis and characterization of reduced scandium halide containing one- and two-dimensional metal bonded arrays. [Sc--ScCl3; Cs3Sc2Cl9; CsScCl3

    Energy Technology Data Exchange (ETDEWEB)

    Poeppelmeier, K.R.

    1978-08-01

    The stabilization effect of metal-metal bond formation on reduced scandium compounds was studied. The binary compounds Sc/sub 7/Cl/sub 12/, Sc/sub 5/Cl/sub 8/, Sc/sub 7/Cl/sub 10/ and ScCl were prepared by high temperature techniques and were characterized by single crystal x-ray diffraction. The respective metal arrays in these compounds can be viewed as fragments of scandium metal ranging from discrete six atom metal cluster species (Sc(Sc/sub 6/Cl/sub 12/)), through intermediate single and double infinite chain configurations ((ScCl/sub 2/)(Sc/sub 4/Cl/sub 6/)) and ((ScCl/sub 2/)(Sc/sub 6/Cl/sub 8/)) to double metal close-packed sheets (ScCl). The halogen atoms effectively isolate the clusters, chains and sheets by bonding face, edge or exo positions on the metal arrays. The common occurrence of isolated scandium (III) ions emphasizes that a minimum number of bonding electrons is required to stabilize what are formally anionic metal arrays. The distribution of the reduction electrons in these anisotropic materials was studied by magnetic susceptibility, EPR and uv-X photoelectron spectroscopy. The ternary compounds studied were Cs/sub 3/Sc/sub 2/Cl/sub 9/ and CsScCl/sub 3/. The anion-bridged metal chain of the hexagonal perovskite structure was found to stabilize scandium (II). CsScCl/sub 3/ was found to be grossly nonstoichiometric on the transition metal site and the effects of the mixed valence character were studied between the single valence extremes Cs/sub 3/Sc/sub 2 + x/Cl/sub 9/; 0< x < 1.0.

  2. Scandium functionalized carbon aerogel: Synthesis of nanoparticles and structure of a new ScOCl and properties of NaAlH{sub 4} as a function of pore size

    Energy Technology Data Exchange (ETDEWEB)

    Javadian, Payam; Nielsen, Thomas K. [Center for Energy Materials, Interdisciplinary Nanoscience Center (iNANO), and Department of Chemistry, Aarhus University, DK-8000 Aarhus (Denmark); Ravnsbæk, Dorthe B. [Department of Material Science and Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge 02142, MA (United States); Jepsen, Lars H. [Center for Energy Materials, Interdisciplinary Nanoscience Center (iNANO), and Department of Chemistry, Aarhus University, DK-8000 Aarhus (Denmark); Polanski, Marek [Faculty of Advanced Technology and Chemistry, Military University of Technology, 2 Kaliskiego Str., 00-908 Warsaw (Poland); Plocinski, Tomasz [Faculty of Material Science and Engineering, Warsaw University of Technology, 144 Woloska Str., 02-507 Warsaw (Poland); Kunce, Izabela [Faculty of Advanced Technology and Chemistry, Military University of Technology, 2 Kaliskiego Str., 00-908 Warsaw (Poland); Besenbacher, Flemming [Interdisciplinary Nanoscience Center (iNANO) and Department of Physics and Astronomy, Aarhus University, DK-8000 Aarhus C (Denmark); Bystrzycki, Jerzy [Faculty of Advanced Technology and Chemistry, Military University of Technology, 2 Kaliskiego Str., 00-908 Warsaw (Poland); Jensen, Torben R., E-mail: trj@chem.au.dk [Center for Energy Materials, Interdisciplinary Nanoscience Center (iNANO), and Department of Chemistry, Aarhus University, DK-8000 Aarhus (Denmark)

    2015-11-15

    A new method for scandium-functionalization of carbon aerogels forming nanoparticles of a new scandiumoxochloride, ScOCl is presented. Sodium aluminiumhydride, NaAlH{sub 4}, is successfully melt infiltrated into the nano porous scaffolds with pore sizes of D{sub max}=7, 10, 13, 21, 26 and 39 nm, containing scandium based nano particles (<2.9 wt%) confirmed by elemental analysis and scanning electron microscopy. A systematic study of hydrogen storage properties of the nano composite materials is presented. An aqueous solution of ScCl{sub 3} was initially infiltrated and formed nanoconfined [Sc(OH)(H{sub 2}O){sub 5}]{sub 2}Cl{sub 4}(H{sub 2}O){sub 2}, which transforms to nanoparticles of a new scandium oxochloride, ScOCl at 192 °C and to Sc{sub 2}O{sub 3} at 420 °C. ScOCl crystallizes in an orthorhombic unit cell a=3.4409(8), b=3.9613(6) and c=8.178(2) Å, space group Pmmn, and is built from layers of [ScO{sub 4}Cl{sub 2}] octahedra forming neutral ScOCl layers. Temperature programmed desorption mass spectroscopy shows slightly improved kinetics for release of hydrogen with decreasing pore size. Continuous cycling of hydrogen release and uptake measured by the Sieverts' method reveal a larger preserved hydrogen storage capacity for scandium-functionalized aerogel with the larger pores (39 nm). - Highlights: • New synthesis approach for nanoporous Sc-functionalization carbon aerogel (Sc-CA). • The new scandium oxochloride, ScOCl, structure is obtained. • NaAlH{sub 4} nanoconfined in Sc-CA with pores ranging between 7 nm

  3. 53

    African Journals Online (AJOL)

    échapper à son contrôle. 4. La participation de la société civile. La situation avant 1990 était assez simple: une société civile réduite à un clergé condescendant, un syndicat unique affilié au parti unique, une absence d'association et d'ONG .

  4. Stability of p53 homologs.

    Directory of Open Access Journals (Sweden)

    Tobias Brandt

    Full Text Available Most proteins have not evolved for maximal thermal stability. Some are only marginally stable, as for example, the DNA-binding domains of p53 and its homologs, whose kinetic and thermodynamic stabilities are strongly correlated. Here, we applied high-throughput methods using a real-time PCR thermocycler to study the stability of several full-length orthologs and paralogs of the p53 family of transcription factors, which have diverse functions, ranging from tumour suppression to control of developmental processes. From isothermal denaturation fluorimetry and differential scanning fluorimetry, we found that full-length proteins showed the same correlation between kinetic and thermodynamic stability as their isolated DNA-binding domains. The stabilities of the full-length p53 orthologs were marginal and correlated with the temperature of their organism, paralleling the stability of the isolated DNA-binding domains. Additionally, the paralogs p63 and p73 were significantly more stable and long-lived than p53. The short half-life of p53 orthologs and the greater persistence of the paralogs may be biologically relevant.

  5. The use of the erbium, chromium:yttrium-scandium-gallium-garnet laser in endodontic treatment: the results of an in vitro study.

    Science.gov (United States)

    Schoop, Ulrich; Goharkhay, Kawe; Klimscha, Johannes; Zagler, Manuela; Wernisch, Johann; Georgopoulos, Apostolos; Sperr, Wolfgang; Moritz, Andreas

    2007-07-01

    The use of the erbium, chromium:yttrium-scandium-gallium-garnet (Er,Cr:YSGG) laser has become accepted in the field of cavity preparation. The development of miniaturized and flexible fiber tips has allowed this device to be used in endodontics. The authors conducted an in vitro study to assess the effects of Er,Cr:YSGG laser irradiation on root canals. The authors inoculated root canals with two bacteria, laser irradiated them at two power settings and subjected them to a quantitative microbiological evaluation. They used scanning electron microscopy (SEM) to assess morphological changes in endodontically processed and laser-irradiated root canal walls. They measured temperature increases on the root surface to determine possible thermal side effects. The bacteriological evaluation revealed a disinfecting effect in the root dentin samples that was dependent on the output power but not specific for the bacterial species investigated. SEM showed the removal of the smear layer from the root canal walls and the exposure of dentinal tubules. The temperature rise during irradiation was moderate when standardized power settings were used. The Er,Cr:YSGG laser can be used to eliminate bacteria in root canals. It also effectively removes smear layer and debris from the canal wall. Practitioners can use the Er,Cr:YSGG laser to prepare root canals for endodontic therapy.

  6. Aluminum-Scandium Alloys: Material Characterization, Friction Stir Welding, and Compatibility With Hydrogen Peroxide (MSFC Center Director's Discretionary Fund Final Report, Proj. No. 04-14)

    Science.gov (United States)

    Lee, J. A.; Chen, P. S.

    2004-01-01

    This Technical Memorandum describes the development of several high-strength aluminum (Al) alloys that are compatible with hydrogen peroxide (H2O2) propellant for NASA Hypersonic-X (Hyper-X) vehicles fuel tanks and structures. The yield strengths for some of these Al-magnesium-based alloys are more than 3 times stronger than the conventional 5254-H112 Al alloy, while maintaining excellent H2O2 compatibility similar to class 1 5254 alloy. The alloy development strategy is to add scandium, zirconium, and other transitional metals with unique electrochemical properties, which will not act as catalysts, to decompose the highly concentrated 90 percent H2O2. Test coupons are machined from sheet metals for H2O2 long-term exposure testing and mechanical properties testing. In addition, the ability to weld the new alloys using friction stir welding has also been explored. The new high-strength alloys could represent an enabling material technology for Hyper-X vehicles, where flight weight reduction is a critical requirement.

  7. High-fluence and high-density treatment of perioral rhytides using a new, fractionated 2,790-nm ablative erbium-doped Yttrium Scandium Gallium Garnet Laser.

    Science.gov (United States)

    Ciocon, David H; Hussain, Mussarat; Goldberg, David J

    2011-06-01

    In this study, we evaluated the safety and efficacy of a novel 2,790-nm erbium-doped yttrium scandium gallium garnet (Er:YSGG) laser system for the treatment of facial photodamage and perioral wrinkles using a single-treatment, high-fluence, high-density protocol. Eleven female participants with Fitzpatrick skin types II to III and facial wrinkles underwent a single full-face fractional ablative treatment with a 2,790-nm Er:YSGG laser. Follow-up visits were completed at 1, 2, and 6 weeks 3 and 6 months. Quartile improvement scale (0-4) and Fitzpatrick wrinkle scores (1-9) were used for the assessments. Based on blinded photographic assessments, the mean difference in Fitzpatrick wrinkle scores for full face wrinkles was 1.5 ± 1.2 (a reduction from 6.6 to 5.1; paired t-test, p = .003). There was also a statistically significant mean reduction of 1.7 ± 1.3 in perioral wrinkle scores (from 6.7 to 5.0; p = .002). No serious adverse events were reported. A novel, fractionated, ablative 2,790-nm Er:YSGG laser can safely and effectively treat photodamage and perioral wrinkles in a single treatment using a high-fluence, high-density protocol. Cutera provided the equipment used in this study and funding to Dr. Goldberg. © 2011 by the American Society for Dermatologic Surgery, Inc.

  8. Impact of layer and substrate properties on the surface acoustic wave velocity in scandium doped aluminum nitride based SAW devices on sapphire

    Energy Technology Data Exchange (ETDEWEB)

    Gillinger, M., E-mail: manuel.gillinger@tuwien.ac.at; Knobloch, T.; Schneider, M.; Schmid, U. [Institute of Sensor and Actuator Systems, TU Wien, 1040 Vienna (Austria); Shaposhnikov, K.; Kaltenbacher, M. [Institute of Mechanics and Mechatronics, TU Wien, 1040 Vienna (Austria)

    2016-06-06

    This paper investigates the performance of surface acoustic wave (SAW) devices consisting of reactively sputter deposited scandium doped aluminum nitride (Sc{sub x}Al{sub 1-x}N) thin films as piezoelectric layers on sapphire substrates for wireless sensor or for RF-MEMS applications. To investigate the influence of piezoelectric film thickness on the device properties, samples with thickness ranging from 500 nm up to 3000 nm are fabricated. S{sub 21} measurements and simulations demonstrate that the phase velocity is predominantly influenced by the mass density of the electrode material rather than by the thickness of the piezoelectric film. Additionally, the wave propagation direction is varied by rotating the interdigital transducer structures with respect to the crystal orientation of the substrate. The phase velocity is about 2.5% higher for a-direction compared to m-direction of the sapphire substrate, which is in excellent agreement with the difference in the anisotropic Young's modulus of the substrate corresponding to these directions.

  9. Vulture News - Vol 53 (2005)

    African Journals Online (AJOL)

    The advantages and disadvantages of vulture restaurants versus simply leaving livestock (and game) carcasses in the veldt · EMAIL FREE FULL TEXT EMAIL FREE FULL TEXT · DOWNLOAD FULL TEXT DOWNLOAD FULL TEXT. Mark D Anderson, Angus Anthony, 42-45. http://dx.doi.org/10.4314/vulnew.v53i1.37635 ...

  10. p53 isoform Δ113p53 is a p53 target gene that antagonizes p53 apoptotic activity via BclxL activation in zebrafish

    OpenAIRE

    Chen, Jun; Ng, Sok Meng; Chang, Changqing; Zhang, Zhenhai; Bourdon, Jean-Christophe; Lane, David P; Peng, Jinrong

    2009-01-01

    p53 is a well-known tumor suppressor and is also involved in processes of organismal aging and developmental control. A recent exciting development in the p53 field is the discovery of various p53 isoforms. One p53 isoform is human Δ133p53 and its zebrafish counterpart Δ113p53. These N-terminal-truncated p53 isoforms are initiated from an alternative p53 promoter, but their expression regulation and physiological significance at the organismal level are not well understood. We show here that ...

  11. Structure and temperature effects on Nd3+ spectra in polycrystalline mixed scandium aluminum garnets Y3ScxAl5-xO12

    Science.gov (United States)

    Lupei, A.; Lupei, V.; Hau, S.; Gheorghe, C.; Voicu, F.

    2015-09-01

    New spectroscopic data obtained from high resolution low temperature absorption and emission spectra of Nd3+ in mixed scandium aluminum garnets Y3ScxAl5-xO12 - (x = 0-2) translucent ceramics revealed transition dependent composition effects: modification of the shapes (Lorentz at x = 0 and 2, quasi-Gauss at x = 1, x-dependent asymmetric for other x values, with obvious multicenter structure for low x), widths and shifts of the lines. Nd3+ electronic structure dependence on structural changes with composition is analyzed in terms of nephelauxetic effect and maximum splitting of manifolds: Sc3+ co-doping reduces the nephelauxetic effect, and the increase of 4F3/2 splitting from 85 cm-1 (x = 0) to 98 cm-1 (x = 2) denotes the lowering of local symmetry. The multicenter structure and inhomogeneous broadening of Nd3+ lines is attributed to crystal field distributions determined by the random occupancy of the octahedral sites by Sc3+ and Al3+. For low x (0.2) the resolved two satellites S1, S2 that accompany Nd:YAG lines are correlated to anisotropic crystal field perturbations produced by the n.n. Sc3+ by analogy to those determined by Y3+-antisites (excess of Y3+ ions that enter in octahedral sites of the melt-grown YAG crystals). The temperature evolution of the Nd3+ spectral characteristics (line intensity, shift, broadening) in the 10-300 K range is analyzed in terms of thermal population of the Stark levels, of the effect on electron-phonon interaction and on lattice expansion. The relevance of the spectroscopic properties on the laser emission characteristics in these systems is discussed.

  12. Dissolved scandium, yttrium, and lanthanum in the surface waters of the North Atlantic: Potential use as an indicator of scavenging intensity

    Science.gov (United States)

    Till, C. P.; Shelley, R. U.; Landing, W. M.; Bruland, K. W.

    2017-08-01

    Recent work has begun to elucidate the biogeochemical cycling of scandium (Sc) in the open ocean, but so far no surface distribution data have been reported of dissolved Sc, and no basin-scale surface distributions have been reported of yttrium (Y) or lanthanum (La). This work presents basin-wide surface Sc, Y, and La data in a section across the North Atlantic subtropical gyre (2011 GEOTRACES GA03) and investigates the potential utility of these distributions. This work uses dissolved and aerosol concentration data for La and Sc to estimate their surface ocean residence times in both the center of the oligotrophic gyre and near the African coastline. This work additionally shows that the surface distribution of Sc in the North Atlantic correlates with the shape of the gyre as inferred by isotherm depth, with lower Sc concentrations at the gyre boundaries. This pattern suggests that Sc could be drawn down by the elevated particle flux at the gyre boundaries. In this case, Sc removal could be used as an indicator of scavenging intensity. In order to account for variable input of Sc to the surface ocean, we propose normalizing the Sc distribution to that of Y or La, which are much less particle reactive and are input via dust to the surface North Atlantic in constant ratios with Sc. Such normalization improves the correlation with isotherm depth. We propose that the variations in dissolved Y/Sc and La/Sc ratios may be due to preferential Sc scavenging and could therefore indicate scavenging intensity.

  13. On new ternary equiatomic scandium transition metal aluminum compounds ScTAl with T = Cr, Ru, Ag, Re, Pt, and Au

    Energy Technology Data Exchange (ETDEWEB)

    Radzieowski, Mathis; Janka, Oliver [Muenster Univ. (Germany). Inst. fuer Anorganische und Analytische Chemie; Benndorf, Christopher [Muenster Univ. (Germany). Inst. fuer Anorganische und Analytische Chemie; Muenster Univ. (Germany). Inst. fuer Physikalische Chemie; Haverkamp, Sandra [Muenster Univ. (Germany). Inst. fuer Physikalische Chemie; Eckert, Hellmut [Muenster Univ. (Germany). Inst. fuer Physikalische Chemie; University of Sao Paulo, Sao Carlos, SP (Brazil). Inst. of Physics

    2016-08-01

    The new equiatomic scandium transition metal aluminides ScTAl for T = Cr, Ru, Ag, Re, Pt, and Au were obtained by arc-melting of the elements followed by subsequent annealing for crystal growth. The samples were studied by powder and single crystal X-ray diffraction. The structures of three compounds were refined from single crystal X-ray diffractometer data: ScCrAl, MgZn{sub 2} type, P6{sub 3}/mmc, a = 525.77(3), c = 858.68(5) pm, R{sub 1} = 0.0188, wR{sub 2} = 0.0485, 204 F{sup 2} values, 13 variables, ScPtAl, TiNiSi type, Pnma, a = 642.83(4), b = 428.96(2), c = 754.54(5) pm, R{sub 1} = 0.0326, wR{sub 2} = 0.0458, 448 F{sup 2} values, 20 variables and ScAuAl, HfRhSn type, P anti 62c, a = 722.88(4), c = 724.15(4) pm, R{sub 1} = 0.0316, wR{sub 2} = 0.0653, 512 F{sup 2} values, 18 variables. Phase pure samples of all compounds were furthermore investigated by magnetic susceptibility measurements, and Pauli-paramagnetism but no superconductivity was observed down to 2.1 K for all of them. The local structural features and disordering phenomena have been characterized by {sup 27}Al and {sup 45}Sc magic angle spinning (MAS) and static NMR spectroscopic investigations.

  14. Treatment of infraorbital dark circles in atopic dermatitis with a 2790-nm erbium: yttrium scandium gallium garnet laser: a pilot study.

    Science.gov (United States)

    Park, Kui Young; Oh, In Young; Moon, Nam Ju; Seo, Seong Jun

    2013-04-01

    Although many Asian atopic patients have orbital darkening symptom and the demand to treat this condition is increasing, little has been reported in the literature on the treatment of infraorbital dark circles in atopic dermatitis. To evaluate the clinical efficacy and safety of 2790-nm erbium:yttrium scandium gallium garnet (Er:YSGG) laser therapy for reducing infraorbital dark circles in atopic dermatitis patients. Ten Korean patients over 21 year with mild atopic dermatitis and infraorbital dark circles were enrolled in this study. Patients who need active atopic dermatitis treatments are excluded because of the possibility of aggravation after laser treatment. They were treated for dark circles using a 2790-nm Er:YSGG laser. The treatment parameters were 1.8-2.2 J/cm² fluence, 6-mm spot size, and 0.3-ms pulse width with 10% overlap over the infraorbital areas once with a 4-week interval between treatments. Efficacy was assessed with a quartile grading score ranging from 0 to 5 by a blinded investigator, and the patients also documented their degree of satisfaction with the same grading score. All possible side effects were evaluated. The clinical assessment showed 74.5% (2.7) and 72.5% (2.5) improvements, and the patient satisfaction scale scores improved an average of 74% (2.4) and 71.5% (2.3) at 2 months and 4 months after treatment, respectively. There were no severe side effects or aggravation of atopic dermatitis. Our study suggests that 2790-nm Er:YSGG laser therapy can be effectively and safely used in the treatment of infraorbital dark circles in atopic dermatitis patients.

  15. The influence of cation ordering, oxygen vacancy distribution and proton siting on observed properties in ceramic electrolytes: the case of scandium substituted barium titanate.

    Science.gov (United States)

    Torino, Nico; Henry, Paul F; Knee, Christopher S; Bjørheim, Tor Svendsen; Rahman, Seikh M H; Suard, Emma; Giacobbe, Carlotta; Eriksson, Sten G

    2017-07-04

    The origin of the 2-order of magnitude difference in the proton conductivity of the hydrated forms of hexagonal and cubic oxygen deficient BaScxTi1-xO3-δ (x = 0.2 and x = 0.7) was probed using a combination of neutron diffraction and density functional theory techniques to support published X-ray diffraction, conductivity, thermogravimetric and differential scanning calorimetry studies. Cation ordering is found in the 6H structure type (space group P63/mmc) adopted by BaSc0.2Ti0.8O3-δ with scandium preferentially substituting in the vertex sharing octahedra (2a crystallographic site) and avoiding the face-sharing octahedra (4f site). This is coupled with oxygen vacancy ordering in the central plane of the face-sharing octahedra (O1 site). In BaSc0.7Ti0.3O3-δ a simple cubic perovskite (space group Pm3[combining macron]m) best represents the average structure from Rietveld analysis with no evidence of either cation ordering or oxygen vacancy ordering. Significant diffuse scattering is observed, indicative of local order. Hydration in both cases leads to complete filling of the available oxygen vacancies and permits definition of the proton sites. We suggest that the more localised nature of the proton sites in the 6H structure is responsible for the significantly lower proton conduction observed in the literature. Within the 6H structure type final model, proton diffusion requires a 3-step process via higher energy proton sites that are unoccupied at room temperature and is also likely to be anisotropic whereas the highly disordered cubic perovskite proton position allows 3-dimensional diffusion by well-described modes. Finally, we propose how this knowledge can be used to further materials design for ceramic electrolytes for proton conducting fuel cells.

  16. Acetylation Is Indispensable for p53 Activation

    OpenAIRE

    Tang, Yi; Zhao, Wenhui; Chen, Yue; Zhao, Yingming; Gu, Wei

    2008-01-01

    The activation of the tumor suppressor p53 facilitates the cellular response to genotoxic stress; however, the p53 response can only be executed if its interaction with its inhibitor Mdm2 is abolished. There have been conflicting reports on the question of whether p53 posttranslational modifications, such as phosphorylation or acetylation, are essential or only play a subtle, fine-tuning role in the p53 response. Thus, it remains unclear whether p53 modification is absolutely required for its...

  17. Pathologies Associated with the p53 Response

    Science.gov (United States)

    Gudkov, Andrei V.; Komarova, Elena A.

    2010-01-01

    Although p53 is a major cancer preventive factor, under certain extreme stress conditions it may induce severe pathologies. Analyses of animal models indicate that p53 is largely responsible for the toxicity of ionizing radiation or DNA damaging drugs contributing to hematopoietic component of acute radiation syndrome and largely determining severe adverse effects of cancer treatment. p53-mediated damage is strictly tissue specific and occurs in tissues prone to p53-dependent apoptosis (e.g., hematopoietic system and hair follicles); on the contrary, p53 can serve as a survival factor in tissues that respond to p53 activation by cell cycle arrest (e.g., endothelium of small intestine). There are multiple experimental indications that p53 contributes to pathogenicity of acute ischemic diseases. Temporary reversible suppression of p53 by small molecules can be an effective and safe approach to reduce severity of p53-associated pathologies. PMID:20595398

  18. Arginine methylation regulates the p53 response

    DEFF Research Database (Denmark)

    Jansson, Martin; Durant, Stephen T; Cho, Er-Chieh

    2008-01-01

    Activation of the p53 tumour suppressor protein in response to DNA damage leads to apoptosis or cell-cycle arrest. Enzymatic modifications are widely believed to affect and regulate p53 activity. We describe here a level of post-translational control that has an important functional consequence...... on the p53 response. We show that the protein arginine methyltransferase (PRMT) 5, as a co-factor in a DNA damage responsive co-activator complex that interacts with p53, is responsible for methylating p53. Arginine methylation is regulated during the p53 response and affects the target gene specificity...... of p53. Furthermore, PRMT5 depletion triggers p53-dependent apoptosis. Thus, methylation on arginine residues is an underlying mechanism of control during the p53 response....

  19. p53 Acetylation: Regulation and Consequences

    Science.gov (United States)

    Reed, Sara M.; Quelle, Dawn E.

    2014-01-01

    Post-translational modifications of p53 are critical in modulating its tumor suppressive functions. Ubiquitylation, for example, plays a major role in dictating p53 stability, subcellular localization and transcriptional vs. non-transcriptional activities. Less is known about p53 acetylation. It has been shown to govern p53 transcriptional activity, selection of growth inhibitory vs. apoptotic gene targets, and biological outcomes in response to diverse cellular insults. Yet recent in vivo evidence from mouse models questions the importance of p53 acetylation (at least at certain sites) as well as canonical p53 functions (cell cycle arrest, senescence and apoptosis) to tumor suppression. This review discusses the cumulative findings regarding p53 acetylation, with a focus on the acetyltransferases that modify p53 and the mechanisms regulating their activity. We also evaluate what is known regarding the influence of other post-translational modifications of p53 on its acetylation, and conclude with the current outlook on how p53 acetylation affects tumor suppression. Due to redundancies in p53 control and growing understanding that individual modifications largely fine-tune p53 activity rather than switch it on or off, many questions still remain about the physiological importance of p53 acetylation to its role in preventing cancer. PMID:25545885

  20. p53 Acetylation: Regulation and Consequences

    Directory of Open Access Journals (Sweden)

    Sara M. Reed

    2014-12-01

    Full Text Available Post-translational modifications of p53 are critical in modulating its tumor suppressive functions. Ubiquitylation, for example, plays a major role in dictating p53 stability, subcellular localization and transcriptional vs. non-transcriptional activities. Less is known about p53 acetylation. It has been shown to govern p53 transcriptional activity, selection of growth inhibitory vs. apoptotic gene targets, and biological outcomes in response to diverse cellular insults. Yet recent in vivo evidence from mouse models questions the importance of p53 acetylation (at least at certain sites as well as canonical p53 functions (cell cycle arrest, senescence and apoptosis to tumor suppression. This review discusses the cumulative findings regarding p53 acetylation, with a focus on the acetyltransferases that modify p53 and the mechanisms regulating their activity. We also evaluate what is known regarding the influence of other post-translational modifications of p53 on its acetylation, and conclude with the current outlook on how p53 acetylation affects tumor suppression. Due to redundancies in p53 control and growing understanding that individual modifications largely fine-tune p53 activity rather than switch it on or off, many questions still remain about the physiological importance of p53 acetylation to its role in preventing cancer.

  1. p53 Acetylation: Regulation and Consequences

    Energy Technology Data Exchange (ETDEWEB)

    Reed, Sara M. [Department of Pharmacology, The University of Iowa Carver College of Medicine, Iowa City, IA 52242 (United States); Medical Scientist Training Program, The University of Iowa Carver College of Medicine, Iowa City, IA 52242 (United States); Quelle, Dawn E., E-mail: dawn-quelle@uiowa.edu [Department of Pharmacology, The University of Iowa Carver College of Medicine, Iowa City, IA 52242 (United States); Medical Scientist Training Program, The University of Iowa Carver College of Medicine, Iowa City, IA 52242 (United States); Department of Pathology, The University of Iowa Carver College of Medicine, Iowa City, IA 52242 (United States)

    2014-12-23

    Post-translational modifications of p53 are critical in modulating its tumor suppressive functions. Ubiquitylation, for example, plays a major role in dictating p53 stability, subcellular localization and transcriptional vs. non-transcriptional activities. Less is known about p53 acetylation. It has been shown to govern p53 transcriptional activity, selection of growth inhibitory vs. apoptotic gene targets, and biological outcomes in response to diverse cellular insults. Yet recent in vivo evidence from mouse models questions the importance of p53 acetylation (at least at certain sites) as well as canonical p53 functions (cell cycle arrest, senescence and apoptosis) to tumor suppression. This review discusses the cumulative findings regarding p53 acetylation, with a focus on the acetyltransferases that modify p53 and the mechanisms regulating their activity. We also evaluate what is known regarding the influence of other post-translational modifications of p53 on its acetylation, and conclude with the current outlook on how p53 acetylation affects tumor suppression. Due to redundancies in p53 control and growing understanding that individual modifications largely fine-tune p53 activity rather than switch it on or off, many questions still remain about the physiological importance of p53 acetylation to its role in preventing cancer.

  2. Effects of erbium-and chromium-doped yttrium scandium gallium garnet and diode lasers on the surfaces of restorative dental materials: a scanning electron microscope study.

    Science.gov (United States)

    Hatipoglu, M; Barutcigil, C

    2015-01-01

    The aim of this study is to evaluate the potential effects of laser irradiation, which is commonly performed in periodontal surgery, on the surfaces of restorative materials. Five different restorative dental materials were used in this study, as follows: (1) Resin composite, (2) poly acid-modified resin composite (compomer), (3) conventional glass ionomer cement (GIC), (4) resin-modified glass ionomer cement (RMGIC), and (5) amalgam. Four cylindrical samples (8 mm diameter, 2 mm height) were prepared for each restorative material. In addition, four freshly extracted, sound human incisors teeth were selected. Two different laser systems commonly used in periodontal surgery were examined in this study: A 810 nm diode laser at a setting of 1 W with continuous-phase laser irradiation for 10 s, and an erbium-and chromium-doped yttrium scandium gallium garnet (Er, Cr: YSGG) laser at settings of 2.5 W, 3.25 W, and 4 W with 25 Hz laser irradiation for 10 s. Scanning electron microscopy (SEM) analysis was performed to evaluate the morphology and surface deformation of the restorative materials and tooth surfaces. According to the SEM images, the Er, Cr: YSGG laser causes irradiation markings that appear as demineralized surfaces on tooth samples. The Er, Cr: YSGG laser also caused deep defects on composite, compomer, and RMGIC surfaces because of its high power, and the ablation was deeper for these samples. High-magnification SEM images of GIC samples showed the melting and combustion effects of the Er, Cr: YSGG laser, which increased as the laser power was increased. In amalgam samples, neither laser left significant harmful effects at the lowest power setting. The diode laser did cause irradiation markings, but they were insignificant compared with those left by the Er, Cr: YSGG laser on the surfaces of the different materials and teeth. Within the limitations of this study, it can be concluded that Er, Cr: YSGG laser irradiation could cause distortions of the surfaces

  3. 42 CFR 1008.53 - Affected parties.

    Science.gov (United States)

    2010-10-01

    ... 42 Public Health 5 2010-10-01 2010-10-01 false Affected parties. 1008.53 Section 1008.53 Public Health OFFICE OF INSPECTOR GENERAL-HEALTH CARE, DEPARTMENT OF HEALTH AND HUMAN SERVICES OIG AUTHORITIES ADVISORY OPINIONS BY THE OIG Scope and Effect of OIG Advisory Opinions § 1008.53 Affected parties. An...

  4. 15 CFR 400.53 - Information.

    Science.gov (United States)

    2010-01-01

    ... 15 Commerce and Foreign Trade 2 2010-01-01 2010-01-01 false Information. 400.53 Section 400.53..., Record and Information § 400.53 Information. (a) Request for information. The Board may request submission of any information, including business proprietary information, and written argument necessary or...

  5. 47 CFR 53.211 - Audit planning.

    Science.gov (United States)

    2010-10-01

    ... 47 Telecommunication 3 2010-10-01 2010-10-01 false Audit planning. 53.211 Section 53.211 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) COMMON CARRIER SERVICES (CONTINUED) SPECIAL PROVISIONS CONCERNING BELL OPERATING COMPANIES Separate Affiliate; Safeguards § 53.211 Audit planning. (a...

  6. 40 CFR 230.53 - Aesthetics.

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 24 2010-07-01 2010-07-01 false Aesthetics. 230.53 Section 230.53... Characteristics § 230.53 Aesthetics. (a) Aesthetics associated with the aquatic ecosystem consist of the perception of beauty by one or a combination of the senses of sight, hearing, touch, and smell. Aesthetics of...

  7. 28 CFR 32.53 - Review.

    Science.gov (United States)

    2010-07-01

    ... 28 Judicial Administration 1 2010-07-01 2010-07-01 false Review. 32.53 Section 32.53 Judicial... BENEFIT CLAIMS Director Appeals and Reviews § 32.53 Review. (a) Upon the filing of the approval (under subpart E of this part) of a claim, the Director shall review the same. (b) The Director may review— (1...

  8. 19 CFR 10.53 - Antiques.

    Science.gov (United States)

    2010-04-01

    ... 19 Customs Duties 1 2010-04-01 2010-04-01 false Antiques. 10.53 Section 10.53 Customs Duties U.S. CUSTOMS AND BORDER PROTECTION, DEPARTMENT OF HOMELAND SECURITY; DEPARTMENT OF THE TREASURY ARTICLES CONDITIONALLY FREE, SUBJECT TO A REDUCED RATE, ETC. General Provisions Works of Art § 10.53 Antiques. (a...

  9. 43 CFR 2.53 - Government contracts.

    Science.gov (United States)

    2010-10-01

    ... 43 Public Lands: Interior 1 2010-10-01 2010-10-01 false Government contracts. 2.53 Section 2.53 Public Lands: Interior Office of the Secretary of the Interior RECORDS AND TESTIMONY; FREEDOM OF INFORMATION ACT Privacy Act § 2.53 Government contracts. (a) Required contract provisions. When a contract...

  10. 40 CFR 79.53 - Tier 2.

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 16 2010-07-01 2010-07-01 false Tier 2. 79.53 Section 79.53 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) REGISTRATION OF FUELS AND FUEL ADDITIVES Testing Requirements for Registration § 79.53 Tier 2. (a) Generally. Subject to...

  11. 7 CFR 3430.53 - Program income.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 15 2010-01-01 2010-01-01 false Program income. 3430.53 Section 3430.53 Agriculture...-GENERAL AWARD ADMINISTRATIVE PROVISIONS Post-Award and Closeout § 3430.53 Program income. (a) General... for program income related to projects financed in whole or in part with Federal funds. (b) Addition...

  12. 27 CFR 53.140 - Registration.

    Science.gov (United States)

    2010-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 2 2010-04-01 2010-04-01 false Registration. 53.140..., Registration, Etc. § 53.140 Registration. (a) General rule. Except as provided in § 53.141, tax-free sales....141. (e) Cross references. (1) For exceptions to the requirement for registration, see section 4222(b...

  13. 14 CFR 23.53 - Takeoff performance.

    Science.gov (United States)

    2010-01-01

    ... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Takeoff performance. 23.53 Section 23.53... STANDARDS: NORMAL, UTILITY, ACROBATIC, AND COMMUTER CATEGORY AIRPLANES Flight Performance § 23.53 Takeoff performance. (a) For normal, utility, and acrobatic category airplanes, the takeoff distance must be...

  14. 36 CFR 5.3 - Business operations.

    Science.gov (United States)

    2010-07-01

    ... 36 Parks, Forests, and Public Property 1 2010-07-01 2010-07-01 false Business operations. 5.3 Section 5.3 Parks, Forests, and Public Property NATIONAL PARK SERVICE, DEPARTMENT OF THE INTERIOR COMMERCIAL AND PRIVATE OPERATIONS § 5.3 Business operations. Engaging in or soliciting any business in park...

  15. 48 CFR 53.242 - Contract administration.

    Science.gov (United States)

    2010-10-01

    ... 48 Federal Acquisition Regulations System 2 2010-10-01 2010-10-01 false Contract administration. 53.242 Section 53.242 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION (CONTINUED) CLAUSES AND FORMS FORMS Prescription of Forms 53.242 Contract administration...

  16. 14 CFR 171.53 - Reports.

    Science.gov (United States)

    2010-01-01

    ... 14 Aeronautics and Space 3 2010-01-01 2010-01-01 false Reports. 171.53 Section 171.53 Aeronautics... FACILITIES NON-FEDERAL NAVIGATION FACILITIES Instrument Landing System (ILS) Facilities § 171.53 Reports. The owner of each facility to which this subpart applies shall make the following reports, at the times...

  17. 7 CFR 1794.53 - Environmental report.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 12 2010-01-01 2010-01-01 false Environmental report. 1794.53 Section 1794.53... AGRICULTURE (CONTINUED) ENVIRONMENTAL POLICIES AND PROCEDURES Procedure for Environmental Assessments With Scoping § 1794.53 Environmental report. (a) After scoping procedures have been completed, RUS shall...

  18. 45 CFR 86.53 - Recruitment.

    Science.gov (United States)

    2010-10-01

    ... 45 Public Welfare 1 2010-10-01 2010-10-01 false Recruitment. 86.53 Section 86.53 Public Welfare... in Employment in Education Programs or Activities Prohibited § 86.53 Recruitment. (a) Nondiscriminatory recruitment and hiring. A recipient shall not discriminate on the basis of sex in the recruitment...

  19. 7 CFR 15a.53 - Recruitment.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 1 2010-01-01 2010-01-01 false Recruitment. 15a.53 Section 15a.53 Agriculture Office... Activities Prohibited § 15a.53 Recruitment. (a) Nondiscriminatory recruitment and hiring. A recipient shall not discriminate on the basis of sex in the recruitment and hiring of employees. Where a recipient has...

  20. 48 CFR 53.105 - Computer generation.

    Science.gov (United States)

    2010-10-01

    ... 48 Federal Acquisition Regulations System 2 2010-10-01 2010-10-01 false Computer generation. 53.105 Section 53.105 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION (CONTINUED) CLAUSES AND FORMS FORMS General 53.105 Computer generation. (a) Agencies may computer-generate the...

  1. 14 CFR 460.53 - Security.

    Science.gov (United States)

    2010-01-01

    ... 14 Aeronautics and Space 4 2010-01-01 2010-01-01 false Security. 460.53 Section 460.53 Aeronautics and Space COMMERCIAL SPACE TRANSPORTATION, FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF....53 Security. An operator must implement security requirements to prevent any space flight participant...

  2. 42 CFR 53.113 - Community service.

    Science.gov (United States)

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Community service. 53.113 Section 53.113 Public... To Pay; Community Service; Nondiscrimination. § 53.113 Community service. (a) Applicability. The... community service assurance. (b) Definitions. As used in this section: (1) The term community service...

  3. 9 CFR 3.53 - Primary enclosures.

    Science.gov (United States)

    2010-01-01

    ... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Primary enclosures. 3.53 Section 3.53... Facilities and Operating Standards § 3.53 Primary enclosures. All primary enclosures for rabbits shall conform to the following requirements: (a) General. (1) Primary enclosures shall be structurally sound and...

  4. 49 CFR 38.53 - Doorways.

    Science.gov (United States)

    2010-10-01

    ... 49 Transportation 1 2010-10-01 2010-10-01 false Doorways. 38.53 Section 38.53 Transportation Office of the Secretary of Transportation AMERICANS WITH DISABILITIES ACT (ADA) ACCESSIBILITY SPECIFICATIONS FOR TRANSPORTATION VEHICLES Rapid Rail Vehicles and Systems § 38.53 Doorways. (a) Clear width. (1...

  5. 29 CFR 1926.53 - Ionizing radiation.

    Science.gov (United States)

    2010-07-01

    ... 29 Labor 8 2010-07-01 2010-07-01 false Ionizing radiation. 1926.53 Section 1926.53 Labor... § 1926.53 Ionizing radiation. (a) In construction and related activities involving the use of sources of ionizing radiation, the pertinent provisions of the Nuclear Regulatory Commission's Standards for...

  6. 33 CFR 53.7 - Requirements.

    Science.gov (United States)

    2010-07-01

    ... 33 Navigation and Navigable Waters 1 2010-07-01 2010-07-01 false Requirements. 53.7 Section 53.7 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY PERSONNEL COAST GUARD WHISTLEBLOWER PROTECTION § 53.7 Requirements. (a) No person within the Department of Homeland Security may...

  7. 27 CFR 53.1 - Introduction.

    Science.gov (United States)

    2010-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 2 2010-04-01 2010-04-01 false Introduction. 53.1 Section... THE TREASURY (CONTINUED) FIREARMS MANUFACTURERS EXCISE TAXES-FIREARMS AND AMMUNITION Introduction § 53.1 Introduction. The regulations in this part (part 53, subchapter C, chapter I, title 27, Code of...

  8. 33 CFR 53.9 - Responsibilities.

    Science.gov (United States)

    2010-07-01

    ... 33 Navigation and Navigable Waters 1 2010-07-01 2010-07-01 false Responsibilities. 53.9 Section 53.9 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY PERSONNEL COAST GUARD WHISTLEBLOWER PROTECTION § 53.9 Responsibilities. (a) The Inspector General, Department of Homeland Security...

  9. 7 CFR 550.53 - Financial reporting.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 6 2010-01-01 2010-01-01 false Financial reporting. 550.53 Section 550.53 Agriculture... Reports and Records § 550.53 Financial reporting. Financial Status Report. (a) Each REE Agency shall.... A financial status report shall consist of the following information: (1) The name and address of...

  10. Gene p53 mutations, protein p53, and anti-p53 antibodies as biomarkers of cancer process.

    Science.gov (United States)

    Lutz, Waldemar; Nowakowska-Swirta, Ewa

    2002-01-01

    The finding that gene mutations and changes in their expression form the basis of cancer processes, has prompted molecular epidemiologists to use biomarkers for detecting damaged genes or proteins synthesized under their control in easily available cellular material or systemic liquids. Mutations in the suppressor gen p53 are thought to be essential for cancer development. This gen is one of the most important regulators of transcription, cellular cycle, DNA repair and apoptosis detected till now. Inactivation of gene p53 leads to uncontrolled cell divisions, and further to transformation of normal cells into the carcinous ones. Observations that mutations in gene p53 appear under conditions of occupational and environmental exposures to chemical and physical carcinogens, such as vinyl chloride, radon, or aflatoxin B1, have proved to be of enormous importance for the occupational and environmental health. Changes in expression of gene p53, and also its mutations, cause variations of cellular protein p53 concentration. Higher cellular protein p53 levels are associated with increased protein transfer to the extracellular liquid and to blood. It has been observed that increased blood serum protein p53 concentrations may have a prognostic value in early diagnosis of lung cancer. The results of a number of studies confirm that accumulation of a mutated form of protein p53, and presumably also large quantities of wild forms of that protein in the cells, may be a factor that triggers the production of anti-p53 antibodies. Statistical analysis showed that anti-p53 antibodies can be regarded as a specific biomarker of cancer process. The prevalence of anti-p53 antibodies correlated with the degree of cancer malignancy. The increased incidence of anti-p53 antibodies was also associated with higher frequency of mutations in gene p53. There are some reports confirming that anti-p53 antibodies emerging in blood serum in the subclinical phase of cancer development may be

  11. Identification of p53 in mitochondria.

    Science.gov (United States)

    Vaseva, Angelina V; Moll, Ute M

    2013-01-01

    p53 is a master regulator of cell death pathways and has transcription-dependent and transcription-independent modes of action. Mitochondria are major signal transducers in apoptosis and are critical for p53-dependent cell death. Our lab and others have discovered that a fraction of stress-induced wild-type p53 protein rapidly translocates to mitochondria upon various stress stimuli and exerts p53-dependent apoptosis. Suborganellar localization by various methods shows that p53 localizes to the surface of mitochondria. Direct targeting of p53 to mitochondria is sufficient to induce apoptosis in p53-null cells, without requiring further DNA damage. Recently, p53 has been also shown to localize to other mitochondrial compartments such as the mitochondrial matrix where it plays a role in maintaining mitochondrial genome integrity. Here, we describe subcellular fractionation as a classic technique for detecting mitochondrial p53 in cell extracts. It consists of cell homogenization by hypo-osmotic swelling, removal of nuclear components by low-speed centrifugation, and mitochondrial isolation by a discontinuous sucrose density gradient. Additionally, we describe a method for submitochondrial fractionation, performed by phosphate buffer mediated swelling/shrinking. p53 and other mitochondrial proteins can then be detected by standard immunoblotting procedures. The quality of mitochondrial isolates/subfractions can be verified for purity and intactness.

  12. Dial 9-1-1 for p53: Mechanisms of p53 Activation by Cellular Stress

    OpenAIRE

    Ljungman, Mats

    2000-01-01

    The tumor suppressor protein, p53, is part of the cell's emergency team that is called upon following cellular insult. How do cells sense DNA damage and other cellular stresses and what signal transduction pathways are used to alert p53? How is the resulting nuclear accumulation of p53 accomplished and what determines the outcome of p53 induction? Many posttranslational modifications of p53, such as phosphorylation, dephosphorylation, acetylation and ribosylation, have been shown to occur fol...

  13. The RD53A Integrated Circuit

    CERN Document Server

    Garcia-Sciveres, Maurice

    2017-01-01

    Implementation details for the RD53A pixel readout integrated circuit designed by the RD53 Collaboration. This is a companion to the specifications document and will eventually become a reference for chip users. RD53A is not intended to be a final production IC for use in an experiment, and contains design variations for testing purposes, making the pixel matrix non-uniform. The chip size is 20.0 mm by 11.8 mm.

  14. Influence of c-axis orientation and scandium concentration on infrared active modes of magnetron sputtered Sc{sub x}Al{sub 1−x}N thin films

    Energy Technology Data Exchange (ETDEWEB)

    Mayrhofer, P. M.; Bittner, A.; Schmid, U. [Institute of Sensor and Actuator Systems, Vienna University of Technology, Floragasse 7, 1040 Vienna (Austria); Eisenmenger-Sittner, C. [Institute of Solid State Physics, Vienna University of Technology, Wiedner Hauptstrasse 8, 1040 Vienna (Austria); Euchner, H. [Institute of Materials Science and Technology, Vienna University of Technology, Karlsplatz 13, 1040 Vienna (Austria)

    2013-12-16

    Doping of wurtzite aluminium nitride (AlN) with scandium (Sc) significantly enhances the piezoelectric properties of AlN. Sc{sub x}Al{sub 1−x}N thin films with different Sc concentrations (x = 0 to 0.15) were deposited by DC reactive magnetron sputtering. Infrared (IR) absorbance spectroscopy was applied to investigate the Sc concentration dependent shift of the IR active modes E{sub 1}(TO) and A{sub 1}(TO). These results are compared to ab initio simulations, being in excellent agreement with the experimental findings. In addition, IR spectroscopy is established as an economical and fast method to distinguish between thin films with a high degree of c-axis orientation and those exhibiting mixed orientations.

  15. p53 mutations in urinary bladder cancer

    OpenAIRE

    Berggren, P; Steineck, G; Adolfsson, J; Hansson, J; Jansson, O; Larsson, P; Sandstedt, B; Wijkstr?m, H; Hemminki, K

    2001-01-01

    We have screened for mutations in exons 5?8 of the p53 gene in a series consisting of 189 patients with urinary bladder neoplasms. 82 (44%) neoplasms were lowly malignant (Ta, G1?G2a) and 106 (56%) were highly malignant (G2b?G4 or ?T1). Only one mutation was in a lowly malignant urinary bladder neoplasm, in total we found p53 mutations in 26 (14%) of the 189 patients. 30% of the samples had loss of heterozygosity (LOH) for one or both of the p53 exogenic (CA)n repeat and the p53 intragenic (A...

  16. Lysosomal destabilization in p53-induced apoptosis

    OpenAIRE

    Yuan, Xi-Ming; Li, Wei; Dalen, Helge; Lotem, Joseph; Kama, Rachel; Sachs, Leo; Brunk, Ulf T.

    2002-01-01

    The tumor suppressor wild-type p53 can induce apoptosis. M1-t-p53 myeloid leukemic cells have a temperature-sensitive p53 protein that changes its conformation to wild-type p53 after transfer from 37°C to 32°C. We have now found that these cells showed an early lysosomal rupture after transfer to 32°C. Mitochondrial damage, including decreased membrane potential and release of cytochrome c, and the appearance of apoptotic cells occurred later. Lysosomal rupture, mitochondrial damage, and apop...

  17. Inhibiting p53 Acetylation Reduces Cancer Chemotoxicity.

    Science.gov (United States)

    Zheng, Shunsheng; Koh, Xin Yu; Goh, Hui Chin; Rahmat, Siti Aishah B; Hwang, Le-Ann; Lane, David P

    2017-08-15

    Chemotoxicity due to unwanted p53 activation in the bone marrow remains an unmet clinical challenge. Doxorubicin, a first-line chemotherapy drug, often causes myelosuppression in patients, thus limiting its effectiveness. In this study, we discovered that C646, a reversible p300 inhibitor, downregulates p53 transcription and selectively protects noncancerous cells from p53-dependent apoptosis. C646 treatment blocked acetylation of specific lysine residues that regulate p53 activity. Exploitation of differential p53 genetic backgrounds between human hematopoietic and colorectal cancer cells improved the therapeutic index of doxorubicin with C646 cotreatment. C646 administration in mice afflicted with p53-mutant tumors protected them from doxorubicin-induced neutropenia and anemia while retaining antitumor efficacy. We deduce that temporary and reversible inhibition of p53 acetylation in cancer subjects, especially those with p53-mutant tumors, may protect them from severe chemotoxicity while allowing treatment regimens to effectively proceed. Cancer Res; 77(16); 4342-54. ©2017 AACR. ©2017 American Association for Cancer Research.

  18. 1 CFR 21.53 - Nonstatutory materials.

    Science.gov (United States)

    2010-01-01

    ... 1 General Provisions 1 2010-01-01 2010-01-01 false Nonstatutory materials. 21.53 Section 21.53 General Provisions ADMINISTRATIVE COMMITTEE OF THE FEDERAL REGISTER PREPARATION, TRANSMITTAL, AND... Nonstatutory materials. Nonstatutory documents shall be cited by document designation and by Federal Register...

  19. Expression of p53 in oligodendrogliomas

    NARCIS (Netherlands)

    J.M. Kros (Johan); J.J.C.J. Godschalk (J. J C J); K.K. Krishnadath (Kausilia); C.G. van Eden (C.)

    1993-01-01

    textabstractThe expression of the nuclear protein p53 in oligodendrogliomas was investigated by immunohistochemistry, using a monoclonal anti-p53 antibody (DO-7) on formalin-fixed, paraffin-embedded material in 84 histologically verified cases, and compared with the histopathological grade and

  20. 43 CFR 6.53 - Unpatented inventions.

    Science.gov (United States)

    2010-10-01

    ... 43 Public Lands: Interior 1 2010-10-01 2010-10-01 false Unpatented inventions. 6.53 Section 6.53... Unpatented inventions. The Secretary of the Interior may also have transferable interests in inventions which... benefit of the public, a license may be granted with respect to such an invention only if (a) a patent...

  1. 18 CFR 157.53 - Testing.

    Science.gov (United States)

    2010-04-01

    ... 157.53 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY REGULATIONS UNDER NATURAL GAS ACT APPLICATIONS FOR CERTIFICATES OF PUBLIC CONVENIENCE AND... Exemption of Natural Gas Service for Drilling, Testing, or Purging from Certificate Requirements § 157.53...

  2. 32 CFR 1605.53 - Designation.

    Science.gov (United States)

    2010-07-01

    ... 32 National Defense 6 2010-07-01 2010-07-01 false Designation. 1605.53 Section 1605.53 National Defense Other Regulations Relating to National Defense SELECTIVE SERVICE SYSTEM SELECTIVE SERVICE SYSTEM... shall be assigned in numerical sequence beginning with the numeral 1. ...

  3. 7 CFR 915.53 - Exemption certificates.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 8 2010-01-01 2010-01-01 false Exemption certificates. 915.53 Section 915.53 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements and Orders; Fruits, Vegetables, Nuts), DEPARTMENT OF AGRICULTURE AVOCADOS GROWN IN SOUTH FLORIDA...

  4. 7 CFR 53.20 - Identification.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 3 2010-01-01 2010-01-01 false Identification. 53.20 Section 53.20 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Standards, Inspections, Marketing Practices), DEPARTMENT OF AGRICULTURE (CONTINUED) REGULATIONS AND STANDARDS UNDER THE...

  5. 7 CFR 53.3 - Authority.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 3 2010-01-01 2010-01-01 false Authority. 53.3 Section 53.3 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Standards, Inspections, Marketing Practices), DEPARTMENT OF AGRICULTURE (CONTINUED) REGULATIONS AND STANDARDS UNDER THE AGRICULTURAL...

  6. 34 CFR 106.53 - Recruitment.

    Science.gov (United States)

    2010-07-01

    ... 34 Education 1 2010-07-01 2010-07-01 false Recruitment. 106.53 Section 106.53 Education... Recruitment. (a) Nondiscriminatory recruitment and hiring. A recipient shall not discriminate on the basis of sex in the recruitment and hiring of employees. Where a recipient has been found to be presently...

  7. 10 CFR 74.53 - Process monitoring.

    Science.gov (United States)

    2010-01-01

    ... 10 Energy 2 2010-01-01 2010-01-01 false Process monitoring. 74.53 Section 74.53 Energy NUCLEAR... process, a licensee shall establish a production quality control program capable of monitoring the status of material in process. The program shall include: (1) A statistical test that has at least a 95...

  8. 48 CFR 53.111 - Contract clause.

    Science.gov (United States)

    2010-10-01

    ... 48 Federal Acquisition Regulations System 2 2010-10-01 2010-10-01 false Contract clause. 53.111... AND FORMS FORMS General 53.111 Contract clause. Contracting officers shall insert the clause at 52.253-1, Computer Generated Forms, in solicitations and contracts that require the contractor to submit...

  9. 48 CFR 53.236-1 - Construction.

    Science.gov (United States)

    2010-10-01

    ... 48 Federal Acquisition Regulations System 2 2010-10-01 2010-10-01 false Construction. 53.236-1... AND FORMS FORMS Prescription of Forms 53.236-1 Construction. The following forms are prescribed, as stated below, for use in contracting for construction, alteration, or repair, or dismantling, demolition...

  10. 44 CFR 5.3 - Definitions.

    Science.gov (United States)

    2010-10-01

    ... 44 Emergency Management and Assistance 1 2010-10-01 2010-10-01 false Definitions. 5.3 Section 5.3 Emergency Management and Assistance FEDERAL EMERGENCY MANAGEMENT AGENCY, DEPARTMENT OF HOMELAND SECURITY... transaction of public business and preserved, or appropriate for preservation, as evidence of the organization...

  11. 33 CFR 62.53 - Racons.

    Science.gov (United States)

    2010-07-01

    ... 33 Navigation and Navigable Waters 1 2010-07-01 2010-07-01 false Racons. 62.53 Section 62.53 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY AIDS TO NAVIGATION UNITED STATES... transmit a coded reply to the interrogating radar. This reply serves to identify the aid station by...

  12. 29 CFR 1956.53 - [Reserved

    Science.gov (United States)

    2010-07-01

    ... 29 Labor 9 2010-07-01 2010-07-01 false 1956.53 Section 1956.53 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) STATE PLANS FOR THE DEVELOPMENT AND ENFORCEMENT OF STATE STANDARDS APPLICABLE TO STATE AND LOCAL GOVERNMENT EMPLOYEES...

  13. Emerging Non-Canonical Functions and Regulation by p53: p53 and Stemness.

    Science.gov (United States)

    Olivos, David J; Mayo, Lindsey D

    2016-11-26

    Since its discovery nearly 40 years ago, p53 has ascended to the forefront of investigated genes and proteins across diverse research disciplines and is recognized most exclusively for its role in cancer as a tumor suppressor. Levine and Oren (2009) reviewed the evolution of p53 detailing the significant discoveries of each decade since its first report in 1979. In this review, we will highlight the emerging non-canonical functions and regulation of p53 in stem cells. We will focus on general themes shared among p53's functions in non-malignant stem cells and cancer stem-like cells (CSCs) and the influence of p53 on the microenvironment and CSC niche. We will also examine p53 gain of function (GOF) roles in stemness. Mutant p53 (mutp53) GOFs that lead to survival, drug resistance and colonization are reviewed in the context of the acquisition of advantageous transformation processes, such as differentiation and dedifferentiation, epithelial-to-mesenchymal transition (EMT) and stem cell senescence and quiescence. Finally, we will conclude with therapeutic strategies that restore wild-type p53 (wtp53) function in cancer and CSCs, including RING finger E3 ligases and CSC maintenance. The mechanisms by which wtp53 and mutp53 influence stemness in non-malignant stem cells and CSCs or tumor-initiating cells (TICs) are poorly understood thus far. Further elucidation of p53's effects on stemness could lead to novel therapeutic strategies in cancer research.

  14. Microbial Regulation of p53 Tumor Suppressor.

    Directory of Open Access Journals (Sweden)

    Alexander I Zaika

    2015-09-01

    Full Text Available p53 tumor suppressor has been identified as a protein interacting with the large T antigen produced by simian vacuolating virus 40 (SV40. Subsequent research on p53 inhibition by SV40 and other tumor viruses has not only helped to gain a better understanding of viral biology, but also shaped our knowledge of human tumorigenesis. Recent studies have found, however, that inhibition of p53 is not strictly in the realm of viruses. Some bacterial pathogens also actively inhibit p53 protein and induce its degradation, resulting in alteration of cellular stress responses. This phenomenon was initially characterized in gastric epithelial cells infected with Helicobacter pylori, a bacterial pathogen that commonly infects the human stomach and is strongly linked to gastric cancer. Besides H. pylori, a number of other bacterial species were recently discovered to inhibit p53. These findings provide novel insights into host-bacteria interactions and tumorigenesis associated with bacterial infections.

  15. AHP 2B: China's na53 mʑi 53 Tibetans: Life, Language and Folklore

    Directory of Open Access Journals (Sweden)

    Libu Lakhi (Li Jianfu 李建富, Dawa Tenzin ཟླ་བ་བསྟན་འཛིན།

    2009-06-01

    Full Text Available This remarkable book is the product of a fruitful collaboration among a native speaker of na53 mʑi53 kha11 tho11, Tibetan and Chinese consultants, and a dedicated group of Westerners resident in China. It affords the reader an intimate glimpse into traditional na53 mʑi53 life, now well on its way to disappearing along with hundreds of similar minority cultures in the world.

  16. AHP 2A: China's na53 mʑi 53 Tibetans: Life, Language and Folklore

    Directory of Open Access Journals (Sweden)

    Libu Lakhi (Li Jianfu 李建富, Dawa Tenzin ཟླ་བ་བསྟན་འཛིན།

    2009-06-01

    Full Text Available This remarkable book is the product of a fruitful collaboration among a native speaker of na53 mʑi53 kha11 tho11, Tibetan and Chinese consultants, and a dedicated group of Westerners resident in China. It affords the reader an intimate glimpse into traditional na53 mʑi53 life, now well on its way to disappearing along with hundreds of similar minority cultures in the world.

  17. 48 CFR 53.302-17-53.302-1419A - Illustration of optional forms.

    Science.gov (United States)

    2010-10-01

    ... 48 Federal Acquisition Regulations System 2 2010-10-01 2010-10-01 false Illustration of optional... FEDERAL ACQUISITION REGULATION (CONTINUED) CLAUSES AND FORMS FORMS Illustrations of Forms 53.302-17—53.302-1419A Illustration of optional forms. Editorial Note: The forms appearing in sections 53.302-17 through...

  18. 48 CFR 53.303-254-53.303-347 - Illustration of agency forms.

    Science.gov (United States)

    2010-10-01

    ... 48 Federal Acquisition Regulations System 2 2010-10-01 2010-10-01 false Illustration of agency... FEDERAL ACQUISITION REGULATION (CONTINUED) CLAUSES AND FORMS FORMS Illustrations of Forms 53.303-254—53.303-347 Illustration of agency forms. Editorial Note: The forms appearing in sections 53.303-DD-254...

  19. 48 CFR 53.301-18-53.301-1449 - Illustration of standard forms.

    Science.gov (United States)

    2010-10-01

    ... 48 Federal Acquisition Regulations System 2 2010-10-01 2010-10-01 false Illustration of standard... FEDERAL ACQUISITION REGULATION (CONTINUED) CLAUSES AND FORMS FORMS Illustrations of Forms 53.301-18—53.301-1449 Illustration of standard forms. Editorial Note: The forms appearing in sections 53.301-18 through...

  20. p53, oxidative stress, and aging.

    Science.gov (United States)

    Liu, Dongping; Xu, Yang

    2011-09-15

    Mammalian aging is associated with elevated levels of oxidative damage of DNA, proteins, and lipids as a result of unbalanced prooxidant and antioxidant activities. Accumulating evidence indicates that oxidative stress is a major physiological inducer of aging. p53, the guardian of the genome that is important for cellular responses to oxidative stresses, might be a key coordinator of oxidative stress and aging. In response to low levels of oxidative stresses, p53 exhibits antioxidant activities to eliminate oxidative stress and ensure cell survival; in response to high levels of oxidative stresses, p53 exhibits pro-oxidative activities that further increase the levels of stresses, leading to cell death. p53 accomplishes these context-dependent roles by regulating the expression of a panel of genes involved in cellular responses to oxidative stresses and by modulating other pathways important for oxidative stress responses. The mechanism that switches p53 function from antioxidant to prooxidant remains unclear, but could account for the findings that increased p53 activities have been linked to both accelerated aging and increased life span in mice. Therefore, a balance of p53 antioxidant and prooxidant activities in response to oxidative stresses could be important for longevity by suppressing the accumulation of oxidative stresses and DNA damage.

  1. The MDM2-p53 pathway revisited

    Science.gov (United States)

    Nag, Subhasree; Qin, Jiangjiang; Srivenugopal, Kalkunte S.; Wang, Minghai; Zhang, Ruiwen

    2013-01-01

    The p53 tumor suppressor is a key transcription factor regulating cellular pathways such as DNA repair, cell cycle, apoptosis, angiogenesis, and senescence. It acts as an important defense mechanism against cancer onset and progression, and is negatively regulated by interaction with the oncoprotein MDM2. In human cancers, the TP53 gene is frequently mutated or deleted, or the wild-type p53 function is inhibited by high levels of MDM2, leading to downregulation of tumor suppressive p53 pathways. Thus, the inhibition of MDM2-p53 interaction presents an appealing therapeutic strategy for the treatment of cancer. However, recent studies have revealed the MDM2-p53 interaction to be more complex involving multiple levels of regulation by numerous cellular proteins and epigenetic mechanisms, making it imperative to reexamine this intricate interplay from a holistic viewpoint. This review aims to highlight the multifaceted network of molecules regulating the MDM2-p53 axis to better understand the pathway and exploit it for anticancer therapy. PMID:23885265

  2. Mechanisms of p53-Mediated Apoptosis

    Science.gov (United States)

    2007-03-01

    terminus. Cell 81:1021–1029. 27. Juan , L. J., W. J. Shia, M. H. Chen, W. M. Yang, E. Seto, Y. S. Lin, and C. W. VOL. 25, 2005 THE C TERMINUS REGULATES p53...functionally resembles p53. Nat. Med. 4:839–843. 45. Pariat, M., S. Carillo, M. Molinari, C. Salvat , L. Debussche, L. Bracco, J. Milner, and M. Piechaczyk. 1997...apoptosis. Nature 2000;408:377-81. 27. Juan LJ, Shia WJ, Chen MH, et al. Histone deacetylases specifically down-regulate p53- dependent gene

  3. Two scandium-biuret complexes: [Sc(C2H5N3O2)(H2O)5]Cl3 x H2O and [Sc(C2H5N3O2)4](NO3)3.

    Science.gov (United States)

    Harrison, William T A

    2008-05-01

    The scandium(III) cations in the structures of pentaaqua(biuret-kappa(2)O,O')scandium(III) trichloride monohydrate, [Sc(C(2)H(5)N(3)O(2))(H(2)O)(5)]Cl(3) x H(2)O, (I), and tetrakis(biuret-kappa(2)O,O')scandium(III) trinitrate, [Sc(C(2)H(5)N(3)O(2))(4)](NO(3))(3), (II), are found to adopt very different coordinations with the same biuret ligand. The roles of hydrogen bonding and the counter-ion in the establishment of the structures are described. In (I), the Sc(3+) cation adopts a fairly regular pentagonal bipyramidal coordination geometry arising from one O,O'-bidentate biuret molecule and five water molecules. A dense network of N-H...Cl, O-H...O and O-H...Cl hydrogen bonds help to establish the packing, resulting in dimeric associations of two cations and two water molecules. In (II), the Sc(3+) cation (site symmetry 2) adopts a slightly squashed square-antiprismatic geometry arising from four O,O'-bidentate biuret molecules. A network of N-H...O hydrogen bonds help to establish the packing, which features [010] chains of cations. One of the nitrate ions is disordered about an inversion centre. Both structures form three-dimensional hydrogen-bond networks.

  4. GPCR Interaction: 53 [GRIPDB[Archive

    Lifescience Database Archive (English)

    Full Text Available is the truncation mutant starting at amino acids 53, bradykinin did not induce di...merization of the truncation mutant of B2R(65) starting amino acids 65. Both receptor variants are similar t

  5. African Studies Abstracts Online : number 53, 2016

    NARCIS (Netherlands)

    African Studies Centre Leiden (ASCL),

    2016-01-01

    ASA Online provides a quarterly overview of journal articles and edited works on Africa in the field of the social sciences and the humanities available in the ASC library. Issue 53 (2016). African Studies Centre, Leiden.

  6. RD53A Integrated Circuit Specifications

    CERN Document Server

    Garcia-Sciveres, Mauricio

    2015-01-01

    Specifications for the RD53 collaboration’s first engineering wafer run of an integrated circuit (IC) for hybrid pixel detector readout, called RD53A. RD53A is intended to demonstrate in a large format IC the suitability of the technology (including radiation tolerance), the stable low threshold operation, and the high hit and trigger rate capabilities, required for HL-LHC upgrades of ATLAS and CMS. The wafer scale production will permit the experiments to prototype bump bonding assembly with realistic sensors in this new technology and to measure the performance of hybrid assemblies. RD53A is not intended to be a final production IC for use in an experiment, and will contain design variations for testing purposes, making the pixel matrix non-uniform.

  7. 18 CFR 1308.53 - Service.

    Science.gov (United States)

    2010-04-01

    ... 18 Conservation of Power and Water Resources 2 2010-04-01 2010-04-01 false Service. 1308.53... Subpoenas § 1308.53 Service. A subpoena may be served at any place, and may be served by any individual not a party who is at least 18 years of age, or as otherwise provided by law. Service may be made by an...

  8. p53 switches off pluripotency on differentiation.

    Science.gov (United States)

    Lin, Tongxiang; Lin, Yi

    2017-02-28

    The role of p53 as "a guardian of the genome" has been well established in somatic cells. However, its role in pluripotent stem cells remains much more elusive. Here, we discuss research progress in understanding the role of p53 in pluripotent stem cells and in pluripotent stem cell-like cancer stem cells. The p53 protein, which plays a key role in embryonic stem cells, was first discovered in 2005. Landmark studies of p53-related reprogramming elucidated this protein's importance in induced pluripotent stem cells in 2009. The p53-related safety concerns in pluripotent stem cells have been raised in stem cell-based therapy although the use of iPSCs in therapeutic application is promising. Because cancer stem cells have profiles similar to those of pluripotent stem cells, we also describe potential strategies for studies in cancer stem cells and cancer treatments. The new discoveries of p53 family proteins in pluripotent stem cells have made possible stable progress in stem cell transplantation efficiency and safety, as well as treatment strategies targeting cancer stem cells based on pluripotent stem cell technology.

  9. Emerging Non-Canonical Functions and Regulation by p53: p53 and Stemness

    Directory of Open Access Journals (Sweden)

    David J. Olivos

    2016-11-01

    Full Text Available Since its discovery nearly 40 years ago, p53 has ascended to the forefront of investigated genes and proteins across diverse research disciplines and is recognized most exclusively for its role in cancer as a tumor suppressor. Levine and Oren (2009 reviewed the evolution of p53 detailing the significant discoveries of each decade since its first report in 1979. In this review, we will highlight the emerging non-canonical functions and regulation of p53 in stem cells. We will focus on general themes shared among p53’s functions in non-malignant stem cells and cancer stem-like cells (CSCs and the influence of p53 on the microenvironment and CSC niche. We will also examine p53 gain of function (GOF roles in stemness. Mutant p53 (mutp53 GOFs that lead to survival, drug resistance and colonization are reviewed in the context of the acquisition of advantageous transformation processes, such as differentiation and dedifferentiation, epithelial-to-mesenchymal transition (EMT and stem cell senescence and quiescence. Finally, we will conclude with therapeutic strategies that restore wild-type p53 (wtp53 function in cancer and CSCs, including RING finger E3 ligases and CSC maintenance. The mechanisms by which wtp53 and mutp53 influence stemness in non-malignant stem cells and CSCs or tumor-initiating cells (TICs are poorly understood thus far. Further elucidation of p53’s effects on stemness could lead to novel therapeutic strategies in cancer research.

  10. Mdm2 RING mutation enhances p53 transcriptional activity and p53-p300 interaction.

    Directory of Open Access Journals (Sweden)

    Hilary V Clegg

    Full Text Available The p53 transcription factor and tumor suppressor is regulated primarily by the E3 ubiquitin ligase Mdm2, which ubiquitinates p53 to target it for proteasomal degradation. Aside from its ubiquitin ligase function, Mdm2 has been believed to be capable of suppressing p53's transcriptional activity by binding with and masking the transactivation domain of p53. The ability of Mdm2 to restrain p53 activity by binding alone, without ubiquitination, was challenged by a 2007 study using a knockin mouse harboring a single cysteine-to-alanine point mutation (C462A in Mdm2's RING domain. Mouse embryonic fibroblasts with this mutation, which abrogates Mdm2's E3 ubiquitin ligase activity without affecting its ability to bind with p53, were unable to suppress p53 activity. In this study, we utilized the Mdm2(C462A mouse model to characterize in further detail the role of Mdm2's RING domain in the control of p53. Here, we show in vivo that the Mdm2(C462A protein not only fails to suppress p53, but compared to the complete absence of Mdm2, Mdm2(C462A actually enhances p53 transcriptional activity toward p53 target genes p21/CDKN1A, MDM2, BAX, NOXA, and 14-3-3σ. In addition, we found that Mdm2(C462A facilitates the interaction between p53 and the acetyltransferase CBP/p300, and it fails to heterodimerize with its homolog and sister regulator of p53, Mdmx, suggesting that a fully intact RING domain is required for Mdm2's inhibition of the p300-p53 interaction and for its interaction with Mdmx. These findings help us to better understand the complex regulation of the Mdm2-p53 pathway and have important implications for chemotherapeutic agents targeting Mdm2, as they suggest that inhibition of Mdm2's E3 ubiquitin ligase activity may be sufficient for increasing p53 activity in vivo, without the need to block Mdm2-p53 binding.

  11. RELAP5-3D User Problems

    Energy Technology Data Exchange (ETDEWEB)

    Riemke, Richard Allan

    2002-09-01

    The Reactor Excursion and Leak Analysis Program with 3D capability1 (RELAP5-3D) is a reactor system analysis code that has been developed at the Idaho National Engineering and Environmental Laboratory (INEEL) for the U. S. Department of Energy (DOE). The 3D capability in RELAP5-3D includes 3D hydrodynamics2 and 3D neutron kinetics3,4. Assessment, verification, and validation of the 3D capability in RELAP5-3D is discussed in the literature5,6,7,8,9,10. Additional assessment, verification, and validation of the 3D capability of RELAP5-3D will be presented in other papers in this users seminar. As with any software, user problems occur. User problems usually fall into the categories of input processing failure, code execution failure, restart/renodalization failure, unphysical result, and installation. This presentation will discuss some of the more generic user problems that have been reported on RELAP5-3D as well as their resolution.

  12. RELAP5-3D User Problems

    Energy Technology Data Exchange (ETDEWEB)

    Riemke, Richard Allan

    2001-09-01

    The Reactor Excursion and Leak Analysis Program with 3D capability1 (RELAP5-3D) is a reactor system analysis code that has been developed at the Idaho National Engineering and Environmental Laboratory (INEEL) for the U. S. Department of Energy (DOE). The 3D capability in RELAP5-3D includes 3D hydrodynamics2 and 3D neutron kinetics3,4. Assessment, verification, and validation of the 3D capability in RELAP5-3D is discussed in the literature5,6,7,8,9. Additional assessment, verification, and validation of the 3D capability of RELAP5-3D will be presented in other papers in this users seminar. As with any software, user problems occur. User problems usually fall into the categories of input processing failure, code execution failure, restart/renodalization failure, unphysical result, and installation. This presentation will discuss some of the more generic user problems that have been reported on RELAP5-3D as well as their resolution.

  13. p53 regulation and activity in mouse embryonic stem cells

    OpenAIRE

    Solozobova, Valeriya

    2010-01-01

    P53 is a tumour development p53. The aim of this work was to study the regulation of p53 in embryonic stem cells and its activation in response to DNA damage. p53 was found that p53 becomes transcriptionally active in ES cells after DNA damage. Embryonic stem cells contain a relatively high amount of p53 protein and p53 RNA. After differentiation p53 level is rapidly downregulated. The high abundance of p53 in undifferentiated ES cells is a result of enhanced translation.

  14. The p53HMM algorithm: using profile hidden markov models to detect p53-responsive genes

    Directory of Open Access Journals (Sweden)

    Yu Xin

    2009-04-01

    Full Text Available Abstract Background A computational method (called p53HMM is presented that utilizes Profile Hidden Markov Models (PHMMs to estimate the relative binding affinities of putative p53 response elements (REs, both p53 single-sites and cluster-sites. These models incorporate a novel "Corresponded Baum-Welch" training algorithm that provides increased predictive power by exploiting the redundancy of information found in the repeated, palindromic p53-binding motif. The predictive accuracy of these new models are compared against other predictive models, including position specific score matrices (PSSMs, or weight matrices. We also present a new dynamic acceptance threshold, dependent upon a putative binding site's distance from the Transcription Start Site (TSS and its estimated binding affinity. This new criteria for classifying putative p53-binding sites increases predictive accuracy by reducing the false positive rate. Results Training a Profile Hidden Markov Model with corresponding positions matching a combined-palindromic p53-binding motif creates the best p53-RE predictive model. The p53HMM algorithm is available on-line: http://tools.csb.ias.edu Conclusion Using Profile Hidden Markov Models with training methods that exploit the redundant information of the homotetramer p53 binding site provides better predictive models than weight matrices (PSSMs. These methods may also boost performance when applied to other transcription factor binding sites.

  15. The p53 Isoform Δ133p53β Promotes Cancer Stem Cell Potential

    Directory of Open Access Journals (Sweden)

    Nikola Arsic

    2015-04-01

    Full Text Available Cancer stem cells (CSC are responsible for cancer chemoresistance and metastasis formation. Here we report that Δ133p53β, a TP53 splice variant, enhanced cancer cell stemness in MCF-7 breast cancer cells, while its depletion reduced it. Δ133p53β stimulated the expression of the key pluripotency factors SOX2, OCT3/4, and NANOG. Similarly, in highly metastatic breast cancer cells, aggressiveness was coupled with enhanced CSC potential and Δ133p53β expression. Like in MCF-7 cells, SOX2, OCT3/4, and NANOG expression were positively regulated by Δ133p53β in these cells. Finally, treatment of MCF-7 cells with etoposide, a cytotoxic anti-cancer drug, increased CSC formation and SOX2, OCT3/4, and NANOG expression via Δ133p53, thus potentially increasing the risk of cancer recurrence. Our findings show that Δ133p53β supports CSC potential. Moreover, they indicate that the TP53 gene, which is considered a major tumor suppressor gene, also acts as an oncogene via the Δ133p53β isoform.

  16. The p53 Isoform Δ133p53β Promotes Cancer Stem Cell Potential

    Science.gov (United States)

    Arsic, Nikola; Gadea, Gilles; Lagerqvist, E. Louise; Busson, Muriel; Cahuzac, Nathalie; Brock, Carsten; Hollande, Frederic; Gire, Veronique; Pannequin, Julie; Roux, Pierre

    2015-01-01

    Summary Cancer stem cells (CSC) are responsible for cancer chemoresistance and metastasis formation. Here we report that Δ133p53β, a TP53 splice variant, enhanced cancer cell stemness in MCF-7 breast cancer cells, while its depletion reduced it. Δ133p53β stimulated the expression of the key pluripotency factors SOX2, OCT3/4, and NANOG. Similarly, in highly metastatic breast cancer cells, aggressiveness was coupled with enhanced CSC potential and Δ133p53β expression. Like in MCF-7 cells, SOX2, OCT3/4, and NANOG expression were positively regulated by Δ133p53β in these cells. Finally, treatment of MCF-7 cells with etoposide, a cytotoxic anti-cancer drug, increased CSC formation and SOX2, OCT3/4, and NANOG expression via Δ133p53, thus potentially increasing the risk of cancer recurrence. Our findings show that Δ133p53β supports CSC potential. Moreover, they indicate that the TP53 gene, which is considered a major tumor suppressor gene, also acts as an oncogene via the Δ133p53β isoform. PMID:25754205

  17. Urodele p53 tolerates amino acid changes found in p53 variants linked to human cancer

    Directory of Open Access Journals (Sweden)

    Villiard Éric

    2007-09-01

    Full Text Available Abstract Background Urodele amphibians like the axolotl are unique among vertebrates in their ability to regenerate and their resistance to develop cancers. It is unknown whether these traits are linked at the molecular level. Results Blocking p53 signaling in axolotls using the p53 inhibitor, pifithrin-α, inhibited limb regeneration and the expression of p53 target genes such as Mdm2 and Gadd45, suggesting a link between tumor suppression and regeneration. To understand this relationship we cloned the p53 gene from axolotl. When comparing its sequence with p53 from other organisms, and more specifically human we observed multiple amino acids changes found in human tumors. Phylogenetic analysis of p53 protein sequences from various species is in general agreement with standard vertebrate phylogeny; however, both mice-like rodents and teleost fishes are fast evolving. This leads to long branch attraction resulting in an artefactual basal emergence of these groups in the phylogenetic tree. It is tempting to assume a correlation between certain life style traits (e.g. lifespan and the evolutionary rate of the corresponding p53 sequences. Functional assays of the axolotl p53 in human or axolotl cells using p53 promoter reporters demonstrated a temperature sensitivity (ts, which was further confirmed by performing colony assays at 37°C. In addition, axolotl p53 was capable of efficient transactivation at the Hmd2 promoter but has moderate activity at the p21 promoter. Endogenous axolotl p53 was activated following UV irradiation (100 j/m2 or treatment with an alkylating agent as measured using serine 15 phosphorylation and the expression of the endogenous p53 target Gadd45. Conclusion Urodele p53 may play a role in regeneration and has evolved to contain multiple amino acid changes predicted to render the human protein defective in tumor suppression. Some of these mutations were probably selected to maintain p53 activity at low temperature. However

  18. HPV and p53 in cervical cancer.

    OpenAIRE

    Ngan, H Y; Stanley, M; Liu, S S; Ma, H K

    1994-01-01

    Objective - To determine the prevalence of HPV 16 and 18 E6 by DNA detection and p53 abnormal protein expression in cervical cancers in Hong Kong. Materials and methods - Seventy-three squamous cell cervical cancer biopsy were analysed. Detection of HPV DNA was carried out by the polymerase chain reaction and Southern blotting (PCR/SB) technique using primers to the HPV16 and 18 E6 region and consensus primers to the L1 region. Abnormal expression of the p53 protein was detected by immunohist...

  19. Diverse p53/DNA binding modes expand the repertoire of p53 response elements.

    Science.gov (United States)

    Vyas, Pratik; Beno, Itai; Xi, Zhiqun; Stein, Yan; Golovenko, Dmitrij; Kessler, Naama; Rotter, Varda; Shakked, Zippora; Haran, Tali E

    2017-10-03

    The tumor suppressor protein p53 acts as a transcription factor, binding sequence-specifically to defined DNA sites, thereby activating the expression of genes leading to diverse cellular outcomes. Canonical p53 response elements (REs) are made of two decameric half-sites separated by a variable number of base pairs (spacers). Fifty percent of all validated p53 REs contain spacers between 1 and 18 bp; however, their functional significance is unclear at present. Here, we show that p53 forms two different tetrameric complexes with consensus or natural REs, both with long spacers: a fully specific complex where two p53 dimers bind to two specific half-sites, and a hemispecific complex where one dimer binds to a specific half-site and the second binds to an adjacent spacer sequence. The two types of complexes have comparable binding affinity and specificity, as judged from binding competition against bulk genomic DNA. Structural analysis of the p53 REs in solution shows that these sites are not bent in both their free and p53-bound states when the two half-sites are either abutting or separated by spacers. Cell-based assay supports the physiological relevance of our findings. We propose that p53 REs with long spacers comprise separate specific half-sites that can lead to several different tetrameric complexes. This finding expands the universe of p53 binding sites and demonstrates that even isolated p53 half-sites can form tetrameric complexes. Moreover, it explains the manner in which p53 binds to clusters of more than one canonical binding site, common in many natural REs.

  20. WDR5 positively regulates p53 stability by inhibiting p53 ubiquitination.

    Science.gov (United States)

    Xie, Qingqing; Li, Zengpeng; Chen, Jianming

    2017-05-27

    WD40 repeat protein WDR5 is a core component of the Set/MLL histone methyltransferase complex which catalyzes histone H3 Lys4 trimethylation and activates gene transcription in human cells. WDR5 promotes Set/MLL complex assembly and mediates the complex binding to Lys4-dimethylated histone H3 tail. Most earlier studies report that WDR5 exerts profound effects on various cellular and organismal processes mainly through epigenetic regulation of gene transcription. However, the functions of WDR5 in lung cancer remain largely unknown. Here, we report that WDR5 positively regulates p53 stability by inhibiting p53 ubiquitination in human lung cancer A549 cells. Overexpression of WDR5 dramatically increases p53 protein levels and its half-life in A549 cells, while depletion of WDR5 with WDR5-specific siRNAs significantly decreases p53 protein levels. We also observe that WDR5 is required for p53 induction in response to cisplatin treatment. Mechanistically, WDR5 colocalizes with p53 and inhibits p53 ubiquitination, resulting in p53 stabilization. Consequently, overexpression of WDR5 induces G1 phase arrest in A549 cells, and knocking down WDR5 by siRNAs reduces the population at G1 phase. Furthermore, p53 expression levels is at least in part determined by the p53 positive regulator WDR5 in some cancer cells. Taken together, these data suggest that WDR5 is directly involved in p53 signaling pathway. Our studies provide a new insight into WDR5 functions in A549 cells. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. S100A4 interacts with p53 in the nucleus and promotes p53 degradation.

    Science.gov (United States)

    Orre, L M; Panizza, E; Kaminskyy, V O; Vernet, E; Gräslund, T; Zhivotovsky, B; Lehtiö, J

    2013-12-05

    S100A4 is a small calcium-binding protein that is commonly overexpressed in a range of different tumor types, and it is widely accepted that S100A4 has an important role in the process of cancer metastasis. In vitro binding assays has shown that S100A4 interacts with the tumor suppressor protein p53, indicating that S100A4 may have additional roles in tumor development. In the present study, we show that endogenous S100A4 and p53 interact in complex samples, and that the interaction increases after inhibition of MDM2-dependent p53 degradation using Nutlin-3A. Further, using proximity ligation assay, we show that the interaction takes place in the cell nucleus. S100A4 knockdown experiments in two p53 wild-type cell lines, A549 and HeLa, resulted in stabilization of p53 protein, indicating that S100A4 is promoting p53 degradation. Finally, we demonstrate that S100A4 knockdown leads to p53-dependent cell cycle arrest and increased cisplatin-induced apoptosis. Thus, our data add a new layer to the oncogenic properties of S100A4 through its inhibition of p53-dependent processes.

  2. 40 CFR 53.1 - Definitions.

    Science.gov (United States)

    2010-07-01

    ... slope of a linear plot fitted to corresponding candidate and reference method mean measurement data... MONITORING REFERENCE AND EQUIVALENT METHODS General Provisions § 53.1 Definitions. Terms used but not defined... entity who submits an application for a Federal reference method or Federal equivalent method...

  3. 21 CFR 808.53 - Arizona.

    Science.gov (United States)

    2010-04-01

    ... AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES EXEMPTIONS FROM FEDERAL PREEMPTION OF STATE AND LOCAL MEDICAL DEVICE REQUIREMENTS Listing of Specific State and Local Exemptions § 808.53 Arizona. The following Arizona medical device requirements are preempted...

  4. 28 CFR 2.53 - Mandatory parole.

    Science.gov (United States)

    2010-07-01

    ... Judicial Administration DEPARTMENT OF JUSTICE PAROLE, RELEASE, SUPERVISION AND RECOMMITMENT OF PRISONERS, YOUTH OFFENDERS, AND JUVENILE DELINQUENTS United States Code Prisoners and Parolees § 2.53 Mandatory parole. (a) A prisoner (including a prisoner sentenced under the Narcotic Addict Rehabilitation Act...

  5. 46 CFR 32.53-3 - Exemptions.

    Science.gov (United States)

    2010-10-01

    ... System § 32.53-3 Exemptions. (a) The Assistant Commandant for Marine Safety and Environmental Protection grants exemptions for crude oil tankers of less than 40,000 deadweight tons not fitted with high capacity.... (c) Each request must be supported by documentation showing that: (1) The system would be detrimental...

  6. Final measurement. Deliverable D5.3

    NARCIS (Netherlands)

    Holtzer, A.C.G.; Giessen, A.M. van der; Djurica, M.; Gruber, G.; Krengel, M.; Kokkinos, P.; Varvarigos, M.; Prusa, J.; Schulting, H.W.; Holzmann-Kaiser, U.; Schmoll, C.; Hatzakis, I.; Silva, F.M. da; Reymund, A.; Strebler, R.; Moreno, J.J.R.; Munoz, C.G.; Gheorghe, G.; Nikolopoulos, V.; Mavridis, T.; Bektas, O.; Yuce, E.; Volk, M.; Sterle, J.; Skarmeta, A.

    2015-01-01

    This deliverable D5.3 presents the GEN6 Final Measurement. It describes the outputs, outcomes and impact of the GEN6 project, based on other project deliverables inputs of the pilot leaders of the active GEN6 pilots and the individual consortium partners. The final measurement aims to show the

  7. Reference: 53 [Arabidopsis Phenome Database[Archive

    Lifescience Database Archive (English)

    Full Text Available 53 http://metadb.riken.jp/db/SciNetS_ria224i/cria224u4ria224u14521841i Hunter Christine... heterochronic gene ZIPPY is an ARGONAUTE family member. 19 1734-9 14521841 2003 Sep Current biology Hunter Christine|Poethig R Scott|Sun Hui

  8. 19 CFR 134.53 - Examination packages.

    Science.gov (United States)

    2010-04-01

    ... TREASURY COUNTRY OF ORIGIN MARKING Articles Found Not Legally Marked § 134.53 Examination packages. (a) Site of marking—(1) Customs custody. Articles (or containers) in examination packages may be marked by... the public stores. (2) Importer's premises or elsewhere. If it is impracticable to mark the articles...

  9. FTIR Microspectroscopy Probes Particle-Radiation Effect on HCT116 cells (p53+/+, p53-/-).

    Science.gov (United States)

    Yan, Jingwen; Zhang, Fengqiu; Huang, Qing

    2018-02-01

    p53 is a crucial tumor suppressor and plays an important role in cell cycle arrest, DNA damage repair, promotion of cell senescence and apoptosis, prevention of DNA damage and maintaining genomic stability and integrity. It has been reported that p53 might also be related to radiation sensitivity, for which the involved effects and processes could be further examined biochemically at the molecular level. In this study, we explored a new spectroscopic approach to probe the radiation-induced biological effects related to p53. Infrared microspectroscopy was used to detect the metabolic changes related to p53 under particle radiation. After alpha-particle irradiation of HCT116 cells (p53+/+, p53-/-), cell cycle arrest, DNA damage and lipid peroxidation in the cancer cells were observed using Fourier-transform infrared (FTIR) spectroscopy and microspectroscopy imaging. A remarkable difference in radiosensitivity between the two genotypes of cells was observed as well. This work provides a biochemical analysis of the p53-related radiation effects in cells and demonstrates the potential usefulness of FTIR microspectroscopy in the field of radiation research.

  10. p53 Aggregates penetrate cells and induce the co-aggregation of intracellular p53.

    Directory of Open Access Journals (Sweden)

    Karolyn J Forget

    Full Text Available Prion diseases are unique pathologies in which the infectious particles are prions, a protein aggregate. The prion protein has many particular features, such as spontaneous aggregation, conformation transmission to other native PrP proteins and transmission from an individual to another. Protein aggregation is now frequently associated to many human diseases, for example Alzheimer's disease, Parkinson's disease or type 2 diabetes. A few proteins associated to these conformational diseases are part of a new category of proteins, called prionoids: proteins that share some, but not all, of the characteristics associated with prions. The p53 protein, a transcription factor that plays a major role in cancer, has recently been suggested to be a possible prionoid. The protein has been shown to accumulate in multiple cancer cell types, and its aggregation has also been reproduced in vitro by many independent groups. These observations suggest a role for p53 aggregates in cancer development. This study aims to test the «prion-like» features of p53. Our results show in vitro aggregation of the full length and N-terminally truncated protein (p53C, and penetration of these aggregates into cells. According to our findings, the aggregates enter cells using macropinocytosis, a non-specific pathway of entry. Lastly, we also show that once internalized by the cell, p53C aggregates can co-aggregate with endogenous p53 protein. Together, these findings suggest prion-like characteristics for p53 protein, based on the fact that p53 can spontaneously aggregate, these aggregates can penetrate cells and co-aggregate with cellular p53.

  11. Inhibition of p53-induced apoptosis without affecting expression of p53-regulated genes

    OpenAIRE

    Lotem, Joseph; Gal, Hilah; Kama, Rachel; Amariglio, Ninette; Rechavi, Gideon; Domany, Eytan; Sachs, Leo; Givol, David

    2003-01-01

    Using DNA microarray and clustering of expressed genes we have analyzed the mechanism of inhibition of wild-type p53-induced apoptosis by the cytokine interleukin 6 (IL-6) and the calcium mobilizer thapsigargin (TG). Clustering analysis of 1,786 genes, the expression level of which changed after activation of wild-type p53 in the absence or presence of IL-6 or TG, showed that these compounds did not cause a general inhibition of the ability of p53 to up-regulate or down-regulate gene ex...

  12. TP53 Codon 72 Polymorphism and P53 Protein Expression in Colorectal Cancer Specimens in Isfahan

    Directory of Open Access Journals (Sweden)

    Mehdi Nikbahkt Dastjerdi

    2011-02-01

    Full Text Available The TP53 tumor suppressor gene plays important roles in genomic stability. A common polymorphism at codon 72 of TP53 gene has been associated with increased risk for many human cancers. The p53 protein is expressed in colorectal cancer, but the reported prevalence of its expression varies widely. In the present study, the p53 protein expression in different genotypes of its codon 72 , was investigated. We undertook a case-control study on 250 controls and 250 paraffin block specimens of sporadic colorectal adenocarcinomas from the city of Isfahan. PCR amplification of TP53 codon 72 polymorphism: TP53 codon 72 genotypes were detected by PCR using specific primer pairs for amplifying the proline or the arginine Alleles. The PCR reaction was done separately for each of the two polymorphic variants. The amplified products were subjected to electrophoresis on 1% agarose gel in 1× TBE buffer and visualized on a transilluminator using ethidium bromide. Immunohistochemical Staining: We evaluated the expression patterns of p53 protein, as potential prognostic marker in colorectal cancer specimens by immunohistochemical staining. Statistical analyses: The χ2-test was used to assess the significance of any difference in the prevalence of TP53 codon 72 polymorphism between colorectal cancer patients and controls. The odds ratio and 95% CI (confidence intervals was used as a measure of the strength of the association. Statistical significance level was set to P≤0.05. In control samples, the genotype distribution for TP53 polymorphism showed 30.4%, 45.2% and 24.4% for the arginine/arginine, arginine/proline and proline/proline genotypes, respectively. Allelic frequencies corresponded to 0.663 for the arginine allele and 0.338 for the proline allele. In the cancer group 38.8% of the cases were arginine/arginine, 40.4% were arginine/proline and 20.8% were proline/proline. The corresponding frequencies were 0.590 for the arginine allele and 0.410 for the

  13. Supernumerary molars. A review of 53 cases

    OpenAIRE

    Menardía Pejoan, V.; Berini Aytés, Leonardo; Gay Escoda, Cosme

    2000-01-01

    Supernumerary molars are not uncommon and may be found nearly anywhere in the dental alveolar arches. A series of 36 patients that presented with 53 supernumerary molars are reviewed. They occurred more frequently in the maxilla (86.8%), had little or no clinical significance, tended to be impacted, and were not associated with the impactation of the third molar. Four cases of maxillary fifth molars are described

  14. The p53-MDM2 network: from oscillations to apoptosis

    Indian Academy of Sciences (India)

    PRAKASH KUMAR

    developed a class of small molecules known as nutlins which occupy the p53 binding pocket in MDM2, thus preventing the binding of MDM2 to p53 and facilitating the activation of the p53 pathways in human cancer cell lines. The efficacy of the strategy has been demonstrated in experiments paving. Figure 4. Pulses of p53 ...

  15. 48 CFR 53.106 - Special construction and printing.

    Science.gov (United States)

    2010-10-01

    ... printing. 53.106 Section 53.106 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION (CONTINUED) CLAUSES AND FORMS FORMS General 53.106 Special construction and printing. Contracting offices may request exceptions (see 53.103) to standard forms for special construction and printing. Examples of...

  16. USP3 stabilizes p53 protein through its deubiquitinase activity.

    Science.gov (United States)

    Fu, Song; Shao, Shize; Wang, Longqiang; Liu, Haijun; Hou, Haitao; Wang, Yanan; Wang, Huan; Huang, Xiangpeng; Lv, Renhua

    2017-10-14

    p53 is the guardian of the genome integrity and the degradation of p53 protein is mediated by MDM2. Here we report that USP3 interacts with p53 and regulates p53 stability. Depletion of USP3 lead to accelerated degradation of p53 in normal cells thereby enhanced cell proliferation and transformation. Reconstitution of wildtype USP3, but not the USP3 C168S mutant, restored the stability of p53 protein and inhibited cell proliferation and transformation. These findings suggest that USP3 is an important regulator of p53 and regulates normal cell transformation. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. Deletions linked to TP53 loss drive cancer through p53-independent mechanisms.

    Science.gov (United States)

    Liu, Yu; Chen, Chong; Xu, Zhengmin; Scuoppo, Claudio; Rillahan, Cory D; Gao, Jianjiong; Spitzer, Barbara; Bosbach, Benedikt; Kastenhuber, Edward R; Baslan, Timour; Ackermann, Sarah; Cheng, Lihua; Wang, Qingguo; Niu, Ting; Schultz, Nikolaus; Levine, Ross L; Mills, Alea A; Lowe, Scott W

    2016-03-24

    Mutations disabling the TP53 tumour suppressor gene represent the most frequent events in human cancer and typically occur through a two-hit mechanism involving a missense mutation in one allele and a 'loss of heterozygosity' deletion encompassing the other. While TP53 missense mutations can also contribute gain-of-function activities that impact tumour progression, it remains unclear whether the deletion event, which frequently includes many genes, impacts tumorigenesis beyond TP53 loss alone. Here we show that somatic heterozygous deletion of mouse chromosome 11B3, a 4-megabase region syntenic to human 17p13.1, produces a greater effect on lymphoma and leukaemia development than Trp53 deletion. Mechanistically, the effect of 11B3 loss on tumorigenesis involves co-deleted genes such as Eif5a and Alox15b (also known as Alox8), the suppression of which cooperates with Trp53 loss to produce more aggressive disease. Our results imply that the selective advantage produced by human chromosome 17p deletion reflects the combined impact of TP53 loss and the reduced dosage of linked tumour suppressor genes.

  18. Deletions linked to TP53 loss drive cancer through p53–independent mechanisms

    Science.gov (United States)

    Xu, Zhengmin; Scuoppo, Claudio; Rillahan, Cory D.; Gao, Jianjiong; Spitzer, Barbara; Bosbach, Benedikt; Kastenhuber, Edward R.; Baslan, Timour; Ackermann, Sarah; Cheng, Lihua; Wang, Qingguo; Niu, Ting; Schultz, Nikolaus; Levine, Ross L.; Mills, Alea A.; Lowe, Scott W.

    2016-01-01

    Mutations disabling the TP53 tumour suppressor gene represent the most frequent events in human cancer and typically occur through a two-hit mechanism involving a missense mutation in one allele and a ‘loss of heterozygosity’ deletion encompassing the other. While TP53 missense mutations can also contribute gain-of-function activities that impact tumour progression, it remains unclear whether the deletion event, which frequently includes many genes, impacts tumorigenesis beyond TP53 loss alone. Here we show that somatic heterozygous deletion of mouse chromosome 11B3, a 4-megabase region syntenic to human 17p13.1, produces a greater effect on lymphoma and leukaemia development than Trp53 deletion. Mechanistically, the effect of 11B3 loss on tumorigenesis involves co-deleted genes such as Eif5a and Alox15b (also known as Alox8), the suppression of which cooperates with Trp53 loss to produce more aggressive disease. Our results imply that the selective advantage produced by human chromosome 17p deletion reflects the combined impact of TP53 loss and the reduced dosage of linked tumour suppressor genes. PMID:26982726

  19. Mutant p53 in Cancer: New Functions and Therapeutic Opportunities

    Science.gov (United States)

    Muller, Patricia A.J.; Vousden, Karen H.

    2014-01-01

    Many different types of cancer show a high incidence of TP53 mutations, leading to the expression of mutant p53 proteins. There is growing evidence that these mutant p53s have both lost wild-type p53 tumor suppressor activity and gained functions that help to contribute to malignant progression. Understanding the functions of mutant p53 will help in the development of new therapeutic approaches that may be useful in a broad range of cancer types. PMID:24651012

  20. The p53 target Wig-1 regulates p53 mRNA stability through an AU-rich element

    DEFF Research Database (Denmark)

    Vilborg, Anna; Glahder, Jacob-Andreas Harald; Wilhelm, Margareta T

    2009-01-01

    The p53 target gene Wig-1 encodes a double-stranded-RNA-binding zinc finger protein. We show here that Wig-1 binds to p53 mRNA and stabilizes it through an AU-rich element (ARE) in the 3' UTR of the p53 mRNA. This effect is mirrored by enhanced p53 protein levels in both unstressed cells and cells...... exposed to p53-activating stress agents. Thus, the p53 target Wig-1 is a previously undescribed ARE-regulating protein that acts as a positive feedback regulator of p53, with implications both for the steady-state levels of p53 and for the p53 stress response. Our data reveal a previously undescribed link...... between the tumor suppressor p53 and posttranscriptional gene regulation via AREs in mRNA....

  1. 47 CFR 76.53 - Reference points.

    Science.gov (United States)

    2010-10-01

    ... CABLE TELEVISION SERVICE Carriage of Television Broadcast Signals § 76.53 Reference points. The...°41′30″ 97°20′16″ Kentucky: Ashland 38°28′36″ 82°38′23″ Bowling Green 36°59′41″ 86°26′33″ Covington 39...°19′38″ 82°06′09″ Bowling Green 41°22′37″ 83°39′03″ Canton 40°47′50″ 81°22′37″ Cincinnati 39°06′07″ 84...

  2. Isg15 controls p53 stability and functions

    Science.gov (United States)

    Huang, Yi-Fu; Wee, Sheena; Gunaratne, Jayantha; Lane, David P; Bulavin, Dmitry V

    2014-01-01

    Degradation of p53 is a cornerstone in the control of its functions as a tumor suppressor. This process is attributed to ubiquitin-dependent modification of p53. In addition to polyubiquitination, we found that p53 is targeted for degradation through ISGylation. Isg15, a ubiquitin-like protein, covalently modifies p53 at 2 sites in the N and C terminus, and ISGylated p53 can be degraded by the 20S proteasome. ISGylation primarily targets a misfolded, dominant-negative p53, and Isg15 deletion in normal cells results in suppression of p53 activity and functions. We propose that Isg15-dependent degradation of p53 represents an alternative mechanism of controlling p53 protein levels, and, thus, it is an attractive pathway for drug discovery. PMID:24844324

  3. Expression of Androgen Receptor Is Negatively Regulated By p53

    Directory of Open Access Journals (Sweden)

    Fatouma Alimirah

    2007-12-01

    Full Text Available Increased expression of androgen receptor (AR in prostate cancer (PC is associated with transition to androgen independence. Because the progression of PC to advanced stages is often associated with the loss of p53 function, we tested whether the p53 could regulate the expression of AR gene. Here we report that p53 negatively regulates the expression of AR in prostate epithelial cells (PrECs. We found that in LNCaP human prostate cancer cells that express the wild-type p53 and AR and in human normal PrECs, the activation of p53 by genotoxic stress or by inhibition of p53 nuclear export downregulated the expression of AR. Furthermore, forced expression of p53 in LNCaP cells decreased the expression of AR. Conversely, knockdown of p53 expression in LNCaP cells increased the AR expression. Consistent with the negative regulation of AR expression by p53, the p53-null HCT116 cells expressed higher levels of AR compared with the isogenic HCT116 cells that express the wildtype p53. Moreover, we noted that in etoposide treated LNCaP cells p53 bound to the promoter region of the AR gene, which contains a potential p53 DNA-binding consensus sequence, in chromatin immunoprecipitation assays. Together, our observations provide support for the idea that the loss of p53 function in prostate cancer cells contributes to increased expression of AR.

  4. Nuclear inclusion bodies of mutant and wild-type p53 in cancer: a hallmark of p53 inactivation and proteostasis remodelling by p53 aggregation.

    Science.gov (United States)

    De Smet, Frederik; Saiz Rubio, Mirian; Hompes, Daphne; Naus, Evelyne; De Baets, Greet; Langenberg, Tobias; Hipp, Mark S; Houben, Bert; Claes, Filip; Charbonneau, Sarah; Delgado Blanco, Javier; Plaisance, Stephane; Ramkissoon, Shakti; Ramkissoon, Lori; Simons, Colinda; van den Brandt, Piet; Weijenberg, Matty; Van England, Manon; Lambrechts, Sandrina; Amant, Frederic; D'Hoore, André; Ligon, Keith L; Sagaert, Xavier; Schymkowitz, Joost; Rousseau, Frederic

    2017-05-01

    Although p53 protein aggregates have been observed in cancer cell lines and tumour tissue, their impact in cancer remains largely unknown. Here, we extensively screened for p53 aggregation phenotypes in tumour biopsies, and identified nuclear inclusion bodies (nIBs) of transcriptionally inactive mutant or wild-type p53 as the most frequent aggregation-like phenotype across six different cancer types. p53-positive nIBs co-stained with nuclear aggregation markers, and shared molecular hallmarks of nIBs commonly found in neurodegenerative disorders. In cell culture, tumour-associated stress was a strong inducer of p53 aggregation and nIB formation. This was most prominent for mutant p53, but could also be observed in wild-type p53 cell lines, for which nIB formation correlated with the loss of p53's transcriptional activity. Importantly, protein aggregation also fuelled the dysregulation of the proteostasis network in the tumour cell by inducing a hyperactivated, oncogenic heat-shock response, to which tumours are commonly addicted, and by overloading the proteasomal degradation system, an observation that was most pronounced for structurally destabilized mutant p53. Patients showing tumours with p53-positive nIBs suffered from a poor clinical outcome, similar to those with loss of p53 expression, and tumour biopsies showed a differential proteostatic expression profile associated with p53-positive nIBs. p53-positive nIBs therefore highlight a malignant state of the tumour that results from the interplay between (1) the functional inactivation of p53 through mutation and/or aggregation, and (2) microenvironmental stress, a combination that catalyses proteostatic dysregulation. This study highlights several unexpected clinical, biological and therapeutically unexplored parallels between cancer and neurodegeneration. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2016 Pathological Society of Great

  5. Glycogen synthase kinase3 beta phosphorylates serine 33 of p53 and activates p53's transcriptional activity

    Directory of Open Access Journals (Sweden)

    Price Brendan D

    2001-07-01

    Full Text Available Abstract Background The p53 protein is activated by genotoxic stress, oncogene expression and during senescence, p53 transcriptionally activates genes involved in growth arrest and apoptosis. p53 activation is regulated by post-translational modification, including phosphorylation of the N-terminal transactivation domain. Here, we have examined how Glycogen Synthase Kinase (GSK3, a protein kinase involved in tumorigenesis, differentiation and apoptosis, phosphorylates and regulates p53. Results The 2 isoforms of GSK3, GSK3α and GSK3β, phosphorylate the sequence Ser-X-X-X-Ser(P when the C-terminal serine residue is already phosphorylated. Several p53 kinases were examined for their ability to create GSK3 phosphorylation sites on the p53 protein. Our results demonstrate that phosphorylation of serine 37 of p53 by DNA-PK creates a site for GSK3β phosphorylation at serine 33 in vitro. GSK3α did not phosphorylate p53 under any condition. GSK3β increased the transcriptional activity of the p53 protein in vivo. Mutation of either serine 33 or serine 37 of p53 to alanine blocked the ability of GSK3β to regulate p53 transcriptional activity. GSK3β is therefore able to regulate p53 function in vivo. p53's transcriptional activity is commonly increased by DNA damage. However, GSK3β kinase activity was inhibited in response to DNA damage, suggesting that GSK3β regulation of p53 is not involved in the p53-DNA damage response. Conclusions GSK3β can regulate p53's transcriptional activity by phosphorylating serine 33. However, GSK3β does not appear to be part of the p53-DNA damage response pathway. Instead, GSK3β may provide the link between p53 and non-DNA damage mechanisms for p53 activation.

  6. Analysis list: Trp53 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Trp53 Embryo,Embryonic fibroblast + mm9 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/target/Trp53....1.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/target/Trp53.5.tsv http://dbarchive.bi...osciencedbc.jp/kyushu-u/mm9/target/Trp53.10.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/colo/Trp53.Em...bryo.tsv,http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/colo/Trp53.Embryonic_fibr

  7. A p53 Super-tumor Suppressor Reveals a Tumor Suppressive p53-Ptpn14-Yap Axis in Pancreatic Cancer.

    Science.gov (United States)

    Mello, Stephano S; Valente, Liz J; Raj, Nitin; Seoane, Jose A; Flowers, Brittany M; McClendon, Jacob; Bieging-Rolett, Kathryn T; Lee, Jonghyeob; Ivanochko, Danton; Kozak, Margaret M; Chang, Daniel T; Longacre, Teri A; Koong, Albert C; Arrowsmith, Cheryl H; Kim, Seung K; Vogel, Hannes; Wood, Laura D; Hruban, Ralph H; Curtis, Christina; Attardi, Laura D

    2017-10-09

    The p53 transcription factor is a critical barrier to pancreatic cancer progression. To unravel mechanisms of p53-mediated tumor suppression, which have remained elusive, we analyzed pancreatic cancer development in mice expressing p53 transcriptional activation domain (TAD) mutants. Surprisingly, the p5353,54 TAD2 mutant behaves as a "super-tumor suppressor," with an enhanced capacity to both suppress pancreatic cancer and transactivate select p53 target genes, including Ptpn14. Ptpn14 encodes a negative regulator of the Yap oncoprotein and is necessary and sufficient for pancreatic cancer suppression, like p53. We show that p53 deficiency promotes Yap signaling and that PTPN14 and TP53 mutations are mutually exclusive in human cancers. These studies uncover a p53-Ptpn14-Yap pathway that is integral to p53-mediated tumor suppression. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

  8. TBP-like Protein (TLP) Disrupts the p53-MDM2 Interaction and Induces Long-lasting p53 Activation.

    Science.gov (United States)

    Maeda, Ryo; Tamashiro, Hiroyuki; Takano, Kazunori; Takahashi, Hiro; Suzuki, Hidefumi; Saito, Shinta; Kojima, Waka; Adachi, Noritaka; Ura, Kiyoe; Endo, Takeshi; Tamura, Taka-Aki

    2017-02-24

    Stress-induced activation of p53 is an essential cellular response to prevent aberrant cell proliferation and cancer development. The ubiquitin ligase MDM2 promotes p53 degradation and limits the duration of p53 activation. It remains unclear, however, how p53 persistently escapes MDM2-mediated negative control for making appropriate cell fate decisions. Here we report that TBP-like protein (TLP), a member of the TBP family, is a new regulatory factor for the p53-MDM2 interplay and thus for p53 activation. We found that TLP acts to stabilize p53 protein to ensure long-lasting p53 activation, leading to potentiation of p53-induced apoptosis and senescence after genotoxic stress. Mechanistically, TLP interferes with MDM2 binding and ubiquitination of p53. Moreover, single cell imaging analysis shows that TLP depletion accelerates MDM2-mediated nuclear export of p53. We further show that a cervical cancer-derived TLP mutant has less p53 binding ability and lacks a proliferation-repressive function. Our findings uncover a role of TLP as a competitive MDM2 blocker, proposing a novel mechanism by which p53 escapes the p53-MDM2 negative feedback loop to modulate cell fate decisions. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  9. The role of p53 gene family in reproduction.

    Science.gov (United States)

    Hu, Wenwei

    2009-12-01

    The p53 family of genes (p53, p63, and p73) is conserved over evolutionary time scales. Although the functions of p53 gene and its protein as a tumor suppressor have been firmly established, the earliest functions for the p53 ancestral genes in worms and flies are to ensure germ-line genomic integrity and the fidelity of the developmental process. In vertebrates, the p53 family of genes retains those functions in germ-line genomic integrity but have added important functions in regulation of reproduction. Loss of the p53, p63, or p73 genes in female mice leads to a significant decrease of fertility. The p53 gene product regulates maternal reproduction at the implantation stage of the embryo. p63 and p73 play important roles in monitoring the genomic quality of oocytes. The p53 pathway appears to play a similar role in human fertility. In humans, certain alleles containing a functional single-nucleotide polymorphism (SNP) in the p53 pathway are under positive evolutionary selection. Selected alleles of these SNPs in the p53 pathway are associated with decreased fertility. This important function of the p53 pathway in reproduction provides a plausible explanation for the evolution of p53 as a tumor suppressor gene and the positive selection of some alleles in the p53 gene and its pathway. These observations provide a good possible example of antagonistic pleiotrophy for fertility, tumor suppression, and longevity.

  10. Chemical Variations on the p53 Reactivation Theme

    Directory of Open Access Journals (Sweden)

    Carlos J. A. Ribeiro

    2016-05-01

    Full Text Available Among the tumor suppressor genes, p53 is one of the most studied. It is widely regarded as the “guardian of the genome”, playing a major role in carcinogenesis. In fact, direct inactivation of the TP53 gene occurs in more than 50% of malignancies, and in tumors that retain wild-type p53 status, its function is usually inactivated by overexpression of negative regulators (e.g., MDM2 and MDMX. Hence, restoring p53 function in cancer cells represents a valuable anticancer approach. In this review, we will present an updated overview of the most relevant small molecules developed to restore p53 function in cancer cells through inhibition of the p53-MDMs interaction, or direct targeting of wild-type p53 or mutated p53. In addition, optimization approaches used for the development of small molecules that have entered clinical trials will be presented.

  11. Restriction of human herpesvirus 6B replication by p53

    DEFF Research Database (Denmark)

    Øster, Bodil; Kofod-Olsen, Emil; Bundgaard, Bettina

    2008-01-01

    Human herpesvirus 6B (HHV-6B) induces significant accumulation of p53 in both the nucleus and cytoplasm during infection. Activation of p53 by DNA damage is known to induce either growth arrest or apoptosis; nevertheless, HHV-6B-infected cells are arrested in their cell cycle independently of p53......, and only a minor fraction of the infected cells undergoes apoptosis. Using pifithrin-alpha, a p53 inhibitor, and p53-null cells, this study showed that infected epithelial cells accumulated viral transcripts and proteins to a significantly higher degree in the absence of active p53. Moreover, HHV-6B......-induced cytopathic effects were greatly enhanced in the absence of p53. This suggests that, in epithelial cells, some of the functions of p53 leading to cell-cycle arrest and apoptosis are restrained by HHV-6B infection, whereas other cellular defences, causing inhibition of virus transcription, are partially...

  12. [P53 protein in adenocarcinoma of the large intestine].

    Science.gov (United States)

    Paluszkiewicz, P; Pawłowska-Wakowicz, B; Cybulski, M; Berbeć, H

    1997-01-01

    P53 gen mutations play significant role in neoplastic transformation of colorectal mucosa. We investigated p53 immunostaining in 80 cases of spontaneous human colorectal adenocarcinomas (with monoclonal DO7 antibody and LSAB+ kit). We found positive, nuclear p53 immunostaining in 64% of nonmucinous adenocarcinoma tissues and in 19% of mucinous adenocarcinomas tissues. P53 protein deposits were most often found in colorectal adenocarcinomas localised in rectum (66.67%) and in advanced (Dukes C, D) colorectal adenocarcinomas (59.38%) as well. There was no statistical significance between the p53 positive immunostaining and the histological differentiation of the colorectal adenocarcinomas. The overall survival of patients with tumours positive for p53 protein was significantly shorter than that of patients with colorectal cancers negative for p53 protein. We conclude that p53 immunohistochemical analysis may be treated as a supplementary prognostic marker for patients with colorectal adenocarcinoma, especially it may be useful for adjuvant therapy selection.

  13. Modeling the basal dynamics of p53 system

    National Research Council Canada - National Science Library

    Sun, Tingzhe; Yang, Weiwei; Liu, Jing; Shen, Pingping

    2011-01-01

    .... Most previous models have ignored the basal dynamics of p53 under nonstressed conditions. To explore the basal dynamics of p53, we constructed a stochastic delay model by incorporating two negative feedback loops...

  14. Census and evaluation of p53 target genes

    Science.gov (United States)

    Fischer, M

    2017-01-01

    The tumor suppressor p53 functions primarily as a transcription factor. Mutation of the TP53 gene alters its response pathway, and is central to the development of many cancers. The discovery of a large number of p53 target genes, which confer p53’s tumor suppressor function, has led to increasingly complex models of p53 function. Recent meta-analysis approaches, however, are simplifying our understanding of how p53 functions as a transcription factor. In the survey presented here, a total set of 3661 direct p53 target genes is identified that comprise 3509 potential targets from 13 high-throughput studies, and 346 target genes from individual gene analyses. Comparison of the p53 target genes reported in individual studies with those identified in 13 high-throughput studies reveals limited consistency. Here, p53 target genes have been evaluated based on the meta-analysis data, and the results show that high-confidence p53 target genes are involved in multiple cellular responses, including cell cycle arrest, DNA repair, apoptosis, metabolism, autophagy, mRNA translation and feedback mechanisms. However, many p53 target genes are identified only in a small number of studies and have a higher likelihood of being false positives. While numerous mechanisms have been proposed for mediating gene regulation in response to p53, recent advances in our understanding of p53 function show that p53 itself is solely an activator of transcription, and gene downregulation by p53 is indirect and requires p21. Taking into account the function of p53 as an activator of transcription, recent results point to an unsophisticated means of regulation. PMID:28288132

  15. CLCA2 as a p53-Inducible Senescence Mediator

    OpenAIRE

    Chizu Tanikawa; Hidewaki Nakagawa; Yoichi Furukawa; Yusuke Nakamura; Koichi Matsuda

    2012-01-01

    p53 is a tumor suppressor gene that is frequently mutated in multiple cancer tissues. Activated p53 protein regulates its downstream genes and subsequently inhibits malignant transformation by inducing cell cycle arrest, apoptosis, DNA repair, and senescence. However, genes involved in the p53-mediated senescence pathway are not yet fully elucidated. Through the screening of two genome-wide expression profile data sets, one for cells in which exogenous p53 was introduced and the other for sen...

  16. Radiation induces p53-dependent cell apoptosis in bladder cancer cells with wild-type- p53 but not in p53-mutated bladder cancer cells.

    Science.gov (United States)

    Hinata, Nobuyuki; Shirakawa, Toshiro; Zhang, Zhujun; Matsumoto, Akira; Fujisawa, Masato; Okada, Hiroshi; Kamidono, Sadao; Gotoh, Akinobu

    2003-12-01

    Purpose. It has been reported in several studies that the absence in cancer cells of the p53 tumor suppressor gene, mutations of which are frequently found in bladder cancer, increases their resistance to ionizing radiation. Other studies, however, suggest that mutations of the p53 gene could increase the radiosensitivity of cancer cells, although the evidence is still inconclusive. In the present study, we investigated the relationship between p53 status and radiation response in five different bladder cancer cell lines. Materials and Methods. Five different human bladder cancer cell lines (KK47: with wt- p53, RT4: with wt- p53, T24: with mutated p53, 5637: with mutated p53, UM-UC-3: with mutated p53) were used in the study. Cells were irradiated with 0, 2, 4, 6 or 8 Gy, then trypsinized and re-plated for clonogenic survival assay, quantitative RT-PCR assay, flow-cytometry analysis and TUNEL assay. Results. The clonogenic assay demonstrated that KK47 and RT4 had significantly higher radiosensitivity than other cell lines. Quantitative RT-PCR analysis showed that radiation induced increased expression of p53, Bax, and p21 mRNA in KK47 and RT4. After irradiation, G1 cell-cycle arrest was observed in KK47 and RT4 under flow cytometry analysis, while T24, 5637, and UM-UC-3 showed an increase in the proportion of G2 cells. Increased cell apoptosis was also observed under TUNEL assay in KK47 and RT4, but not in other cell lines. It was demonstrated that ionizing radiation induces p53-dependent cell apoptosis in bladder cancer cells with wt- p53 but not in those with mutated p53.

  17. 29 CFR 96.53 - Audit resolution generally.

    Science.gov (United States)

    2010-07-01

    ... 29 Labor 1 2010-07-01 2010-07-01 true Audit resolution generally. 96.53 Section 96.53 Labor Office of the Secretary of Labor AUDIT REQUIREMENTS FOR GRANTS, CONTRACTS, AND OTHER AGREEMENTS Audit Resolution § 96.53 Audit resolution generally. The DOL official(s) responsible for audit resolution shall...

  18. 48 CFR 53.215 - Contracting by negotiation.

    Science.gov (United States)

    2010-10-01

    ... 48 Federal Acquisition Regulations System 2 2010-10-01 2010-10-01 false Contracting by negotiation. 53.215 Section 53.215 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION (CONTINUED) CLAUSES AND FORMS FORMS Prescription of Forms 53.215 Contracting by negotiation. ...

  19. 42 CFR 431.53 - Assurance of transportation.

    Science.gov (United States)

    2010-10-01

    ... 42 Public Health 4 2010-10-01 2010-10-01 false Assurance of transportation. 431.53 Section 431.53... Requirements § 431.53 Assurance of transportation. A State plan must— (a) Specify that the Medicaid agency will ensure necessary transportation for recipients to and from providers; and (b) Describe the methods that...

  20. 28 CFR 65.53 - Confidentiality of information.

    Science.gov (United States)

    2010-07-01

    ... 28 Judicial Administration 2 2010-07-01 2010-07-01 false Confidentiality of information. 65.53 Section 65.53 Judicial Administration DEPARTMENT OF JUSTICE (CONTINUED) EMERGENCY FEDERAL LAW ENFORCEMENT ASSISTANCE Additional Requirements § 65.53 Confidentiality of information. Section 812 of title I of the...

  1. Targeting the p53 Pathway in Ewing Sarcoma

    Directory of Open Access Journals (Sweden)

    Paul M. Neilsen

    2011-01-01

    Full Text Available The p53 tumour suppressor plays a pivotal role in the prevention of oncogenic transformation. Cancers frequently evade the potent antitumour surveillance mechanisms of p53 through mutation of the TP53 gene, with approximately 50% of all human malignancies expressing dysfunctional, mutated p53 proteins. Interestingly, genetic lesions in the TP53 gene are only observed in 10% of Ewing Sarcomas, with the majority of these sarcomas expressing a functional wild-type p53. In addition, the p53 downstream signaling pathways and DNA-damage cell cycle checkpoints remain functionally intact in these sarcomas. This paper summarizes recent insights into the functional capabilities and regulation of p53 in Ewing Sarcoma, with a particular focus on the cross-talk between p53 and the EWS-FLI1 gene rearrangement frequently associated with this disease. The development of several activators of p53 is discussed, with recent evidence demonstrating the potential of small molecule p53 activators as a promising systemic therapeutic approach for the treatment of Ewing Sarcomas with wild-type p53.

  2. 7 CFR 53.1 - Meaning of words.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 3 2010-01-01 2010-01-01 false Meaning of words. 53.1 Section 53.1 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Standards..., CERTIFICATION, AND STANDARDS) Regulations Definitions § 53.1 Meaning of words. Words used in this subpart in the...

  3. 7 CFR 1786.53 - Discounted present value.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 12 2010-01-01 2010-01-01 false Discounted present value. 1786.53 Section 1786.53... Special Discounted Prepayments on RUS Direct/Insured Loans § 1786.53 Discounted present value. The Discounted Present Value shall be calculated five business days before prepayment is made by summing the...

  4. The role of the tumor suppressor p53 in spermatogenesis

    NARCIS (Netherlands)

    Beumer, T. L.; Roepers-Gajadien, H. L.; Gademan, I. S.; van Buul, P. P.; Gil-Gomez, G.; Rutgers, D. H.; de rooij, D. G.

    1998-01-01

    The p53 protein appeared to be involved in both spermatogonial cell proliferation and radiation response. During normal spermatogenesis in the mouse, spermatogonia do not express p53, as analyzed by immunohistochemistry. However, after a dose of 4 Gy of X-rays, a distinct p53 staining was present in

  5. 27 CFR 53.103 - Lease considered as sale.

    Science.gov (United States)

    2010-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 2 2010-04-01 2010-04-01 false Lease considered as sale. 53.103 Section 53.103 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE BUREAU... Provisions Applicable to Manufacturers Taxes § 53.103 Lease considered as sale. For purposes of chapter 32 of...

  6. 46 CFR 78.47-53 - Automatic ventilation dampers.

    Science.gov (United States)

    2010-10-01

    ... 46 Shipping 3 2010-10-01 2010-10-01 false Automatic ventilation dampers. 78.47-53 Section 78.47-53... Fire and Emergency Equipment, Etc. § 78.47-53 Automatic ventilation dampers. (a) The manual operating positions for automatic fire dampers in ventilation ducts passing through main vertical zone bulkheads shall...

  7. 46 CFR 67.53 - Methods of establishing title.

    Science.gov (United States)

    2010-10-01

    ... 46 Shipping 2 2010-10-01 2010-10-01 false Methods of establishing title. 67.53 Section 67.53... DOCUMENTATION OF VESSELS Title Requirements for Vessel Documentation § 67.53 Methods of establishing title. Title to a vessel may be established through one of the following methods: (a) Simplified method without...

  8. 27 CFR 53.92 - Exclusions from sale price.

    Science.gov (United States)

    2010-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 2 2010-04-01 2010-04-01 false Exclusions from sale price. 53.92 Section 53.92 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE BUREAU... Provisions Applicable to Manufacturers Taxes § 53.92 Exclusions from sale price. (a) Tax—(1) Tax not part of...

  9. 27 CFR 53.95 - Constructive sale price; basic rules.

    Science.gov (United States)

    2010-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 2 2010-04-01 2010-04-01 false Constructive sale price; basic rules. 53.95 Section 53.95 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND... AMMUNITION Special Provisions Applicable to Manufacturers Taxes § 53.95 Constructive sale price; basic rules...

  10. 27 CFR 53.97 - Constructive sale price; affiliated corporations.

    Science.gov (United States)

    2010-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 2 2010-04-01 2010-04-01 false Constructive sale price; affiliated corporations. 53.97 Section 53.97 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX... AND AMMUNITION Special Provisions Applicable to Manufacturers Taxes § 53.97 Constructive sale price...

  11. 48 CFR 53.301-330 - Architect-Engineer Qualifications.

    Science.gov (United States)

    2010-10-01

    ... 48 Federal Acquisition Regulations System 2 2010-10-01 2010-10-01 false Architect-Engineer Qualifications. 53.301-330 Section 53.301-330 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION (CONTINUED) CLAUSES AND FORMS FORMS Illustrations of Forms 53.301-330 Architect-Engineer...

  12. 41 CFR 109-26.501-53 - Acquisitions by transfer.

    Science.gov (United States)

    2010-07-01

    ... 41 Public Contracts and Property Management 3 2010-07-01 2010-07-01 false Acquisitions by transfer. 109-26.501-53 Section 109-26.501-53 Public Contracts and Property Management Federal Property... PROCUREMENT 26-PROCUREMENT SOURCES AND PROGRAM 26.5-GSA Procurement Programs § 109-26.501-53 Acquisitions by...

  13. 24 CFR 26.53 - Exhaustion of administrative remedies.

    Science.gov (United States)

    2010-04-01

    ... 24 Housing and Urban Development 1 2010-04-01 2010-04-01 false Exhaustion of administrative remedies. 26.53 Section 26.53 Housing and Urban Development Office of the Secretary, Department of Housing... Hearings § 26.53 Exhaustion of administrative remedies. In order to fulfill the requirement of exhausting...

  14. 7 CFR 201.53 - Source of seeds for germination.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 3 2010-01-01 2010-01-01 false Source of seeds for germination. 201.53 Section 201.53..., Inspections, Marketing Practices), DEPARTMENT OF AGRICULTURE (CONTINUED) FEDERAL SEED ACT FEDERAL SEED ACT REGULATIONS Germination Tests in the Administration of the Act § 201.53 Source of seeds for germination. (a...

  15. 27 CFR 53.184 - Refund to exporter or shipper.

    Science.gov (United States)

    2010-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 2 2010-04-01 2010-04-01 false Refund to exporter or shipper. 53.184 Section 53.184 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE... AMMUNITION Refunds and Other Administrative Provisions of Special Application to Manufacturers Taxes § 53.184...

  16. 7 CFR 989.53 - Research and development.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 8 2010-01-01 2010-01-01 false Research and development. 989.53 Section 989.53... GROWN IN CALIFORNIA Order Regulating Handling Research and Development § 989.53 Research and development... establishment of projects involving marketing research and development and marketing promotion including paid...

  17. 10 CFR 39.53 - Energy compensation source.

    Science.gov (United States)

    2010-01-01

    ... 10 Energy 1 2010-01-01 2010-01-01 false Energy compensation source. 39.53 Section 39.53 Energy NUCLEAR REGULATORY COMMISSION LICENSES AND RADIATION SAFETY REQUIREMENTS FOR WELL LOGGING Equipment § 39.53 Energy compensation source. The licensee may use an energy compensation source (ECS) which is...

  18. p53 specific (auto)immunity in mice

    NARCIS (Netherlands)

    Lauwen, Marjolein Monique

    2008-01-01

    Self-tolerance to p53 is a major potential limitation for the activation of the endogenous T-cell repertoire. So far, p53 specific CD8+ and CD4+ T-cell immunity has been described in cancer patients and healthy individuals. However, the restrictions of tolerance on the recruitment of p53 specific T

  19. 20 CFR 631.53 - Certificates of continuing eligibility.

    Science.gov (United States)

    2010-04-01

    ... 20 Employees' Benefits 3 2010-04-01 2010-04-01 false Certificates of continuing eligibility. 631.53 Section 631.53 Employees' Benefits EMPLOYMENT AND TRAINING ADMINISTRATION, DEPARTMENT OF LABOR PROGRAMS UNDER TITLE III OF THE JOB TRAINING PARTNERSHIP ACT Substate Programs § 631.53 Certificates of...

  20. 40 CFR 53.64 - Test procedure: Static fractionator test.

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 5 2010-07-01 2010-07-01 false Test procedure: Static fractionator test. 53.64 Section 53.64 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR... Performance Characteristics of Class II Equivalent Methods for PM2.5 § 53.64 Test procedure: Static...

  1. 7 CFR 400.53 - Yield certification and acceptability.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 6 2010-01-01 2010-01-01 false Yield certification and acceptability. 400.53 Section 400.53 Agriculture Regulations of the Department of Agriculture (Continued) FEDERAL CROP INSURANCE CORPORATION, DEPARTMENT OF AGRICULTURE GENERAL ADMINISTRATIVE REGULATIONS Actual Production History § 400.53...

  2. 18 CFR 701.53 - Council decisions by Members.

    Science.gov (United States)

    2010-04-01

    ... Members. 701.53 Section 701.53 Conservation of Power and Water Resources WATER RESOURCES COUNCIL COUNCIL ORGANIZATION Headquarters Organization § 701.53 Council decisions by Members. Council decisions by Members may... is deemed necessary. Issues raised at Council meetings shall be decided by majority vote of Members...

  3. 45 CFR 1801.53 - Postponement of payment.

    Science.gov (United States)

    2010-10-01

    ... 45 Public Welfare 4 2010-10-01 2010-10-01 false Postponement of payment. 1801.53 Section 1801.53... HARRY S. TRUMAN SCHOLARSHIP PROGRAM Payment Conditions and Procedures § 1801.53 Postponement of payment... other circumstances. (b) If the Foundation grants a postponement, it may impose conditions as it deems...

  4. 27 CFR 53.2 - Attachment of tax.

    Science.gov (United States)

    2010-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 2 2010-04-01 2010-04-01 false Attachment of tax. 53.2 Section 53.2 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE BUREAU, DEPARTMENT... § 53.2 Attachment of tax. (a) For purposes of this part, the manufacturers excise tax generally...

  5. 48 CFR 53.301-26 - Award/Contract.

    Science.gov (United States)

    2010-10-01

    ... 48 Federal Acquisition Regulations System 2 2010-10-01 2010-10-01 false Award/Contract. 53.301-26 Section 53.301-26 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION (CONTINUED) CLAUSES AND FORMS FORMS Illustrations of Forms 53.301-26 Award/Contract. ER22AP08.000 ...

  6. 48 CFR 53.301-1447 - Solicitation/Contract.

    Science.gov (United States)

    2010-10-01

    ... 48 Federal Acquisition Regulations System 2 2010-10-01 2010-10-01 false Solicitation/Contract. 53.301-1447 Section 53.301-1447 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION (CONTINUED) CLAUSES AND FORMS FORMS Illustrations of Forms 53.301-1447 Solicitation/Contract. ER22AP08.001...

  7. P53 MUTATIONS IN HUMAN LUNG-TUMORS

    NARCIS (Netherlands)

    MILLER, CW; ASLO, A; KOK, K; YOKOTA, J; BUYS, CHCM; TERADA, M; KOEFFLER, HP; Simon, K.

    1992-01-01

    Mutation of one p53 allele and loss of the normal p53 allele [loss of heterozygosity (LOH)] occur in many tumors including lung cancers. These alterations apparently contribute to development of cancer by interfering with the tumor suppressor activity of p53. We directly sequenced amplified DNA in

  8. Role of p53 in Cell Death and Human Cancers

    Science.gov (United States)

    Ozaki, Toshinori; Nakagawara, Akira

    2011-01-01

    p53 is a nuclear transcription factor with a pro-apoptotic function. Since over 50% of human cancers carry loss of function mutations in p53 gene, p53 has been considered to be one of the classical type tumor suppressors. Mutant p53 acts as the dominant-negative inhibitor toward wild-type p53. Indeed, mutant p53 has an oncogenic potential. In some cases, malignant cancer cells bearing p53 mutations display a chemo-resistant phenotype. In response to a variety of cellular stresses such as DNA damage, p53 is induced to accumulate in cell nucleus to exert its pro-apoptotic function. Activated p53 promotes cell cycle arrest to allow DNA repair and/or apoptosis to prevent the propagation of cells with serious DNA damage through the transactivation of its target genes implicated in the induction of cell cycle arrest and/or apoptosis. Thus, the DNA-binding activity of p53 is tightly linked to its tumor suppressive function. In the present review article, we describe the regulatory mechanisms of p53 and also p53-mediated therapeutic strategies to cure malignant cancers. PMID:24212651

  9. 48 CFR 53.205-1 - Paid advertisements.

    Science.gov (United States)

    2010-10-01

    ... 48 Federal Acquisition Regulations System 2 2010-10-01 2010-10-01 false Paid advertisements. 53... (CONTINUED) CLAUSES AND FORMS FORMS Prescription of Forms 53.205-1 Paid advertisements. SF 1449, prescribed in 53.212, shall be used to place orders for paid advertisements as specified in 5.503. ...

  10. 45 CFR 605.53 - Drug and alcohol addicts.

    Science.gov (United States)

    2010-10-01

    ..., Welfare, and Social Services § 605.53 Drug and alcohol addicts. A recipient to which this subpart applies... 45 Public Welfare 3 2010-10-01 2010-10-01 false Drug and alcohol addicts. 605.53 Section 605.53 Public Welfare Regulations Relating to Public Welfare (Continued) NATIONAL SCIENCE FOUNDATION...

  11. p53 expression in colorectal carcinoma in relation to ...

    African Journals Online (AJOL)

    Background: It has been shown that colorectal carcinoma is increasing in incidence in African countries. This could be due to change in life style. Molecular pathogenesis of colorectal cancer commonly involves mutation in p53 gene which leads to expression of p53 protein in tumor cells. Expression of p53 protein has been ...

  12. 21 CFR 640.53 - Testing the blood.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 7 2010-04-01 2010-04-01 false Testing the blood. 640.53 Section 640.53 Food and... ADDITIONAL STANDARDS FOR HUMAN BLOOD AND BLOOD PRODUCTS Cryoprecipitate § 640.53 Testing the blood. (a) Blood... sample of blood collected at the time of collecting the source blood, and such sample container shall be...

  13. p53 and survival in early onset breast cancer

    DEFF Research Database (Denmark)

    Gentile, M; Bergman Jungeström, M; Olsen, K E

    1999-01-01

    The p53 protein has proven to be central in tumorigenesis by its cell cycle regulatory properties and both gene mutations and protein accumulation have been associated with poor prognosis in breast cancer. The present study was undertaken to investigate the prognostic significance of gene mutations......, p53 protein accumulation and of loss of heterozygosity (LOH) at the TP53 locus in young (age ... (46%). Log rank analysis revealed no significant association between survival and TP53 mutations (in general), p53 protein accumulation or LOH. However, missense mutations localised to the zinc binding domain were significantly (P = 0.0007) associated with poorer prognosis. As indicated...

  14. p53 Over-expression and p53 mutations in colon carcinomas: Relation to dietary risk factors

    NARCIS (Netherlands)

    Voskuil, D.W.; Kampman, E.; Kraats, A.A. van; Balder, H.F.; Muijen, G.N.P. van; Goldbohm, R.A.; Veer, P. van 't

    1999-01-01

    Epidemiological studies have suggested that dietary factors may differently affect p53-dependent and p53-independent pathways to colon cancer. Results of such studies may depend on the method used to assess p53 status. This case-control study of 185 colon-cancer cases and 259 controls examines this

  15. Screening of medicinal plant phytochemicals as natural antagonists of p53-MDM2 interaction to reactivate p53 functioning.

    Science.gov (United States)

    Riaz, Muhammad; Ashfaq, Usman A; Qasim, Muhammad; Yasmeen, Erum; Ul Qamar, Muhammad T; Anwar, Farooq

    2017-10-01

    In most types of cancer, overexpression of murine double minute 2 (MDM2) often leads to inactivation of p53. The crystal structure of MDM2, with a 109-residue amino-terminal domain, reveals that MDM2 has a core hydrophobic region to which p53 binds as an amphipathic α helix. The interface depends on the steric complementarity between MDM2 and the hydrophobic region of p53. Especially, on p53's triad, amino acids Phe19, Trp23 and Leu26 bind to the MDM2 core. Results from studies suggest that the structural motif of both p53 and MDM2 can be attributed to similarities in the amphipathic α helix. Thus, in the current investigation it is hypothesized that the similarity in the structural motif might be the cause of p53 inactivation by MDM2. Hence, molecular docking and phytochemical screening approaches are appraised to inhibit the hydrophobic cleft of MDM2 and to stop p53-MDM2 interaction, resulting in reactivation of p53 activity. For this purpose, a library of 2295 phytochemicals were screened against p53-MDM2 to find potential candidates. Of these, four phytochemicals including epigallocatechin gallate, alvaradoin M, alvaradoin E and nordihydroguaiaretic acid were found to be potential inhibitors of p53-MDM2 interaction. The screened phytochemicals, derived from natural extracts, may have negligible side effects and can be explored as potent antagonists of p53-MDM2 interactions, resulting in reactivation of the normal transcription of p53.

  16. P53 mutation analysis of colorectal liver metastases : Relation to actual survival, angiogenic status, and p53 overexpression

    NARCIS (Netherlands)

    de Jong, KP; Gouw, ASH; Peeters, PMJG; Bulthuis, M; Menkema, L; Porte, RJ; Slooff, MJH; van Goor, H; van den Berg, Anke

    2005-01-01

    Purpose: To correlate TP53 mutations with angiogenic status of the tumor and prognosis after liver surgery in patients with colorectal liver metastases and to correlate immunohistochemical staining of p53 protein with TP53 gene mutations. Experimental Design: Tumors of 44 patients with surgically

  17. Japan's declining fertility: "1.53 shock".

    Science.gov (United States)

    Yanagishita, M

    1992-04-01

    In 1990, the Japanese were upset over the low 1989 total fertility rate (TFR) of 1.57 and continued to be so when they learned that the 1990 rate was even lower (1.53). This meant an annual population growth rate of only 0.33% with population decline beginning after 2010. In the early 1990s, Japan began to feel the demographic effects of such low fertility: a shortage of young workers and rising costs of health care for the elderly. Further, this shortage resulted in increasing business closings between 1988-1990 (1-6%). In 1990, the government began a survey to monitor the beliefs of the population on demographic concerns. The survey revealed that people wanted 2.2 children. Ideal family size was 2.6 which remained the same since 1977. Almost 40% found the falling TFR to be undesirable, especially because the population was aging. Moreover 65% of them though the government should undertake efforts to increase births. The major suggestions included reducing economic costs of raising a child (53%), a more favorable environment to have children such as affordable housing (29%), and developing child care facilities and child care leave (13%). 38% of 25-29 year old women were still unmarried, yet only 2% intended to never marry. Women in their late 20s and early 30s were critical of the 3 generation household with women doing all the housework. Women were more likely to be against premarital and extramarital sex than men. 25-33%, especially women 45 years old, felt the abortion law should be restricted. The 1990 abortion rate was 37.4/100 births. 7% relied on sterilization, yet 25-30% felt it to be an acceptable means of contraception. 75% of those that used a contraceptive used the condom. The government continued to ban oral contraceptives (OCs) claiming they would spread AIDS. Men were more in favor of OCs than women. 48% of those who found the falling population undesirable favored a pronatalist policy over importing foreign laborers. 41% wanted Japan to still help

  18. Molecularly targeted therapies for p53-mutant cancers.

    Science.gov (United States)

    Zhao, Dekuang; Tahaney, William M; Mazumdar, Abhijit; Savage, Michelle I; Brown, Powel H

    2017-11-01

    The tumor suppressor p53 is lost or mutated in approximately half of human cancers. Mutant p53 not only loses its anti-tumor transcriptional activity, but also often acquires oncogenic functions to promote tumor proliferation, invasion, and drug resistance. Traditional strategies have been taken to directly target p53 mutants through identifying small molecular compounds to deplete mutant p53, or to restore its tumor suppressive function. Accumulating evidence suggest that cancer cells with mutated p53 often exhibit specific functional dependencies on secondary genes or pathways to survive, providing alternative targets to indirectly treat p53-mutant cancers. Targeting these genes or pathways, critical for survival in the presence of p53 mutations, holds great promise for cancer treatment. In addition, mutant p53 often exhibits novel gain-of-functions to promote tumor growth and metastasis. Here, we review and discuss strategies targeting mutant p53, with focus on targeting the mutant p53 protein directly, and on the progress of identifying genes and pathways required in p53-mutant cells.

  19. Combining Oncolytic Virotherapy with p53 Tumor Suppressor Gene Therapy

    Directory of Open Access Journals (Sweden)

    Christian Bressy

    2017-06-01

    Full Text Available Oncolytic virus (OV therapy utilizes replication-competent viruses to kill cancer cells, leaving non-malignant cells unharmed. With the first U.S. Food and Drug Administration-approved OV, dozens of clinical trials ongoing, and an abundance of translational research in the field, OV therapy is poised to be one of the leading treatments for cancer. A number of recombinant OVs expressing a transgene for p53 (TP53 or another p53 family member (TP63 or TP73 were engineered with the goal of generating more potent OVs that function synergistically with host immunity and/or other therapies to reduce or eliminate tumor burden. Such transgenes have proven effective at improving OV therapies, and basic research has shown mechanisms of p53-mediated enhancement of OV therapy, provided optimized p53 transgenes, explored drug-OV combinational treatments, and challenged canonical roles for p53 in virus-host interactions and tumor suppression. This review summarizes studies combining p53 gene therapy with replication-competent OV therapy, reviews preclinical and clinical studies with replication-deficient gene therapy vectors expressing p53 transgene, examines how wild-type p53 and p53 modifications affect OV replication and anti-tumor effects of OV therapy, and explores future directions for rational design of OV therapy combined with p53 gene therapy.

  20. Creation and preliminary characterization of a Tp53 knockout rat

    Science.gov (United States)

    McCoy, Aaron; Besch-Williford, Cynthia L.; Franklin, Craig L.; Weinstein, Edward J.; Cui, Xiaoxia

    2013-01-01

    SUMMARY The tumor suppressor TP53 plays a crucial role in cancer biology, and the TP53 gene is the most mutated gene in human cancer. Trp53 knockout mouse models have been widely used in cancer etiology studies and in search for a cure of cancer with some limitations that other model organisms might help overcome. Via pronuclear microinjection of zinc finger nucleases (ZFNs), we created a Tp53 knockout rat that contains an 11-bp deletion in exon 3, resulting in a frameshift and premature terminations in the open reading frame. In cohorts of 25 homozygous (Tp53Δ11/Δ11), 37 heterozygous (Tp53Δ11/+) and 30 wild-type rats, the Tp53Δ11/Δ11 rats lived an average of 126 days before death or removal from study because of clinical signs of abnormality or formation of tumors. Half of Tp53Δ11/+ were removed from study by 1 year of age because of tumor formation. Both Tp53Δ11/+ and Tp53Δ11/Δ11 rats developed a wide spectrum of tumors, most commonly sarcomas. Interestingly, there was a strikingly high incidence of brain lesions, especially in Tp53Δ11/Δ11 animals. We believe that this mutant rat line will be useful in studying cancer types rarely observed in mice and in carcinogenicity assays for drug development. PMID:22917926

  1. Combining Oncolytic Virotherapy with p53 Tumor Suppressor Gene Therapy.

    Science.gov (United States)

    Bressy, Christian; Hastie, Eric; Grdzelishvili, Valery Z

    2017-06-16

    Oncolytic virus (OV) therapy utilizes replication-competent viruses to kill cancer cells, leaving non-malignant cells unharmed. With the first U.S. Food and Drug Administration-approved OV, dozens of clinical trials ongoing, and an abundance of translational research in the field, OV therapy is poised to be one of the leading treatments for cancer. A number of recombinant OVs expressing a transgene for p53 (TP53) or another p53 family member (TP63 or TP73) were engineered with the goal of generating more potent OVs that function synergistically with host immunity and/or other therapies to reduce or eliminate tumor burden. Such transgenes have proven effective at improving OV therapies, and basic research has shown mechanisms of p53-mediated enhancement of OV therapy, provided optimized p53 transgenes, explored drug-OV combinational treatments, and challenged canonical roles for p53 in virus-host interactions and tumor suppression. This review summarizes studies combining p53 gene therapy with replication-competent OV therapy, reviews preclinical and clinical studies with replication-deficient gene therapy vectors expressing p53 transgene, examines how wild-type p53 and p53 modifications affect OV replication and anti-tumor effects of OV therapy, and explores future directions for rational design of OV therapy combined with p53 gene therapy.

  2. Analysis list: TP53 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available TP53 Blood,Bone,Breast,Digestive tract,Epidermis,Others,Pluripotent stem cell + hg19 http:...//dbarchive.biosciencedbc.jp/kyushu-u/hg19/target/TP53.1.tsv http://dbarchive.biosciencedbc.jp/kyushu...-u/hg19/target/TP53.5.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/target/TP53.10.tsv http://dbarchiv...e.biosciencedbc.jp/kyushu-u/hg19/colo/TP53.Blood.tsv,http://dbarchive.bioscienced...bc.jp/kyushu-u/hg19/colo/TP53.Bone.tsv,http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/colo/TP53.Breast.tsv,http:

  3. TP53 gene status affects survival in advanced mycosis fungoides

    Directory of Open Access Journals (Sweden)

    Gitte Wooler

    2016-11-01

    Full Text Available TP53 is frequently mutated in different types of neoplasms including leukemia and lymphomas. Mutations of TP53 have also been reported in mycosis fungoides (MF, the most common type of cutaneous lymphoma. However, little is known about the frequency, spectrum of mutations and their prognostic significance in MF. In this study we have optimized the protocol for Sanger sequencing of TP53 using DNA extracted from archival paraffin-embedded biopsies. Of 19 samples from patients with stage IIB MF or higher, 31% harboured mutations in TP53. Overall survival of the patients with mutated TP53 was significantly shorter than median survival in the age- and stage-matched patients treated in our Institution. Distribution of mutations was heterogenous in TP53 exons, however C>T transitions were common suggesting the causal role of ultraviolet radiation. We propose that TP53 mutation status would be useful for risk stratification of patients with advanced MF.

  4. p53 and disease: when the guardian angel fails.

    Science.gov (United States)

    Royds, J A; Iacopetta, B

    2006-06-01

    The p53 tumor suppressor gene (TP53) is mutated more often in human cancers than any other gene yet reported. Of importance, it is mutated frequently in the common human malignancies of the breast and colorectum and also, but less frequently, in other significant human cancers such as glioblastomas. There is also one inherited cancer predisposing syndrome called Li-Fraumeni that is caused by TP53 mutations. In this review, we discuss the significance of p53 mutations in some of the above tumors with a view to outlining how p53 contributes to malignant progression. We also discuss the usefulness of TP53 status as a prognostic marker and its role as a predictor of response to therapy. Finally, we outline some evidence that abnormalities in p53 function contribute to the etiology of other non-neoplastic diseases.

  5. Vision after 53 Years of Blindness

    Directory of Open Access Journals (Sweden)

    Radovan Šikl

    2013-12-01

    Full Text Available Several studies have shown that visual recovery after blindness that occurs early in life is never complete. The current study investigated whether an extremely long period of blindness might also cause a permanent impairment of visual performance, even in a case of adult-onset blindness. We examined KP, a 71-year-old man who underwent a successful sight-restoring operation after 53 years of blindness. A set of psychophysical tests designed to assess KP's face perception, object recognition, and visual space perception abilities were conducted six months and eight months after the surgery. The results demonstrate that regardless of a lengthy period of normal vision and rich pre-accident perceptual experience, KP did not fully integrate this experience, and his visual performance remained greatly compromised. This was particularly evident when the tasks targeted finer levels of perceptual processing. In addition to the decreased robustness of his memory representations, which was hypothesized as the main factor determining visual impairment, other factors that may have affected KP's performance were considered, including compromised visual functions, problems with perceptual organization, deficits in the simultaneous processing of visual information, and reduced cognitive abilities.

  6. Vision after 53 years of blindness.

    Science.gov (United States)

    Sikl, Radovan; Simecček, Michal; Porubanová-Norquist, Michaela; Bezdíček, Ondřej; Kremláček, Jan; Stodůlka, Pavel; Fine, Ione; Ostrovsky, Yuri

    2013-01-01

    Several studies have shown that visual recovery after blindness that occurs early in life is never complete. The current study investigated whether an extremely long period of blindness might also cause a permanent impairment of visual performance, even in a case of adult-onset blindness. We examined KP, a 71-year-old man who underwent a successful sight-restoring operation after 53 years of blindness. A set of psychophysical tests designed to assess KP's face perception, object recognition, and visual space perception abilities were conducted six months and eight months after the surgery. The results demonstrate that regardless of a lengthy period of normal vision and rich pre-accident perceptual experience, KP did not fully integrate this experience, and his visual performance remained greatly compromised. This was particularly evident when the tasks targeted finer levels of perceptual processing. In addition to the decreased robustness of his memory representations, which was hypothesized as the main factor determining visual impairment, other factors that may have affected KP's performance were considered, including compromised visual functions, problems with perceptual organization, deficits in the simultaneous processing of visual information, and reduced cognitive abilities.

  7. Human neuroblastoma cells with acquired resistance to the p53 activator RITA retain functional p53 and sensitivity to other p53 activating agents

    NARCIS (Netherlands)

    Michaelis, M.; Rothweiler, F.; Agha, B.; Barth, S.; Voges, Y.; Loeschmann, N.; von Deimling, A.; Breitling, R.; Doerr, H. Wilhelm; Roedel, F.; Speidel, D.; Cinatl, J.; Cinatl Jr., J.; Stephanou, A.

    Adaptation of wild-type p53 expressing UKF-NB-3 cancer cells to the murine double minute 2 inhibitor nutlin-3 causes de novo p53 mutations at high frequency (13/20) and multi-drug resistance. Here, we show that the same cells respond very differently when adapted to RITA, a drug that, like nutlin-3,

  8. AHP 4: na53 mʑi53 Tibetan Songs, Engagement Chants, and Flute Music

    Directory of Open Access Journals (Sweden)

    LIBU LAKHI (LI JIANFU 李建富, DAWA TENZIN ཟླ་བ་བསྟན་འཛིན།

    2010-06-01

    Full Text Available The present study is a straightforward, pragmatic attempt to document the particulars of na53 mi53 song and musical traditions comprising the local 'performance-scape'. The primary researcher, Libu Lakhi, is a native of the community who was trained in a specialized mode of auto-ethnography developed by Charles Kevin Stuart and Gerald Roche at Qinghai Normal University 青海师范大学, Xining City 西宁市, Qinghai Province 青海省. Drawing on ethnomusicology, socio-linguistics, and the 'performance' school of folkloristics, the model is intended to enable local peoples to document and display their own traditions in a form available to scholars and interested persons on a global scale.

  9. A naturally occurring 4-bp deletion in the intron 4 of p53 creates a spectrum of novel p53 isoforms with anti-apoptosis function

    OpenAIRE

    Shi, Hui; Tao, Ting; Huang, Delai; Ou, Zhao; Chen, Jun; Peng, Jinrong

    2014-01-01

    p53 functions as a tumor suppressor by transcriptionally regulating the expression of genes involved in controlling cell proliferation or apoptosis. p53 and its isoform ?133p53/?113p53 form a negative regulation loop in that p53 activates the expression of ?133p53/?113p53 while ?133p53/?113p53 specifically antagonizes p53 apoptotic activity. This pathway is especially important to safeguard the process of embryogenesis because sudden activation of p53 by DNA damage signals or developmental st...

  10. Oncogenicity evaluation of resveratrol in p53(+/-) (p53 knockout) mice.

    Science.gov (United States)

    Horn, T L; Cwik, M J; Morrissey, R L; Kapetanovic, I; Crowell, J A; Booth, T D; McCormick, D L

    2007-01-01

    A six-month study was conducted in p53(+/-) mice to evaluate the possible oncogenicity of resveratrol (3,5,4'-trihydroxy-trans-stilbene), a cancer chemopreventive agent present in grapes and other foods. p53(+/-) mice (25/sex/group) received daily gavage exposure to vehicle only (negative control), resveratrol doses of 1000, 2000, or 4000 mg/kg/day, or p-cresidine (400 mg/kg/day; positive control). No mortality was seen in mice receiving the low dose of resveratrol. However, the mid and high doses induced mortality associated with impaction of the test article in the gastrointestinal tract. Resveratrol had no effect on body weight, food consumption, or clinical signs in surviving mice in any dose group, but induced dose-related increases in liver weight and serum cholesterol in both sexes. Mild anemia was seen in male mice at the high dose only; hematologic effects were not seen in females. Histopathology identified the kidney (hydronephrosis) and urinary bladder (epithelial hyperplasia) as target tissues for resveratrol toxicity. The incidences of both benign and malignant tumors in mice exposed to resveratrol were comparable to those in vehicle controls. By contrast, the positive control article, p-cresidine, induced urinary bladder cancer in both sexes. When administered to p53(+/-) mice at its maximum tolerated dose, resveratrol demonstrates no evidence of oncogenicity.

  11. Blocking of p53-Snail Binding, Promoted by Oncogenic K-Ras, Recovers p53 Expression and function

    Directory of Open Access Journals (Sweden)

    Sun-Hye Lee

    2009-01-01

    Full Text Available Differentially from other kinds of Ras, oncogenic K-Ras, which is mutated approximately 30% of human cancer, does not induce apoptosis and senescence. Here, we provide the evidence that oncogenic K-Ras abrogates p53 function and expression through induction of Ataxia telangiectasia-mutated and Rad3-related mediated Snail stabilization. Snail directly binds to DNA binding domain of p53 and diminishes the tumor-suppressive function of p53. Thus, elimination of Snail through si-RNA can induce p53 in K-Ras-mutated cells, whereas Snail and mutant K-Ras can suppress p53 in regardless of K-Ras status. Chemicals, isolated from inhibitor screening of p53-Snail binding, can block the Snail-mediated p53 suppression and enhance the expression of p53 as well as the transcriptional activity of p53 in an oncogenic K-Ras-dependent manner. Among the chemicals, two are very similar in structure. These results can answer why K-Ras can coexist with wild type p53 and propose the Snail-p53 binding as the new therapeutic target for K-Ras-mutated cancers including pancreatic, lung, and colon cancers.

  12. Family feud in chemosensitvity: p73 and mutant p53.

    Science.gov (United States)

    Irwin, Meredith S

    2004-03-01

    The importance of p53 in chemotherapy-induced apoptosis of cancer cells is well established. p53 plays a critical role in the cellular response to DNA damage by regulating genes involved in cell cycle progression, apoptosis, and genomic stability. As a result, p53 tumor status is a critical determinant of both responses to anti-cancer treatment and clinical prognosis. Interestingly, tumors expressing certain mutant forms of p53 ("gain of function") are particularly resistant to chemotherapy, even when compared to cells that lack any detectable p53. Until recently, the explanation for this enhanced chemoresistance was not clear. Recent studies have shown that the p53 homologues, p73 and p63, are also activated by chemotherapies, leading to tumor cell death. Now the discovery that mutant p53 interacts with p73, and that regulation of this interaction by a p53 polymorphism can modulate chemosensitvity provide a new model for how p53-family interactions can influence the response of tumors to anti-cancer therapies. Since p53 mutations are found in more than 50% of human tumors, strategies aimed at manipulating these interactions may prove useful in enhancing the chemotherapy response, and perhaps, overcoming chemoresistance.

  13. p53: key conductor of all anti-acne therapies.

    Science.gov (United States)

    Melnik, Bodo C

    2017-09-19

    This review based on translational research predicts that the transcription factor p53 is the key effector of all anti-acne therapies. All-trans retinoic acid (ATRA) and isotretinoin (13-cis retinoic acid) enhance p53 expression. Tetracyclines and macrolides via inhibiting p450 enzymes attenuate ATRA degradation, thereby increase p53. Benzoyl peroxide and hydrogen peroxide elicit oxidative stress, which upregulates p53. Azelaic acid leads to mitochondrial damage associated with increased release of reactive oxygen species inducing p53. p53 inhibits the expression of androgen receptor and IGF-1 receptor, and induces the expression of IGF binding protein 3. p53 induces FoxO1, FoxO3, p21 and sestrin 1, sestrin 2, and tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), the key inducer of isotretinoin-mediated sebocyte apoptosis explaining isotretinoin's sebum-suppressive effect. Anti-androgens attenuate the expression of miRNA-125b, a key negative regulator of p53. It can thus be concluded that all anti-acne therapies have a common mode of action, i.e., upregulation of the guardian of the genome p53. Immortalized p53-inactivated sebocyte cultures are unfortunate models for studying acne pathogenesis and treatment.

  14. p53 RNA interactions: new clues in an old mystery.

    Science.gov (United States)

    Riley, Kasandra J-L; Maher, L James

    2007-11-01

    The p53 tumor suppressor protein is typically considered to be a sequence-specific DNA-binding transcription factor. However, reports over the last 15 years have described RNA binding by p53 in a variety of contexts, suggesting the possibility of new p53 functions. It is clear that p53-RNA interactions are mediated by a nucleic acid-binding domain of p53 independent of the sequence-specific core domain responsible for DNA recognition. Reports disagree on several aspects of the putative RNA interaction, including sequence specificity and biological relevance. Here we review the history and recent advances in the study of p53-RNA interactions. We argue that p53-RNA interactions are sequence nonspecific and depend on incomplete post-translational modification of the p53 C-terminal domain when the protein is expressed in heterologous systems. It is unknown what fraction of p53 protein exists in a state competent for RNA binding in vivo. Thus, potential physiological roles of p53-RNA interactions remain mysterious.

  15. P53 family members modulate the expression of PRODH, but not PRODH2, via intronic p53 response elements.

    Directory of Open Access Journals (Sweden)

    Ivan Raimondi

    Full Text Available The tumor suppressor p53 was previously shown to markedly up-regulate the expression of the PRODH gene, encoding the proline dehydrogenase (PRODH enzyme, which catalyzes the first step in proline degradation. Also PRODH2, which degrades 4-hydroxy-L-proline, a product of protein (e.g. collagen catabolism, was recently described as a p53 target. Here, we confirmed p53-dependent induction of endogenous PRODH in response to genotoxic damage in cell lines of different histological origin. We established that over-expression of TAp73β or TAp63β is sufficient to induce PRODH expression in p53-null cells and that PRODH expression parallels the modulation of endogenous p73 by genotoxic drugs in several cell lines. The p53, p63, and p73-dependent transcriptional activation was linked to specific intronic response elements (REs, among those predicted by bioinformatics tools and experimentally validated by a yeast-based transactivation assay. p53 occupancy measurements were validated in HCT116 and MCF7 human cell lines. Conversely, PRODH2 was not responsive to p63 nor p73 and, at best, could be considered a weak p53 target. In fact, minimal levels of PRODH2 transcript induction by genotoxic stress was observed exclusively in one of four p53 wild-type cell lines tested. Consistently, all predicted p53 REs in PRODH2 were poor matches to the p53 RE consensus and showed very weak responsiveness, only to p53, in the functional assay. Taken together, our results highlight that PRODH, but not PRODH2, expression is under the control of p53 family members, specifically p53 and p73. This supports a deeper link between proteins of the p53-family and metabolic pathways, as PRODH modulates the balance of proline and glutamate levels and those of their derivative alpha-keto-glutarate (α-KG under normal and pathological (tumor conditions.

  16. p53 E3 ubiquitin protein ligase homolog regulates p53 in vivo in the adult mouse eye lens

    Science.gov (United States)

    Jaramillo-Rangel, Gilberto; Ortega-Martínez, Marta; Sepúlveda-Saavedra, Julio; Saucedo-Cárdenas, Odila; Montes-de-Oca-Luna, Roberto

    2013-01-01

    Purpose p53 is a transcription factor that plays an important role in preventing cancer development. p53 participates in relevant aspects of cell biology, including apoptosis and cell cycle control and must be strictly regulated to maintain normal tissue homeostasis. p53 E3 ubiquitin protein ligase homolog (Mdm2) is an important negative regulator of p53. The purpose of this study was to determine if Mdm2 regulates p53 in vivo in the adult lens. Methods We analyzed mice expressing human p53 transgene (Tgp53) selectively in the lens in the presence or absence of Mdm2. Mice with the required genotypes were obtained by crossing transgenic, mdm2+/−, and p53−/− mice. Eye phenotype and lens histology and ultrastructure were analyzed in adult mice. Results In a wild-type genetic background (mdm2+/+), lens damage and microphthalmia were observed only in mice homozygous for Tgp53 (t/t). However, in an mdm2 null background, just one allele of Tgp53 (mdm2−/−/Tgp53t/0 mice) was sufficient to cause lens damage and microphthalmia. Furthermore, Mdm2 in only one allele was sufficient to rescue these deleterious effects, since the mdm2+/−/Tgp53t/0 mice had eye size and lens morphology similar to the control mice. Conclusions Mdm2 regulates p53 in the adult lens in vivo. This information may have relevance for analyzing normal and pathological conditions of the lens, and designing cancer therapies targeting Mdm2–p53 interaction. PMID:24339722

  17. NAD+ Modulates p53 DNA Binding Specificity and Function

    Science.gov (United States)

    McLure, Kevin G.; Takagi, Masatoshi; Kastan, Michael B.

    2004-01-01

    DNA damage induces p53 DNA binding activity, which affects tumorigenesis, tumor responses to therapies, and the toxicities of cancer therapies (B. Vogelstein, D. Lane, and A. J. Levine, Nature 408:307-310, 2000; K. H. Vousden and X. Lu, Nat. Rev. Cancer 2:594-604, 2002). Both transcriptional and transcription-independent activities of p53 contribute to DNA damage-induced cell cycle arrest, apoptosis, and aneuploidy prevention (M. B. Kastan et al., Cell 71:587-597, 1992; K. H. Vousden and X. Lu, Nat. Rev. Cancer 2:594-604, 2002). Small-molecule manipulation of p53 DNA binding activity has been an elusive goal, but here we show that NAD+ binds to p53 tetramers, induces a conformational change, and modulates p53 DNA binding specificity in vitro. Niacinamide (vitamin B3) increases the rate of intracellular NAD+ synthesis, alters radiation-induced p53 DNA binding specificity, and modulates activation of a subset of p53 transcriptional targets. These effects are likely due to a direct effect of NAD+ on p53, as a molecule structurally related to part of NAD+, TDP, also inhibits p53 DNA binding, and the TDP precursor, thiamine (vitamin B1), inhibits intracellular p53 activity. Niacinamide and thiamine affect two p53-regulated cellular responses to ionizing radiation: rereplication and apoptosis. Thus, niacinamide and thiamine form a novel basis for the development of small molecules that affect p53 function in vivo, and these results suggest that changes in cellular energy metabolism may regulate p53. PMID:15509798

  18. Analysis of p53- immunoreactivity in astrocytic brain tumors

    Directory of Open Access Journals (Sweden)

    Shinkarenko T.V.

    2016-12-01

    Full Text Available P53 is an antioncogene with the frequently occured mutations in human tumor cells, leading to corresponding protein overexpression which can be detected by immunohistochemistry. Researches dedicated to the investigation of possibilities of using this technique gave controversial results. The authors investigated features of p53 protein expression in astrocytic brain tumors with different degrees of malignancy. Analyzed the relationship of the expression level of p53 by tumor cells with clinical parameters and Ki-67 proliferation index (PI as well. Tissues were collected from 52 cases with diagnosed astrocytic brain tumors. The sections were immunohistochemically stained with p53 and Ki-67. For each marker, 1000 tumor cells were counted and the ratio of positive tumor cells was calculated using software package ImageJ 1,47v. In normal brain tissue p53- expression was not identified. p53-immunoreactive tumor cells were detected in 25% (1/4 pilocytic astrocytomas, 33.3% (2/6 of diffuse astrocytomas, 53.8% (7/13 anaplastic astrocytomas, 58.6% (17/29 glioblastomas. A high proportion of p53-immunoreactive cells (> 30% was observed only in glioblastomas. The level of p53-imunoreactivity was not related to the age, gender and Grade WHO (p> 0,05. Spearman correlation coefficient between the relative quantity of ki-67- and p53-immunoreactive nuclei showed weak direct correlation (0.023, but the one was not statistically significant (p> 0,05. The level of p53-imunoreactivity is not dependent from age and sex of patients, Grade (WHO and proliferative activity (p>0,05 but the high level of p53-immunoreactive cells (>30% is found in glioblastoma specimens only, that may be due to the accumulation of mutations in DNA of tumor cells. There is insignificant weak relationship between relative quantities of ki-67- and p53-immunoreactive tumor cells (p>0,05.

  19. On p53 revival using system oriented drug dosage design.

    Science.gov (United States)

    Haseeb, Muhammad; Azam, Shumaila; Bhatti, A I; Azam, Rizwan; Ullah, Mukhtar; Fazal, Sahar

    2017-02-21

    We propose a new paradigm in the drug design for the revival of the p53 pathway in cancer cells. It is shown that the current strategy of using small molecule based Mdm2 inhibitors is not enough to adequately revive p53 in cancerous cells, especially when it comes to the extracting pulsating behavior of p53. This fact has come to notice when a novel method for the drug dosage design is introduced using system oriented concepts. As a test case, small molecule drug Mdm2 repressor Nutlin 3a is considered. The proposed method determines the dose of Nutlin to revive p53 pathway functionality. For this purpose, PBK dynamics of Nutlin have also been integrated with p53 pathway model. The p53 pathway is the focus of researchers for the last thirty years for its pivotal role as a frontline cancer suppressant protein due to its effect on cell cycle checkpoints and cell apoptosis in response to a DNA strand break. That is the reason for finding p53 being absent in more than 50% of tumor cancers. Various drugs have been proposed to revive p53 in cancer cells. Small molecule based drugs are at the foremost and are the subject of advanced clinical trials. The dosage design of these drugs is an important issue. We use control systems concepts to develop the drug dosage so that the cancer cells can be treated in appropriate time. We investigate by using a computational model how p53 protein responds to drug Nutlin 3a, an agent that interferes with the MDM2-mediated p53 regulation. The proposed integrated model describes in some detail the regulation network of p53 including the negative feedback loop mediated by MDM2 and the positive feedback loop mediated by Mdm2 mRNA as well as the reversible represses of MDM2 caused by Nutlin. The reported PBK dynamics of Nutlin 3a are also incorporated to see the full effect. It has been reported that p53 response to stresses in two ways. Either it has a sustained (constant) p53 response, or there are oscillations in p53 concentration. The

  20. p53: an overview of over two decades of study.

    Science.gov (United States)

    Cheah, P L; Looi, L M

    2001-06-01

    p53 is the most commonly mutated gene in human cancers. It encodes a 53 kilodalton protein with several evolutionarily conserved domains viz sequence-specific DNA binding, tetramerisation, SH3 molecule binding, C-terminal and N-terminal. Existing in the cell at a very low level and in a relatively inactive form, p53 protein is increased and activated during periods of cellular stress. Unlike other proteins, the increase in protein level and its activation result from modification of the protein rather than genetic transcriptional or translational upregulation. Normally, Mdm2 protein interacts with p53 protein and effectively targets it for ubiquitin proteolysis within an autoregulatory feedback loop. Phosphorylation at the N-terminus reduces p53 interaction with Mdm2 with a resultant increase in p53 protein level. Modification at the C and N termini via phosphorylation or acetylation upregulates binding to specific DNA targets increasing transcription of these downstream genes. The net effect of p53 protein increase and activation lies in arrest of the cell in cycle which allows time for repair of the incurred damage or apoptosis or death of the cell. Failure of these normal protective and adaptive mechanisms caused by mutation of the p53 gene with product of an abnormal protein, loss of p53 protein through interaction with and degradation by HPV E6 protein or overexpressed Mdm2 etc. permits DNA-damaged cells to continue replicating. Left unchecked, this frequently contributes to tumourigenesis. Various methods have been devised to screen for mutations of the p53 gene, still the most common source of failed p53 mechanism. These include immunohistochemical detection of mutated proteins or identification of altered electrophoretic mobility of mutated p53 sequences. Sequencing of the gene nonetheless remains the most accurate method for determination of mutation. Major advances have been made in p53 research but the most meaningful probably lies in the promising

  1. Senescence and aging: the critical roles of p53.

    Science.gov (United States)

    Rufini, A; Tucci, P; Celardo, I; Melino, G

    2013-10-24

    p53 functions as a transcription factor involved in cell-cycle control, DNA repair, apoptosis and cellular stress responses. However, besides inducing cell growth arrest and apoptosis, p53 activation also modulates cellular senescence and organismal aging. Senescence is an irreversible cell-cycle arrest that has a crucial role both in aging and as a robust physiological antitumor response, which counteracts oncogenic insults. Therefore, via the regulation of senescence, p53 contributes to tumor growth suppression, in a manner strictly dependent by its expression and cellular context. In this review, we focus on the recent advances on the contribution of p53 to cellular senescence and its implication for cancer therapy, and we will discuss p53's impact on animal lifespan. Moreover, we describe p53-mediated regulation of several physiological pathways that could mediate its role in both senescence and aging.

  2. "Super p53" mice display retinal astroglial changes.

    Directory of Open Access Journals (Sweden)

    Juan J Salazar

    Full Text Available Tumour-suppressor genes, such as the p53 gene, produce proteins that inhibit cell division under adverse conditions, as in the case of DNA damage, radiation, hypoxia, or oxidative stress (OS. The p53 gene can arrest proliferation and trigger death by apoptosis subsequent to several factors. In astrocytes, p53 promotes cell-cycle arrest and is involved in oxidative stress-mediated astrocyte cell death. Increasingly, astrocytic p53 is proving fundamental in orchestrating neurodegenerative disease pathogenesis. In terms of ocular disease, p53 may play a role in hypoxia due to ischaemia and may be involved in the retinal response to oxidative stress (OS. We studied the influence of the p53 gene in the structural and quantitative characteristics of astrocytes in the retina. Adult mice of the C57BL/6 strain (12 months old were distributed into two groups: 1 mice with two extra copies of p53 ("super p53"; n = 6 and 2 wild-type p53 age-matched control, as the control group (WT; n = 6. Retinas from each group were immunohistochemically processed to locate the glial fibrillary acidic protein (GFAP. GFAP+ astrocytes were manually counted and the mean area occupied for one astrocyte was quantified. Retinal-astrocyte distribution followed established patterns; however, morphological changes were seen through the retinas in relation to p53 availability. The mean GFAP+ area occupied by one astrocyte in "super p53" eyes was significantly higher (p<0.05; Student's t-test than in the WT. In addition, astroglial density was significantly higher in the "super p53" retinas than in the WT ones, both in the whole-retina (p<0,01 Student's t-test and in the intermediate and peripheral concentric areas of the retina (p<0.05 Student's t-test. This fact might improve the resistance of the retinal cells against OS and its downstream signalling pathways.

  3. TRIM65 negatively regulates p53 through ubiquitination

    Energy Technology Data Exchange (ETDEWEB)

    Li, Yang [Department of Respiration, The First Hospital of Jilin University, Changchun 130021 (China); Ma, Chengyuan [Department of Neurosurgery, The First Hospital of Jilin University, Changchun 130021 (China); Zhou, Tong [Department of Endocrinology, The First Hospital of Jilin University, Changchun 130021 (China); Liu, Ying [Department of Respiration, The First Hospital of Jilin University, Changchun 130021 (China); Sun, Luyao [Department of Infectious Diseases, The First Hospital of Jilin University, Changchun 130021 (China); Yu, Zhenxiang, E-mail: zhenxiangyu2015@gmail.com [Department of Respiration, The First Hospital of Jilin University, Changchun 130021 (China)

    2016-04-22

    Tripartite-motif protein family member 65 (TRIM65) is an important protein involved in white matter lesion. However, the role of TRIM65 in human cancer remains less understood. Through the Cancer Genome Atlas (TCGA) gene alteration database, we found that TRIM65 is upregulated in a significant portion of non-small cell lung carcinoma (NSCLC) patients. Our cell growth assay revealed that TRIM65 overexpression promotes cell proliferation, while knockdown of TRIM65 displays opposite effect. Mechanistically, TRIM65 binds to p53, one of the most critical tumor suppressors, and serves as an E3 ligase toward p53. Consequently, TRIM65 inactivates p53 through facilitating p53 poly-ubiquitination and proteasome-mediated degradation. Notably, chemotherapeutic reagent cisplatin induction of p53 is markedly attenuated in response to ectopic expression of TRIM65. Cell growth inhibition by TRIM65 knockdown is more significant in p53 positive H460 than p53 negative H1299 cells, and knockdown of p53 in H460 cells also shows compromised cell growth inhibition by TRIM65 knockdown, indicating that p53 is required, at least in part, for TRIM65 function. Our findings demonstrate TRIM65 as a potential oncogenic protein, highly likely through p53 inactivation, and provide insight into development of novel approaches targeting TRIM65 for NSCLC treatment, and also overcoming chemotherapy resistance. - Highlights: • TRIM65 expression is elevated in NSCLC. • TRIM65 inactivates p53 through mediating p53 ubiquitination and degradation. • TRIM65 attenuates the response of NSCLC cells to cisplatin.

  4. TP53 Mutation and Its Prognostic Significance in Waldenstrom's Macroglobulinemia.

    Science.gov (United States)

    Poulain, Stéphanie; Roumier, Christophe; Bertrand, Elisabeth; Renneville, Aline; Caillault-Venet, Aurélie; Doye, Emmanuelle; Geffroy, Sandrine; Sebda, Sheherazade; Nibourel, Olivier; Nudel, Morgane; Herbaux, Charles; Renaud, Loic; Tomowiak, Cécile; Guidez, Stéphanie; Tricot, Sabine; Roche-Lestienne, Catherine; Quesnel, Bruno; Preudhomme, Claude; Leleu, Xavier

    2017-10-15

    Purpose:TP53 is a tumor-suppressor gene that functions as a regulator influencing cellular responses to DNA damage, and TP53 alterations are associated with pejorative outcome in most B-lymphoid disorders. Little is known regarding TP53 alteration in Waldenstrom's macroglobulinemia (WM).Experimental Design: Here, we have explored the incidence of TP53 alteration using Sanger sequencing and ultradeep-targeted sequencing in 125 WM and 10 immunoglobulin M (IgM) monoclonal gammopathy of undetermined significance (MGUS), along with the clinical features and the associated genomic landscape using single-nucleotide polymorphism array and mutational landscape in an integrative study.Results: Overall, we have identified alteration of TP53 locus including mutation, deletion, and copy-neutral LOH in 11.2% of WM. TP53 mutation was acquired in 7.3% of patients with WM at diagnosis, being absent in IgM MGUS, and was highly correlated to deletion 17p. No correlation with CXCR4 mutations was observed. Patients with TP53 alteration had a greater number of genomic abnormalities. Importantly, WM with TP53 alteration had a significantly shorter overall survival, particularly in symptomatic WM, and independently of the international prognostic scoring system for Waldenstrom macroglobulinemia (IPSSWM) score. Specific treatment for WM with TP53 may have to be studied. Nutlin-3a-targeted p53 signaling induced cytotoxicity preclinically, along with new compounds such as ibrutinib, PrimaMet, or CP31398 that bypass p53 pathway in WM, paving the path for future treatment-tailored options.Conclusions: Our results highlight the clinical significance of detection of TP53 alteration in WM to determine the prognosis of WM and guide the treatment choice. Clin Cancer Res; 23(20); 6325-35. ©2017 AACR. ©2017 American Association for Cancer Research.

  5. Wild-type alternatively spliced p53: binding to DNA and interaction with the major p53 protein in vitro and in cells.

    OpenAIRE

    Wu, Y.; Liu, Y; L. Lee; Miner, Z; Kulesz-Martin, M

    1994-01-01

    A p53 variant protein (p53as) generated from alternatively spliced p53 RNA is expressed in normal and malignant mouse cells and tissues, and p53as antigen activity is preferentially associated with the G2 phase of the cell cycle, suggesting that p53as and p53 protein may have distinct properties. Using p53as and p53 proteins translated in vitro, we now provide evidence that p53as protein has efficient sequence-specific DNA-binding ability. DNA binding by p53 protein is inefficient in comparis...

  6. Battle Against Cancer: An Everlasting Saga of p53

    Directory of Open Access Journals (Sweden)

    Qian Hao

    2014-12-01

    Full Text Available Cancer is one of the most life-threatening diseases characterized by uncontrolled growth and spread of malignant cells. The tumor suppressor p53 is the master regulator of tumor cell growth and proliferation. In response to various stress signals, p53 can be activated and transcriptionally induces a myriad of target genes, including both protein-encoding and non-coding genes, controlling cell cycle progression, DNA repair, senescence, apoptosis, autophagy and metabolism of tumor cells. However, around 50% of human cancers harbor mutant p53 and, in the majority of the remaining cancers, p53 is inactivated through multiple mechanisms. Herein, we review the recent progress in understanding the molecular basis of p53 signaling, particularly the newly identified ribosomal stress—p53 pathway, and the development of chemotherapeutics via activating wild-type p53 or restoring mutant p53 functions in cancer. A full understanding of p53 regulation will aid the development of effective cancer treatments.

  7. Evolution of the p53-MDM2 pathway.

    Science.gov (United States)

    Åberg, Emma; Saccoccia, Fulvio; Grabherr, Manfred; Ore, Wai Ying Josefin; Jemth, Per; Hultqvist, Greta

    2017-08-03

    The p53 signalling pathway, which controls cell fate, has been extensively studied due to its prominent role in tumor development. The pathway includes the tumor supressor protein p53, its vertebrate paralogs p63 and p73, and their negative regulators MDM2 and MDM4. The p53/p63/p73-MDM system is ancient and can be traced in all extant animal phyla. Despite this, correct phylogenetic trees including both vertebrate and invertebrate species of the p53/p63/p73 and MDM families have not been published. Here, we have examined the evolution of the p53/p63/p73 protein family with particular focus on the p53/p63/p73 transactivation domain (TAD) and its co-evolution with the p53/p63/p73-binding domain (p53/p63/p73BD) of MDM2. We found that the TAD and p53/p63/p73BD share a strong evolutionary connection. If one of the domains of the protein is lost in a phylum, then it seems very likely to be followed by loss of function by the other domain as well, and due to the loss of function it is likely to eventually disappear. By focusing our phylogenetic analysis to p53/p63/p73 and MDM proteins from phyla that retain the interaction domains TAD and p53/p63/p73BD, we built phylogenetic trees of p53/p63/p73 and MDM based on both vertebrate and invertebrate species. The trees follow species evolution and contain a total number of 183 and 98 species for p53/p63/p73 and MDM, respectively. We also demonstrate that the p53/p63/p73 and MDM families result from whole genome duplications. The signaling pathway of the TAD and p53/p63/p73BD in p53/p63/p73 and MDM, respectively, dates back to early metazoan time and has since then tightly co-evolved, or disappeared in distinct lineages.

  8. Super p53 for Treatment of Ovarian Cancer

    Science.gov (United States)

    2017-09-01

    AWARD NUMBER: W81XWH-15-1-0036 TITLE: Super p53 for Treatment of Ovarian Cancer PRINCIPAL INVESTIGATOR: Carol S. Lim University of Utah...Super p53 for Treatment of Ovarian Cancer 5b. GRANT NUMBER W81XWH-15-1-0036 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER Carol S. Lim...ABSTRACT In this final report, we show gene therapy using re-engineered super p53 (p53-CC constructs) kills some ovarian cancer cell lines in vitro

  9. NQO1 stabilizes p53 through a distinct pathway

    OpenAIRE

    Asher, Gad; Lotem, Joseph; Kama, Rachel; Sachs, Leo; Shaul, Yosef

    2002-01-01

    Wild-type p53 is a tumor-suppressor gene that encodes a short-lived protein that, upon accumulation, induces growth arrest or apoptosis. Accumulation of p53 occurs mainly by posttranslational events that inhibit its proteosomal degradation. We have reported previously that inhibition of NAD(P)H: quinone oxidoreductase 1 (NQO1) activity by dicoumarol induces degradation of p53, indicating that NQO1 plays a role in p53 stabilization. We now have found that wild-type NQO1, but not the inactive p...

  10. Tobacco, alcohol, and p53 overexpression in early colorectal neoplasia

    Directory of Open Access Journals (Sweden)

    Mansukhani Mahesh

    2003-11-01

    Full Text Available Abstract Background The p53 tumor suppressor gene is commonly mutated in colorectal cancer. While the effect of p53 mutations on colorectal cancer prognosis has been heavily studied, less is known about how epidemiologic risk factors relate to p53 status, particularly in early colorectal neoplasia prior to clinically invasive colorectal cancer (including adenomas, carcinoma in situ (CIS, and intramucosal carcinoma. Methods We examined p53 status, as measured by protein overexpression, in 157 cases with early colorectal neoplasia selected from three New York City colonoscopy clinics. After collecting paraffin-embedded tissue blocks, immunohistochemistry was performed using an anti-p53 monoclonal mouse IgG2a [BP53-12-1] antibody. We analyzed whether p53 status was different for risk factors for colorectal neoplasia relative to a polyp-free control group (n = 508. Results p53 overexpression was found in 10.3%, 21.7%, and 34.9%, of adenomatous polyps, CIS, and intramucosal cases, respectively. Over 90% of the tumors with p53 overexpression were located in the distal colon and rectum. Heavy cigarette smoking (30+ years was associated with cases not overexpressing p53 (OR = 1.8, 95% CI = 1.1–2.9 but not with those cases overexpressing p53 (OR = 1.0, 95% CI = 0.4–2.6. Heavy beer consumption (8+ bottles per week was associated with cases overexpressing p53 (OR = 4.0, 95% CI = 1.3–12.0 but not with cases without p53 overexpression (OR = 1.6, 95% CI = 0.7–3.7. Conclusion Our findings that p53 overexpression in early colorectal neoplasia may be positively associated with alcohol intake and inversely associated with cigarette smoking are consistent with those of several studies of p53 expression and invasive cancer, and suggest that there may be relationships of smoking and alcohol with p53 early in the adenoma to carcinoma sequence.

  11. Expression of Androgen Receptor Is Negatively Regulated By p53

    OpenAIRE

    Fatouma Alimirah; Ravichandran Panchanathan; Jianming Chen; Xiang Zhang; Shuk-Mei Ho; Divaker Choubey

    2007-01-01

    Increased expression of androgen receptor (AR) in prostate cancer (PC) is associated with transition to androgen independence. Because the progression of PC to advanced stages is often associated with the loss of p53 function, we tested whether the p53 could regulate the expression of AR gene. Here we report that p53 negatively regulates the expression of AR in prostate epithelial cells (PrECs). We found that in LNCaP human prostate cancer cells that express the wild-type p53 and AR and in hu...

  12. Rbm24, a target of p53, is necessary for proper expression of p53 and heart development.

    Science.gov (United States)

    Zhang, Min; Zhang, Yanhong; Xu, Enshun; Mohibi, Shakur; de Anda, Danielle Michelle; Jiang, Yuqian; Zhang, Jin; Chen, Xinbin

    2018-01-22

    Activation of p53-dependent apoptosis is critical for tumor suppression but aberrant activation of p53 also leads to developmental defects and heart failure. Here, we found that Rbm24 RNA-binding protein, a target of p53, regulates p53 mRNA translation. Mechanistically, we found that through binding to p53 mRNA and interaction with translation initiation factor eIF4E, Rbm24 prevents eIF4E from binding to p53 mRNA and inhibits the assembly of translation initiation complex. Importantly, we showed that mice deficient in Rbm24 die in utero due to the endocardial cushion defect in the heart at least in part due to aberrant activation of p53-dependent apoptosis. We also showed that the heart developmental defect in Rbm24-null mice can be partially rescued by p53 deficiency through decreased apoptosis in the heart. Together, we postulate that the p53-Rbm24 loop is critical for the heart development and may be explored for mitigating congenital heart diseases and heart failure.

  13. Restoration of p53 using the novel MDM2-p53 antagonist APG115 suppresses dedifferentiated papillary thyroid cancer cells.

    Science.gov (United States)

    Chen, Haibo; Luo, Dingyuan; Zhang, Lin; Lin, Xiaofeng; Luo, Qiuyun; Yi, Hanjie; Wang, Jing; Yan, Xianglei; Li, Baoxia; Chen, Yuelei; Liu, Xingguang; Zhang, Hong; Liu, Sheng; Qiu, Miaozhen; Yang, Dajun; Jiang, Ningyi

    2017-06-27

    Dedifferentiated papillary thyroid cancer (DePTC) is characterized by aggressive growth, recurrence, distant metastasis, and resistance to radioactive iodine (RAI) therapy. DePTC is also accompanied by poor prognosis and high early-mortality. Nevertheless, most DePTC cells show intact p53 downstream functionality. In cells with wild-type p53, the murine double minute2 (MDM2) protein interacts with p53 and abrogates its activity. Inhibition of the MDM2-p53 interaction restores p53 activity and leads to cell cycle arrest and apoptosis. Restoring p53 function by inhibiting its interaction with p53 suppressors such as MDM2 is thus a promising therapeutic strategy for the treatment of DePTC. The novel MDM2-p53 interaction antagonist APG115 is an analogue of SAR405838, and is being tested in a phase I clinical trial. In this study, we evaluated the efficacy of APG115 as a single-agent to treat DePTC. APG115 diminished the viability of p53 wild-type DePTC cells and induced cell cycle arrest and apoptosis. In a human xenograft mouse model, APG115 elicited robust tumor regression and cell apoptosis. These data demonstrate that further research is warranted to determine whether APG115 can be used to effectively treat DePTC patients.

  14. 27 CFR 53.11 - Meaning of terms.

    Science.gov (United States)

    2010-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 2 2010-04-01 2010-04-01 false Meaning of terms. 53.11 Section 53.11 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE BUREAU, DEPARTMENT OF THE TREASURY (CONTINUED) FIREARMS MANUFACTURERS EXCISE TAXES-FIREARMS AND AMMUNITION Definitions...

  15. 41 CFR 105-53.147 - Public Buildings Service.

    Science.gov (United States)

    2010-07-01

    ... space is used more effectively and efficiently; providing leadership in the development and maintenance... 41 Public Contracts and Property Management 3 2010-07-01 2010-07-01 false Public Buildings Service. 105-53.147 Section 105-53.147 Public Contracts and Property Management Federal Property Management...

  16. 12 CFR 5.53 - Change in asset composition.

    Science.gov (United States)

    2010-01-01

    ... 12 Banks and Banking 1 2010-01-01 2010-01-01 false Change in asset composition. 5.53 Section 5.53... composition. (a) Authority. 12 U.S.C. 93a, 1818. (b) Scope. This section requires a national bank to obtain the approval of the OCC before changing the composition of all, or substantially all, of its assets...

  17. 53BP1 sensitizes breast cancer cells to 5-fluorouracil.

    Directory of Open Access Journals (Sweden)

    Xiaoyan Li

    Full Text Available Chemoresistance of breast cancer is a worldwide problem for breast cancer and the resistance to chemotherapeutic agents frequently led to the subsequent recurrence and metastasis. In our previous study, we have found that 53BP1 showed a gradual decrease during the progression of breast cancer and loss of 53BP1 was associated with metastasis and poor prognosis in breast cancer. Here we aimed to reveal whether 53BP1 could sensitize breast cancer to 5-Fu. We found that ectopic expression of 53BP1 can significantly sensitize breast cancer cells to 5-Fu while knockdown of 53BP1 conferred the resistance. The in vivo experiments confirmed that overexpression of 53BP1 in combination with 5-Fu markedly inhibited growth of xenotransplanted tumors in nude mice when compared to either agent alone. Furthermore, we demonstrated that 53BP1 regulated the sensitivity to 5-Fu through thymidylate synthase (TS and dihydropyrimidine dehydrogenase (DPYD. The present studies provide a new clue that combination of 5-Fu and 53BP1 could be a potential novel targeted strategy for overcoming breast cancer chemoresistance.

  18. 30 CFR 203.53 - What relief will MMS grant?

    Science.gov (United States)

    2010-07-01

    ... 30 Mineral Resources 2 2010-07-01 2010-07-01 false What relief will MMS grant? 203.53 Section 203...-Life Leases § 203.53 What relief will MMS grant? (a) If we approve your application and you meet certain conditions, we will reduce the pre-application effective royalty rate by one-half on production up...

  19. 9 CFR 53.6 - Disinfection of animals.

    Science.gov (United States)

    2010-01-01

    ... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Disinfection of animals. 53.6 Section 53.6 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF... of animals. Animals of species not susceptible to the disease for which a quarantine has been...

  20. 9 CFR 53.9 - Mortgage against animals or materials.

    Science.gov (United States)

    2010-01-01

    ... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Mortgage against animals or materials. 53.9 Section 53.9 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT....9 Mortgage against animals or materials. When animals or materials have been destroyed pursuant to...

  1. 9 CFR 53.3 - Appraisal of animals or materials.

    Science.gov (United States)

    2010-01-01

    ... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Appraisal of animals or materials. 53.3 Section 53.3 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF... animals or materials. (a) Animals affected by or exposed to disease, and materials required to be...

  2. The 52Cr(p, γ)53Mn reaction

    NARCIS (Netherlands)

    Vuister, P.H.

    The 52Cr(p, γ)53Mn reaction was investigated in the energy region Ep = 1.36–2.26 MeV. The resonance energies, the corresponding 53Mn excitation energies and the resonance strengths of 199 resonances, assigned to this reaction, are reported. The excitation energies and gamma-ray branchings of 13

  3. 27 CFR 53.175 - Readjustment for local advertising charges.

    Science.gov (United States)

    2010-04-01

    ... television station, or appears in a newspaper or magazine, or is displayed by means of an outdoor advertising... advertising charges. 53.175 Section 53.175 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND... Readjustment for local advertising charges. (a) In general. If a manufacturer has paid the tax imposed by...

  4. 27 CFR 53.186 - Accounting procedures for like articles.

    Science.gov (United States)

    2010-04-01

    ... like articles. 53.186 Section 53.186 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND... Accounting procedures for like articles. (a) Identification of manufacturer. In applying section 6416 of the Code and the regulations thereunder, a person who has purchased like articles from various...

  5. TP53 gene polymorphism: Importance to cancer, ethnicity and birth ...

    Indian Academy of Sciences (India)

    weight has been associated to obesity in adulthood, which can have consequences to health problems (Leong et al. 2003). So, considering the role of p53 in embryonic development and the value of birth weight to human development, analysis of a SNP in p53 gene and its role in birth weight is of importance. A very recent ...

  6. 7 CFR 58.53 - Supervisor of packaging required.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 3 2010-01-01 2010-01-01 false Supervisor of packaging required. 58.53 Section 58.53 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Standards, Inspections, Marketing Practices), DEPARTMENT OF AGRICULTURE (CONTINUED) REGULATIONS AND STANDARDS UNDER THE...

  7. 9 CFR 53.4 - Destruction of animals.

    Science.gov (United States)

    2010-01-01

    ... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Destruction of animals. 53.4 Section 53.4 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF... animals. (a) Except as provided in paragraph (b) of this section, animals infected with or exposed to...

  8. 16 CFR 802.53 - Certain foreign banking transactions.

    Science.gov (United States)

    2010-01-01

    ... 16 Commercial Practices 1 2010-01-01 2010-01-01 false Certain foreign banking transactions. 802.53 Section 802.53 Commercial Practices FEDERAL TRADE COMMISSION RULES, REGULATIONS, STATEMENTS AND... foreign banking transactions. An acquisition which requires the consent or approval of the Board of...

  9. TP53 codon 72 polymorphism in pigmentary phenotypes

    Indian Academy of Sciences (India)

    In our population, p53 genotypes were in Hardy–Weinberg (HW) equilibrium ( χ HM 2 < 3.84), showing a predominance of arginine allele (total Arg allele frequency of 68%). No significant association between p53 genotype and skin colour, hair or eye colour and susceptibility to sun exposure was found. However, further ...

  10. Overexpression of p53 in Nigerian breast cancers and its ...

    African Journals Online (AJOL)

    Background: Mutation of the tumour suppressor gene, p53, is implicated in most cancers. This gene has also been associated with high tumour grade in breast cancers. African women are known to generally have high grade tumours. This study sought to determine the expression of p53 protein as well as the relationship ...

  11. 47 CFR 17.53 - Lighting equipment and paint.

    Science.gov (United States)

    2010-10-01

    ... 47 Telecommunication 1 2010-10-01 2010-10-01 false Lighting equipment and paint. 17.53 Section 17.53 Telecommunication FEDERAL COMMUNICATIONS COMMISSION GENERAL CONSTRUCTION, MARKING, AND LIGHTING OF... Lighting equipment and paint. The lighting equipment, color or filters, and shade of paint referred to in...

  12. 34 CFR 104.53 - Drug and alcohol addicts.

    Science.gov (United States)

    2010-07-01

    ... 34 Education 1 2010-07-01 2010-07-01 false Drug and alcohol addicts. 104.53 Section 104.53 Education Regulations of the Offices of the Department of Education OFFICE FOR CIVIL RIGHTS, DEPARTMENT OF EDUCATION NONDISCRIMINATION ON THE BASIS OF HANDICAP IN PROGRAMS OR ACTIVITIES RECEIVING FEDERAL FINANCIAL...

  13. 27 CFR 53.61 - Imposition and rates of tax.

    Science.gov (United States)

    2010-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 2 2010-04-01 2010-04-01 false Imposition and rates of tax. 53.61 Section 53.61 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE... component parts for firearms are includible in the price for which the article is sold. (3) Nontaxable parts...

  14. 27 CFR 53.115 - Computation of tax.

    Science.gov (United States)

    2010-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 2 2010-04-01 2010-04-01 false Computation of tax. 53.115 Section 53.115 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE BUREAU, DEPARTMENT... Computation of tax. (a) Tax based on price. Tax liability incurred on the use of an article shall be computed...

  15. 7 CFR 53.14 - Financial interest of official grader.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 3 2010-01-01 2010-01-01 false Financial interest of official grader. 53.14 Section... AND STANDARDS UNDER THE AGRICULTURAL MARKETING ACT OF 1946 AND THE EGG PRODUCTS INSPECTION ACT (CONTINUED) LIVESTOCK (GRADING, CERTIFICATION, AND STANDARDS) Regulations Service § 53.14 Financial interest...

  16. 7 CFR 1219.53 - Budget and expenses.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 10 2010-01-01 2010-01-01 false Budget and expenses. 1219.53 Section 1219.53 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS AND ORDERS; MISCELLANEOUS COMMODITIES), DEPARTMENT OF AGRICULTURE HASS AVOCADO PROMOTION, RESEARCH...

  17. 19 CFR 145.53 - Firearms and munitions of war.

    Science.gov (United States)

    2010-04-01

    ... 19 Customs Duties 2 2010-04-01 2010-04-01 false Firearms and munitions of war. 145.53 Section 145.53 Customs Duties U.S. CUSTOMS AND BORDER PROTECTION, DEPARTMENT OF HOMELAND SECURITY; DEPARTMENT OF... munitions of war. Importations of firearms, munitions of war, and related articles are subject to the import...

  18. 12 CFR 229.53 - Substitute check indemnity.

    Science.gov (United States)

    2010-01-01

    ... 12 Banks and Banking 3 2010-01-01 2010-01-01 false Substitute check indemnity. 229.53 Section 229... SYSTEM AVAILABILITY OF FUNDS AND COLLECTION OF CHECKS (REGULATION CC) Substitute Checks § 229.53 Substitute check indemnity. (a) Scope of indemnity. A bank that transfers, presents, or returns a substitute...

  19. 46 CFR 356.53 - Conflicts with international agreements.

    Science.gov (United States)

    2010-10-01

    ... 46 Shipping 8 2010-10-01 2010-10-01 false Conflicts with international agreements. 356.53 Section... DOCUMENTATION International Agreements § 356.53 Conflicts with international agreements. (a) If the owner or... that it is determined that an international agreement covering the petitioner is in conflict with the...

  20. 27 CFR 7.53 - Legibility of mandatory information.

    Science.gov (United States)

    2010-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 1 2010-04-01 2010-04-01 false Legibility of mandatory information. 7.53 Section 7.53 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE BUREAU... information shall be so stated in both the print and audiovisual media that it will be readily apparent to the...

  1. Plk1-mediated phosphorylation of Topors regulates p53 stability.

    Science.gov (United States)

    Yang, Xiaoming; Li, Hongchang; Zhou, Zinan; Wang, Wen-Horng; Deng, Anping; Andrisani, Ourania; Liu, Xiaoqi

    2009-07-10

    Polo-like kinase 1 (Plk1) overexpression is associated with tumorigenesis by an unknown mechanism. Likewise, Plk1 was suggested to act as a negative regulator of tumor suppressor p53, but the mechanism remains to be determined. Herein, we have identified topoisomerase I-binding protein (Topors), a p53-binding protein, as a Plk1 target. We show that Plk1 phosphorylates Topors on Ser(718) in vivo. Significantly, expression of a Plk1-unphosphorylatable Topors mutant (S718A) leads to a dramatic accumulation of p53 through inhibition of p53 degradation. Topors is an ubiquitin and small ubiquitin-like modifier ubiquitin-protein isopeptide ligase (SUMO E3) ligase. Plk1-mediated phosphorylation of Topors inhibits Topors-mediated sumoylation of p53, whereas p53 ubiquitination is enhanced, leading to p53 degradation. These results demonstrate that Plk1 modulates Topors activity in suppressing p53 function and identify a likely mechanism for the tumorigenic potential of Plk1.

  2. Plk1-mediated Phosphorylation of Topors Regulates p53 Stability*

    Science.gov (United States)

    Yang, Xiaoming; Li, Hongchang; Zhou, Zinan; Wang, Wen-Horng; Deng, Anping; Andrisani, Ourania; Liu, Xiaoqi

    2009-01-01

    Polo-like kinase 1 (Plk1) overexpression is associated with tumorigenesis by an unknown mechanism. Likewise, Plk1 was suggested to act as a negative regulator of tumor suppressor p53, but the mechanism remains to be determined. Herein, we have identified topoisomerase I-binding protein (Topors), a p53-binding protein, as a Plk1 target. We show that Plk1 phosphorylates Topors on Ser718 in vivo. Significantly, expression of a Plk1-unphosphorylatable Topors mutant (S718A) leads to a dramatic accumulation of p53 through inhibition of p53 degradation. Topors is an ubiquitin and small ubiquitin-like modifier ubiquitin-protein isopeptide ligase (SUMO E3) ligase. Plk1-mediated phosphorylation of Topors inhibits Topors-mediated sumoylation of p53, whereas p53 ubiquitination is enhanced, leading to p53 degradation. These results demonstrate that Plk1 modulates Topors activity in suppressing p53 function and identify a likely mechanism for the tumorigenic potential of Plk1. PMID:19473992

  3. 40 CFR 53.66 - Test procedure: Volatility test.

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 5 2010-07-01 2010-07-01 false Test procedure: Volatility test. 53.66... Characteristics of Class II Equivalent Methods for PM2.5 § 53.66 Test procedure: Volatility test. (a) Overview. This test is designed to ensure that the candidate method's losses due to volatility when sampling semi...

  4. 40 CFR 53.65 - Test procedure: Loading test.

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 5 2010-07-01 2010-07-01 false Test procedure: Loading test. 53.65... Characteristics of Class II Equivalent Methods for PM2.5 § 53.65 Test procedure: Loading test. (a) Overview. (1) The loading tests are designed to quantify any appreciable changes in a candidate method sampler's...

  5. 46 CFR 188.10-53 - Oceanographic research vessel.

    Science.gov (United States)

    2010-10-01

    ... research, including those studies about the sea such as seismic, gravity meter, and magnetic exploration... 46 Shipping 7 2010-10-01 2010-10-01 false Oceanographic research vessel. 188.10-53 Section 188.10-53 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) OCEANOGRAPHIC RESEARCH VESSELS...

  6. 40 CFR 282.53 - Arkansas State-Administered Program.

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 26 2010-07-01 2010-07-01 false Arkansas State-Administered Program. 282.53 Section 282.53 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) SOLID... administered by the Arkansas Department of Pollution Control and Ecology, was approved by EPA pursuant to 42 U...

  7. 41 CFR 105-53.145 - Federal Supply Service.

    Science.gov (United States)

    2010-07-01

    ... surplus personal property; managing GSA's Governmentwide transportation, traffic management, travel, fleet... 41 Public Contracts and Property Management 3 2010-07-01 2010-07-01 false Federal Supply Service. 105-53.145 Section 105-53.145 Public Contracts and Property Management Federal Property Management...

  8. 26 CFR 53.4955-1 - Tax on political expenditures.

    Science.gov (United States)

    2010-04-01

    ... 26 Internal Revenue 17 2010-04-01 2010-04-01 false Tax on political expenditures. 53.4955-1...) MISCELLANEOUS EXCISE TAXES (CONTINUED) FOUNDATION AND SIMILAR EXCISE TAXES Second Tier Excise Taxes § 53.4955-1 Tax on political expenditures. (a) Relationship between section 4955 excise taxes and substantive...

  9. TP53 codon 72 polymorphism in pigmentary phenotypes

    Indian Academy of Sciences (India)

    2012-01-20

    Jan 20, 2012 ... oedema and possibly pain and blistering (sunburn). Al- though associations between TP53 codon 72 polymorphism and various types of cancer, ..... Radiation-induced cutaneous carcinoma of the head and neck: is there an early role for p53 mutations? Clin. Exp. Dermatol. 31 793–798. Han J, Kraft P, Nan ...

  10. 32 CFR 516.53 - News media and other inquiries.

    Science.gov (United States)

    2010-07-01

    ... 32 National Defense 3 2010-07-01 2010-07-01 true News media and other inquiries. 516.53 Section... Litigation in Which the United States Has An Interest § 516.53 News media and other inquiries. News media... clearance. Local public affairs officers will refer press inquiries to HQDA (SAPA), WASH DC 20310-1500, with...

  11. 27 CFR 478.53 - Change in trade name.

    Science.gov (United States)

    2010-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 3 2010-04-01 2010-04-01 false Change in trade name. 478.53 Section 478.53 Alcohol, Tobacco Products, and Firearms BUREAU OF ALCOHOL, TOBACCO, FIREARMS, AND... license is not required to obtain a new license by reason of a mere change in trade name under which he...

  12. Fermentative metabolism impedes p53-dependent apoptosis in a ...

    Indian Academy of Sciences (India)

    It is known that the Warburg effect and Crabtree effect aredisplayed by Saccharomyces cerevisiae, during growth on abundant glucose. Beyond this similarity, it was also demonstratedthat expression of human pro-apoptotic proteins in S. cerevisiae such as Bax and p53 caused apoptosis. Here, wedemonstrate that p53 ...

  13. 7 CFR 301.53-2 - Regulated articles.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 5 2010-01-01 2010-01-01 false Regulated articles. 301.53-2 Section 301.53-2... articles. The following are regulated articles: (a) The emerald ash borer; firewood of all hardwood (non... article, product, or means of conveyance not listed in paragraph (a) of this section may be designated as...

  14. 14 CFR 21.53 - Statement of conformity.

    Science.gov (United States)

    2010-01-01

    ... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Statement of conformity. 21.53 Section 21... CERTIFICATION PROCEDURES FOR PRODUCTS AND PARTS Type Certificates § 21.53 Statement of conformity. Link to an... conformity (FAA Form 317) to the Administrator for each aircraft engine and propeller presented to the...

  15. Phylogenetic analysis of human Tp53 gene using computational ...

    African Journals Online (AJOL)

    format and was studied for its relationships and percent similarity within human and others species. Genetic variation among TP53 found in human beings and other organisms were studied in detail. Multiple sequence alignment and phylogenetic analysis of the human TP53, transcript variant-1 mRNA sequence through ...

  16. 36 CFR 223.53 - Urgent removal contract extensions.

    Science.gov (United States)

    2010-07-01

    ... 36 Parks, Forests, and Public Property 2 2010-07-01 2010-07-01 false Urgent removal contract extensions. 223.53 Section 223.53 Parks, Forests, and Public Property FOREST SERVICE, DEPARTMENT OF.... Catastrophic events include, but are not limited to, severe wildfire, wind, floods, insects and disease...

  17. 45 CFR 84.53 - Drug and alcohol addicts.

    Science.gov (United States)

    2010-10-01

    ... 45 Public Welfare 1 2010-10-01 2010-10-01 false Drug and alcohol addicts. 84.53 Section 84.53 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ADMINISTRATION NONDISCRIMINATION ON THE BASIS OF HANDICAP IN PROGRAMS OR ACTIVITIES RECEIVING FEDERAL FINANCIAL ASSISTANCE Health, Welfare, and...

  18. 14 CFR 125.53 - Flight locating requirements.

    Science.gov (United States)

    2010-01-01

    ... 14 Aeronautics and Space 3 2010-01-01 2010-01-01 false Flight locating requirements. 125.53... and Miscellaneous Requirements § 125.53 Flight locating requirements. (a) Each certificate holder must have procedures established for locating each flight for which an FAA flight plan is not filed that— (1...

  19. COX-2 and p53 in human sinonasal cancer

    DEFF Research Database (Denmark)

    Holmila, Reetta; Cyr, Diane; Luce, Danièle

    2008-01-01

    to development of cancer. Many signals that activate COX-2 also induce tumor suppressor p53, a transcription factor central in cellular stress response. We investigated COX-2 and p53 expressions by immunohistochemistry in 50 SNCs (23 adenocarcinomas, and 27 squamous cell carcinomas (SCC); 48 analyzed for COX-2......; 41 for p53). Occupational histories and smoking habits were available for majority of the cases. Most of the adenocarcinoma cases with exposure history data had been exposed to wood dust at work in the past (88%, 14/16). For smokers, 63% (12/19) presented with SSC, whereas 64% (7/11) of nonsmokers...... the exposures and p53 accumulation were found; however, the p53 accumulation pattern (p = 0.062 for wood dust exposure) resembled that of COX-2 expression. In summary, our findings show increased COX-2 expression in SNC adenocarcinoma with wood dust exposure, suggesting a role for inflammatory components...

  20. Malign Melanomda Serum P53 Onkoprotein Düzeyleri

    OpenAIRE

    Özbek, Uğur; Şengün, Zeynep; Kurul, Sıdıka; Aydıner, Adnan; Ertürk, Nurcan; Topuz, Erkan

    1994-01-01

    p53, SV 40 trasforme edilmiş hücrelerde bulunmuş ve tanımlanmış bir nukleer fosfoproteindir. P53'ün mutasyona uğramış ya da 'wild-type' formu, hücre bölünmesinde negatif regülatör rolü olan bir tümör-supressör gen olarak kabul edilir. P53 geninin yüksek oranda korunmuş dizilerinden birinde nokta mutasyonu ortaya çıktığında, aktive olmuş onkogen ürünü özellikleri gösteren bir mutant protein eksprese edilir. p53 proteini monoklonal antikorlarla ayırt edilebilir. Mutant p53 serum ...

  1. p53 in the DNA damage repair process

    Science.gov (United States)

    Williams, Ashley B.; Schumacher, Björn

    2016-01-01

    The cells in the human body are continuously challenged by a variety of genotoxic attacks. Erroneous repair of the DNA can lead to mutations and chromosomal aberrations that can alter the functions of tumor suppressor genes or oncogenes, thus causing cancer development. As a central tumor suppressor, p53 guards the genome by orchestrating a variety of DNA damage response (DDR) mechanisms. Already early in metazoan evolution, p53 started controlling the apoptotic demise of genomically compromised cells. p53 plays a prominent role as a facilitator of DNA repair by halting the cell cycle to allow time for the repair machineries to restore genome stability. In addition, p53 took on diverse roles to also directly impact the activity of various DNA repair systems. It thus appears as if p53 is multitasking in protecting from cancer development by maintaining genome stability. PMID:27048304

  2. p53-dependent and p53-independent anticancer activity of a new indole derivative in human osteosarcoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Cappadone, C., E-mail: concettina.cappadone@unibo.it [Department of Pharmacy and Biotechnology, University of Bologna, Bologna (Italy); Stefanelli, C. [Department for Life Quality Studies, University of Bologna, Rimini Campus, Rimini (Italy); Malucelli, E. [Department of Pharmacy and Biotechnology, University of Bologna, Bologna (Italy); Zini, M. [Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna (Italy); Onofrillo, C. [Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna (Italy); Locatelli, A.; Rambaldi, M.; Sargenti, A. [Department of Pharmacy and Biotechnology, University of Bologna, Bologna (Italy); Merolle, L. [ELETTRA–Sincrotrone Trieste S.C.p.A., Trieste (Italy); Farruggia, G. [Department of Pharmacy and Biotechnology, University of Bologna, Bologna (Italy); National Institute of Biostructures and Biosystems, Roma (Italy); Graziadio, A. [Department of Pharmacy and Biotechnology, University of Bologna, Bologna (Italy); Montanaro, L. [Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna (Italy); Iotti, S. [Department of Pharmacy and Biotechnology, University of Bologna, Bologna (Italy); National Institute of Biostructures and Biosystems, Roma (Italy)

    2015-11-13

    Osteosarcoma (OS) is the most common primary malignant tumor of bone, occurring most frequently in children and adolescents. The mechanism of formation and development of OS have been studied for a long time. Tumor suppressor pathway governed by p53 gene are known to be involved in the pathogenesis of osteosarcoma. Moreover, loss of wild-type p53 activity is thought to be a major predictor of failure to respond to chemotherapy in various human cancers. In previous studies, we described the activity of a new indole derivative, NSC743420, belonging to the tubulin inhibitors family, capable to induce apoptosis and arrest of the cell cycle in the G2/M phase of various cancer cell lines. However, this molecule has never been tested on OS cell line. Here we address the activity of NSC743420 by examine whether differences in the p53 status could influence its effects on cell proliferation and death of OS cells. In particular, we compared the effect of the tested molecule on p53-wild type and p53-silenced U2OS cells, and on SaOS2 cell line, which is null for p53. Our results demonstrated that NSC743420 reduces OS cell proliferation by p53-dependent and p53-independent mechanisms. In particular, the molecule induces proliferative arrest that culminate to apoptosis in SaOS2 p53-null cells, while it brings a cytostatic and differentiating effect in U2OS cells, characterized by the cell cycle arrest in G0/G1 phase and increased alkaline phosphatase activity. - Highlights: • The indole derivative NSC743420 induces antitumor effects on osteosarcoma cells. • p53 status could drive the activity of antitumor agents on osteosarcoma cells. • NSC743420 induces cytostatic and differentiating effects on U2OS cells. • NSC743420 causes apoptosis on p53-null SaOS2 cells.

  3. p53 selectively regulates developmental apoptosis of rod photoreceptors.

    Directory of Open Access Journals (Sweden)

    Linda Vuong

    Full Text Available Retinal cells become post-mitotic early during post-natal development. It is likely that p53, a well-known cell cycle regulator, is involved in regulating the genesis, differentiation and death of retinal cells. Furthermore, retinal cells are under constant oxidative stress that can result in DNA damage, due to the extremely high level of metabolic activity associated with phototransduction. If not repaired, this damage may result in p53-dependent cell death and ensuing vision loss. In this study, the role of p53 during retinal development and in the post-mitotic retina is investigated. A previously described super p53 transgenic mouse that expresses an extra copy of the mouse p53 gene driven by its endogenous promoter is utilized. Another transgenic mouse (HIP that expresses the p53 gene in rod and cone photoreceptors driven by the human interphotoreceptor retinoid binding protein promoter was generated. The electroretinogram (ERG of the super p53 mouse exhibited reduced rod-driven scotopic a and b wave and cone-driven photopic b wave responses. This deficit resulted from a reduced number of rod photoreceptors and inner nuclear layer cells. However, the reduced photopic signal arose only from lost inner retinal neurons, as cone numbers did not change. Furthermore, cell loss was non-progressive and resulted from increased apoptosis during retinal developmental as determined by TUNEL staining. In contrast, the continuous and specific expression of p53 in rod and cone photoreceptors in the mature retinas of HIP mice led to the selective loss of both rods and cones. These findings strongly support a role for p53 in regulating developmental apoptosis in the retina and suggest a potential role, either direct or indirect, for p53 in the degenerative photoreceptor loss associated with human blinding disorders.

  4. 40 CFR 53.53 - Test for flow rate accuracy, regulation, measurement accuracy, and cut-off.

    Science.gov (United States)

    2010-07-01

    ... Class II Equivalent Methods for PM2.5 or PM10â2.5 § 53.53 Test for flow rate accuracy, regulation... are to be recorded with an analog recording device, the accuracy of the entire instrument-recorder... 40 Protection of Environment 5 2010-07-01 2010-07-01 false Test for flow rate accuracy, regulation...

  5. A p53-bound enhancer region controls a long intergenic noncoding RNA required for p53 stress response

    NARCIS (Netherlands)

    Melo, C A; Léveillé, N; Rooijers, K; Wijchers, P J; Geeven, G; Tal, A; Melo, S A; de Laat, W; Agami, R

    2016-01-01

    Genome-wide chromatin studies identified the tumor suppressor p53 as both a promoter and an enhancer-binding transcription factor. As an enhancer factor, p53 can induce local production of enhancer RNAs, as well as transcriptional activation of distal neighboring genes. Beyond the regulation of

  6. Fuzzy tandem repeats containing p53 response elements may define species-specific p53 target genes.

    Directory of Open Access Journals (Sweden)

    Iva Simeonova

    2012-06-01

    Full Text Available Evolutionary forces that shape regulatory networks remain poorly understood. In mammals, the Rb pathway is a classic example of species-specific gene regulation, as a germline mutation in one Rb allele promotes retinoblastoma in humans, but not in mice. Here we show that p53 transactivates the Retinoblastoma-like 2 (Rbl2 gene to produce p130 in murine, but not human, cells. We found intronic fuzzy tandem repeats containing perfect p53 response elements to be important for this regulation. We next identified two other murine genes regulated by p53 via fuzzy tandem repeats: Ncoa1 and Klhl26. The repeats are poorly conserved in evolution, and the p53-dependent regulation of the murine genes is lost in humans. Our results indicate a role for the rapid evolution of tandem repeats in shaping differences in p53 regulatory networks between mammalian species.

  7. Fuzzy tandem repeats containing p53 response elements may define species-specific p53 target genes.

    Science.gov (United States)

    Simeonova, Iva; Lejour, Vincent; Bardot, Boris; Bouarich-Bourimi, Rachida; Morin, Aurélie; Fang, Ming; Charbonnier, Laure; Toledo, Franck

    2012-06-01

    Evolutionary forces that shape regulatory networks remain poorly understood. In mammals, the Rb pathway is a classic example of species-specific gene regulation, as a germline mutation in one Rb allele promotes retinoblastoma in humans, but not in mice. Here we show that p53 transactivates the Retinoblastoma-like 2 (Rbl2) gene to produce p130 in murine, but not human, cells. We found intronic fuzzy tandem repeats containing perfect p53 response elements to be important for this regulation. We next identified two other murine genes regulated by p53 via fuzzy tandem repeats: Ncoa1 and Klhl26. The repeats are poorly conserved in evolution, and the p53-dependent regulation of the murine genes is lost in humans. Our results indicate a role for the rapid evolution of tandem repeats in shaping differences in p53 regulatory networks between mammalian species.

  8. ZNF509S1 downregulates PUMA by inhibiting p53K382 acetylation and p53-DNA binding.

    Science.gov (United States)

    Jeon, Bu-Nam; Yoon, Jae-Hyeon; Han, Dohyun; Kim, Min-Kyeong; Kim, Youngsoo; Choi, Seo-Hyun; Song, Jiyang; Kim, Kyung-Sup; Kim, Kunhong; Hur, Man-Wook

    2017-09-01

    Expression of the POK family protein ZNF509L, and -its S1 isoform, is induced by p53 upon exposure to genotoxic stress. Due to alternative splicing of the ZNF509 primary transcript, ZNF509S1 lacks the 6 zinc-fingers and C-terminus of ZNF509L, resulting in only one zinc-finger. ZNF509L and -S1 inhibit cell proliferation by activating p21/CDKN1A and RB transcription, respectively. When cells are exposed to severe DNA damage, p53 activates PUMA (p53-upregulated modulator of apoptosis) transcription. Interestingly, apoptosis due to transcriptional activation of PUMA by p53 is attenuated by ZNF509S1. Thus we investigated the molecular mechanism(s) underlying the transcriptional attenuation and anti-apoptotic effects of ZNF509S1. We show that ZNF509S1 modulation of p53 activity is important in PUMA gene transcription by modulating post-translational modification of p53 by p300. ZNF509S1 directly interacts with p53 and inhibits p300-mediated acetylation of p53 lysine K382, with deacetylation of p53 K382 leading to decreased DNA binding at the p53 response element 1 of the PUMA promoter. ZNF509S1 may play a role not only in cell cycle arrest, by activating RB expression, but also in rescuing cells from apoptotic death by repressing PUMA expression in cells exposed to severe DNA damage. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. p53: Biology and role for cellular radiosensitivity

    Energy Technology Data Exchange (ETDEWEB)

    Dahm-Daphi, J. [Hamburg Univ. (Germany). Abt. fuer Strahlentherapie und Onkologie

    2000-06-01

    Purpose: p53 is the most commonly mutated gene in human tumors with large impact on cellular biology and response to radiation. Many excellent reviews are available on various aspects but for several years none about the role of p53 for radiosensitivity. The latter is the aim of the present paper. Methods: Review of the literature. Results: p53 is a regulator of apoptosis mainly in hematopoetic tissue. In normal tissue and solid tumors presumably other functions have more impact on the cellular response. p53 controls cell-cycle progression after irradiation and also DNA-repair, namely homologous and non-homologous recombination. Mutations of p53 alter these functions which may be responsible for an enhanced cellular and tumor radioresistance. At present only few reports were able to show that under tightly controlled conditions loss of p53 wild-type function leads to enhanced radioresistance. A general proof is still lacking. Conclusion: The emerging picture in the year 2000 shows p53 as a central protein in a multi-enzyme multi-function network which is far from being fully understood. Although p53 appears to be a major regulator it is certainly not the unreplacable component the loss of which uniformly determines radioresistance. Only further understanding of modifiers and cooperators in the cell and in the specific tissue context will elucidate p53's role for radiosensitivity and radiotherapy. (orig.) [German] Hintergrund: p53 ist das am haeufigsten mutierte Gen in menschlichen Tumoren mit grossem Einfluss auf die zellulaere Biologie und Strahlenantwort. Viele ausgezeichnete Uebersichten sind verfuegbar, aber seit Jahren keine, die die Rolle von p53 fuer die Strahlenempfindlichkeit beleuchtet. Dies ist das Ziel der vorliegenden Arbeit. Methode: Literaturuebersicht. Ergebnis: p53 ist ein Regulator der Apoptose in haematopoetischen Gewerben. Im uebrigen Normalgewebe und in soliden Tumoren haben andere Funktionen groessere Bedeutung fuer die Zellantwort. Nach

  10. Expression of p53 protein in pituitary adenomas

    Directory of Open Access Journals (Sweden)

    Oliveira M.C.

    2002-01-01

    Full Text Available Inactivating mutations of TP53, a tumor suppressor gene, are associated with abnormal cell proliferation. Although p53 expression is common in many human malignancies, p53 protein has seldom been evaluated in pituitary tumors. When detected, the percentage of p53-positive cells is low, and, in general, it is exclusive for invasive lesions. The aim of the present study was to use immunohistochemistry to determine the presence of p53 protein in pituitary adenomas from tumor samples of 163 surgeries performed in 148 patients (40% male, 60% female. In 35% of the cases the adenoma was nonfunctional, while in the others it was associated with PRL, GH and/or ACTH endocrine hypersecretion syndrome. Macroadenomas were observed in 83.2% of the cases with available neuroimage evaluation, of which 28% invaded the cavernous, sphenoid and/or ethmoidal sinus, bone, third ventricle or subfrontal lobe. p53 protein was detected in 2/148 patients (1.3%. Immunohistochemistry was positive for PRL and GH in these cases. Due to the high percentage of invasive pituitary adenomas found in our study, the low frequency of p53 detection suggests that it is inadequate as a routine marker for aggressiveness and as a predictive factor of tumor behavior.

  11. Cisplatinum and Taxol Induce Different Patterns of p53 Phosphorylation

    Directory of Open Access Journals (Sweden)

    Giovanna Damia

    2001-01-01

    Full Text Available Posttranslational modifications of p53 induced by two widely used anticancer agents, cisplatinum (DDP and taxol were investigated in two human cancer cell lines. Although both drugs were able to induce phosphorylation at serine 20 (Ser20, only DDP treatment induced p53 phosphorylation at serine 15 (Ser15. Moreover, both drug treatments were able to increase p53 levels and consequently the transcription of waf1 and mdm-2 genes, although DDP treatment resulted in a stronger inducer of both genes. Using two ataxia telangiectasia mutated (ATM cell lines, the role of ATM in druginduced p53 phosphorylations was investigated. No differences in drug-induced p53 phosphorylation could be observed, indicating that ATM is not the kinase involved in these phosphorylation events. In addition, inhibition of DNA-dependent protein kinase activity by wortmannin did not abolish p53 phosphorylation at Ser15 and Ser20, again indicating that DNA-PK is unlikely to be the kinase involved. After both taxol and DDP treatments, an activation of hCHK2 was found and this is likely to be responsible for phosphorylation at Ser20. In contrast, only DDP was able to activate ATR, which is the candidate kinase for phosphorylation of Ser15 by this drug. This data clearly suggests that differential mechanisms are involved in phosphorylation and activation of p53 depending on the drug type.

  12. CLCA2 as a p53-Inducible Senescence Mediator

    Directory of Open Access Journals (Sweden)

    Chizu Tanikawa

    2012-02-01

    Full Text Available p53 is a tumor suppressor gene that is frequently mutated in multiple cancer tissues. Activated p53 protein regulates its downstream genes and subsequently inhibits malignant transformation by inducing cell cycle arrest, apoptosis, DNA repair, and senescence. However, genes involved in the p53-mediated senescence pathway are not yet fully elucidated. Through the screening of two genome-wide expression profile data sets, one for cells in which exogenous p53 was introduced and the other for senescent fibroblasts, we have identified chloride channel accessory 2 (CLCA2 as a p53-inducible senescence-associated gene. CLCA2 was remarkably induced by replicative senescence as well as oxidative stress in a p53-dependent manner. We also found that ectopically expressed CLCA2 induced cellular senescence, and the down-regulation of CLCA2 by small interfering RNA caused inhibition of oxidative stress-induced senescence. Interestingly, the reduced expression of CLCA2 was frequently observed in various kinds of cancers including prostate cancer, whereas its expression was not affected in precancerous prostatic intraepithelial neoplasia. Thus, our findings suggest a crucial role of p53/CLCA2-mediated senescence induction as a barrier for malignant transformation.

  13. TP53 Mutation Status of Tubo-ovarian and Peritoneal High-grade Serous Carcinoma with a Wild-type p53 Immunostaining Pattern.

    Science.gov (United States)

    Na, Kiyong; Sung, Ji-Youn; Kim, Hyun-Soo

    2017-12-01

    Diffuse and strong nuclear p53 immunoreactivity and a complete lack of p53 expression are regarded as indicative of missense and nonsense mutations, respectively, of the TP53 gene. Tubo-ovarian and peritoneal high-grade serous carcinoma (HGSC) is characterized by aberrant p53 expression induced by a TP53 mutation. However, our experience with some HGSC cases with a wild-type p53 immunostaining pattern led us to comprehensively review previous cases and investigate the TP53 mutational status of the exceptional cases. We analyzed the immunophenotype of 153 cases of HGSC and performed TP53 gene sequencing analysis in those with a wild-type p53 immunostaining pattern. Immunostaining revealed that 109 (71.3%) cases displayed diffuse and strong p53 expression (missense mutation pattern), while 39 (25.5%) had no p53 expression (nonsense mutation pattern). The remaining five cases of HGSC showed a wild-type p53 immunostaining pattern. Direct sequencing analysis revealed that three of these cases harbored nonsense TP53 mutations and two had novel splice site deletions. TP53 mutation is almost invariably present in HGSC, and p53 immunostaining can be used as a surrogate marker of TP53 mutation. In cases with a wild-type p53 immunostaining pattern, direct sequencing for TP53 mutational status can be helpful to confirm the presence of a TP53 mutation. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  14. Mutant p53 as a target for cancer treatment.

    Science.gov (United States)

    Duffy, Michael J; Synnott, Naoise C; Crown, John

    2017-09-01

    TP53 (p53) is the single most frequently altered gene in human cancers, with mutations being present in approximately 50% of all invasive tumours. However, in some of the most difficult-to-treat cancers such as high-grade serous ovarian cancers, triple-negative breast cancers, oesophageal cancers, small-cell lung cancers and squamous cell lung cancers, p53 is mutated in at least 80% of samples. Clearly, therefore, mutant p53 protein is an important candidate target against which new anticancer treatments could be developed. Although traditionally regarded as undruggable, several compounds such as p53 reactivation and induction of massive apoptosis-1 (PRIMA-1), a methylated derivative and structural analogue of PRIMA-1, i.e. APR-246, 2-sulfonylpyrimidines such as PK11007, pyrazoles such as PK7088, zinc metallochaperone-1 (ZMC1), a third generation thiosemicarbazone developed by Critical Outcome Techonologies Inc. (COTI-2) as well as specific peptides have recently been reported to reactive mutant p53 protein by converting it to a form exhibiting wild-type properties. Consistent with the reactivation of mutant p53, these compounds have been shown to exhibit anticancer activity in preclinical models expressing mutant p53. To date, two of these compounds, i.e. APR-246 and COTI-2 have progressed to clinical trials. A phase I/IIa clinical trial with APR-246 reported no major adverse effect. Currently, APR-246 is undergoing a phase Ib/II trial in patients with advanced serous ovarian cancer, while COTI-2 is being evaluated in a phase I trial in patients with advanced gynaecological cancers. It remains to be shown however, whether any mutant p53 reactivating compound has efficacy for the treatment of human cancer. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. p53 immunohistochemical staining patterns in oral squamous cell carcinoma

    Directory of Open Access Journals (Sweden)

    G Dundy

    2016-09-01

    Full Text Available Background: Mutation of p53 gene is one of the most common events in oral carcinogenesis. Accumulation of p53 protein has also been detected in premalignant lesions.Materials and Methods:  This study included 40 biopsy samples, which were received in department of pathology, Sarojini Naidu Medical College, Agra, to ascertain p53 expression by immunohistochemically, in patients with oral squamous cell carcinomas and to correlate its expression with histological grade, different sites in oral cavity and tobacco intake/smoking habits.Results: Out of 40 biopsies of oral mucosa, 03 showed normal oral mucosa and 37 were diagnosed as squamous cell carcinoma (SCC, most patients were in 5th and 6th decade and majority (86.5% of oral SCC were males with buccal mucosa being the most common site. There was a statistically significant difference in p53 expression between oral SCC and normal oral mucosa (p value <0.05. Of total 37 cases, 12 cases were well differentiated type, 16 moderately differentiated and 09 of poorly differentiated type of SCC. In each category, about two thirds were positive for p53 staining. Out of total 37 cases of oral SCC, 64.9% were positive and 35.1% were negative for p53 expression, 34 cases had positive history of tobacco intake/smoking habits, of which 23 cases were positive while 11 cases were negative for p53 staining.Conclusion: Abnormal p53 protein was detected in 64.9% of oral squamous cell carcinoma, but not in normal oral mucosa. p53 expression was associated with malignant transformation of oral mucosa. 

  16. POSTRANSLATIONAL MODIFICATIONS OF P53: UPSTREAM SIGNALING PATHWAYS.

    Energy Technology Data Exchange (ETDEWEB)

    ANDERSON,C.W.APPELLA,E.

    2003-10-23

    The p53 tumor suppressor is a tetrameric transcription factor that is posttranslational modified at >20 different sites by phosphorylation, acetylation, or sumoylation in response to various cellular stress conditions. Specific posttranslational modifications, or groups of modifications, that result from the activation of different stress-induced signaling pathways are thought to modulate p53 activity to regulate cell fate by inducing cell cycle arrest, apoptosis, or cellular senescence. Here we review recent progress in characterizing the upstream signaling pathways whose activation in response to various genotoxic and non-genotoxic stresses result in p53 posttranslational modifications.

  17. Targeting p53-MDM2-MDMX Loop for Cancer Therapy

    OpenAIRE

    Zhang, Qi; Zeng, Shelya X.; Lu, Hua

    2014-01-01

    The tumor suppressor p53 plays a central role in anti-tumorigenesis and cancer therapy. It has been described as “the guardian of the genome”, because it is essential for conserving genomic stability by preventing mutation, and its mutation and inactivation are highly related to all human cancers. Two important p53 regulators, MDM2 and MDMX, inactivate p53 by directly inhibiting its transcriptional activity and mediating its ubiquitination in a feedback fashion, as their genes are also the tr...

  18. Combining oncolytic virotherapy with p53 tumor suppressor gene therapy

    OpenAIRE

    Bressy, Christian; Hastie, Eric; Grdzelishvili, Valery Z.

    2017-01-01

    Oncolytic virus (OV) therapy utilizes replication-competent viruses to kill cancer cells, leaving non-malignant cells unharmed. With the first U.S. Food and Drug Administration-approved OV, dozens of clinical trials ongoing, and an abundance of translational research in the field, OV therapy is poised to be one of the leading treatments for cancer. A number of recombinant OVs expressing a transgene for p53 (TP53) or another p53 family member (TP63 or TP73) were engineered with the goal of gen...

  19. p53/HMGB1 Complexes Regulate Autophagy and Apoptosis

    OpenAIRE

    Livesey, Kristen M.; Kang, Rui; Vernon, Philip; Buchser, William; Loughran, Patricia; Watkins, Simon C.; Zhang, Lin; Manfredi, James J.; Zeh, Herbert J.; Li, Luyuan; Lotze, Michael T.; Tang, Daolin

    2012-01-01

    The balance between apoptosis (“programmed cell death”) and autophagy (“programmed cell survival”) is important in tumor development and response to therapy. Here we show that HMGB1 and p53 form a complex which regulates the balance between tumor cell death and survival. We demonstrate that knockout of p53 inHCT116 cells increases expression of cytosolic HMGB1 and induces autophagy. Conversely, knockout of HMGB1 in mouse embryonic fibroblasts increases p53 cytosolic localization and decreases...

  20. Robustness of the p53 network and biological hackers.

    Science.gov (United States)

    Dartnell, Lewis; Simeonidis, Evangelos; Hubank, Michael; Tsoka, Sophia; Bogle, I David L; Papageorgiou, Lazaros G

    2005-06-06

    The p53 protein interaction network is crucial in regulating the metazoan cell cycle and apoptosis. Here, the robustness of the p53 network is studied by analyzing its degeneration under two modes of attack. Linear Programming is used to calculate average path lengths among proteins and the network diameter as measures of functionality. The p53 network is found to be robust to random loss of nodes, but vulnerable to a targeted attack against its hubs, as a result of its architecture. The significance of the results is considered with respect to mutational knockouts of proteins and the directed attacks mounted by tumour inducing viruses.

  1. p53-dependent delayed effects of radiation vary according to time of irradiation of p53 + / - mice.

    Science.gov (United States)

    Okazaki, Ryuji; Ootsuyama, Akira

    2014-01-01

    We previously reported that in p53 (+ / -) mice that had been given a whole-body dose of 3 Gy at 8 weeks of age, p53-dependent delayed effects of radiation, as manifested in T-cell receptor (TCR) variant fractions (VF) instability in mouse splenocytes, were biphasic, namely, induction of TCR-VF mutation reappeared at 44 weeks. The manifestation of the delayed effects and the measures of biological markers varied according to the timing of irradiation. We also reported that the decrease in function of the p53 gene was related to the effects of a delayed mutation. In the present study, we investigated the functions and mutations of the p53 gene in old age for p53 (+ / -) mice following irradiation at various ages. p53 (+ / -) mice were given a whole-body dose of 3 Gy at 8, 28 or 40 weeks of age. There were significant differences for all variables tested at 8 weeks of age. This was similarly the case for mice irradiated at 28 weeks of age, in which there were also significant differences in TCR VF and the percentage of apoptosis. In mice irradiated at 40 weeks of age, there were significant differences for all considered variables except for the p53 allele. We demonstrated that the different patterns of delayed mutation of the p53 gene at 56 weeks of age depended on the age at which mice had undergone 3-Gy whole-body irradiation. Our conclusions are limited to variation in p53-dependent delayed effects according to the time of irradiation.

  2. Thymidylate synthase inhibition induces p53-dependent and p53-independent apoptotic responses in human urinary bladder cancer cells.

    Science.gov (United States)

    Stravopodis, Dimitrios J; Karkoulis, Panagiotis K; Konstantakou, Eumorphia G; Melachroinou, Sophia; Thanasopoulou, Angeliki; Aravantinos, Gerasimos; Margaritis, Lukas H; Anastasiadou, Ema; Voutsinas, Gerassimos E

    2011-02-01

    In search for more effective clinical protocols, the antimetabolite drug 5-fluorouracil (5-FU) has been successfully included in new regimens of bladder cancer combination chemotherapy. In the present study, we have investigated the effects of 5-FU treatment on apoptosis induction in wild-type and mutant p53 urinary bladder cancer cells. We have used MTT-based assays, FACS analysis, Western blotting and semi-quantitative RT-PCR in RT4 and RT112 (grade I, wild-type p53), as well as in T24 (grade III, mutant p53) and TCCSUP (grade IV, mutant p53) human urinary bladder cancer cell lines. In the urothelial bladder cancer cell lines RT4 and T24, 5-FU-induced TS inhibition proved to be associated with cell type-dependent (a) sensitivity to the drug, (b) Caspase-mediated apoptosis, (c) p53 stabilization and activation, as well as Rb phosphorylation and E2F1 expression and (d) transcriptional regulation of p53 target genes and their cognate proteins, while an E2F-dependent transcriptional network did not seem to be critically engaged in such type of responses. We have shown that in the wild-type p53 context of RT4 cells, 5-FU-triggered apoptosis was prominently efficient and mainly regulated by p53-dependent mechanisms, whereas the mutant p53 environment of T24 cells was able to provide notable levels of resistance to apoptosis, basically ascribed to E2F-independent, and still unidentified, pathways. Nevertheless, the differential vulnerability of RT4 and T24 cells to 5-FU administration could also be associated with cell-type-specific transcriptional expression patterns of certain genes critically involved in 5-FU metabolism.

  3. R. Strauss: Symphonia domestica, Op. 53 / David Nice

    Index Scriptorium Estoniae

    Nice, David

    1994-01-01

    Uuest heliplaadist "R. Strauss: Symphonia domestica, Op. 53. National Youth Orchestra of Great Britain / Christopher Seaman. Pickwick IMP Classics CD PCD 1080; Selected comparisons: SNO, Järvi (3/88) Chandos CHAN 8572"

  4. A dynamic P53-MDM2 model with time delay

    Energy Technology Data Exchange (ETDEWEB)

    Mihalas, Gh.I. [Department of Biophysics and Medical Informatics, University of Medicine and Pharmacy, Piata Eftimie Murgu, nr. 3, 300041 Timisoara (Romania)]. E-mail: mihalas@medinfo.umft.ro; Neamtu, M. [Department of Forecasting, Economic Analysis, Mathematics and Statistics, West University of Timisoara, Str. Pestalozzi, nr. 14A, 300115 Timisoara (Romania)]. E-mail: mihaela.neamtu@fse.uvt.ro; Opris, D. [Department of Applied Mathematics, West University of Timisoara, Bd. V. Parvan, nr. 4, 300223 Timisoara (Romania)]. E-mail: opris@math.uvt.ro; Horhat, R.F. [Department of Biophysics and Medical Informatics, University of Medicine and Pharmacy, Piata Eftimie Murgu, nr. 3, 300041 Timisoara (Romania)]. E-mail: rhorhat@yahoo.com

    2006-11-15

    Specific activator and repressor transcription factors which bind to specific regulator DNA sequences, play an important role in gene activity control. Interactions between genes coding such transcription factors should explain the different stable or sometimes oscillatory gene activities characteristic for different tissues. Starting with the model P53-MDM2 described into [Mihalas GI, Simon Z, Balea G, Popa E. Possible oscillatory behaviour in P53-MDM2 interaction computer simulation. J Biol Syst 2000;8(1):21-9] and the process described into [Kohn KW, Pommier Y. Molecular interaction map of P53 and MDM2 logic elements, which control the off-on switch of P53 in response to DNA damage. Biochem Biophys Res Commun 2005;331:816-27] we enveloped a new model of this interaction. Choosing the delay as a bifurcation parameter we study the direction and stability of the bifurcating periodic solutions. Some numerical examples are finally given for justifying the theoretical results.

  5. p53 regulates cytoskeleton remodeling to suppress tumor progression.

    Science.gov (United States)

    Araki, Keigo; Ebata, Takahiro; Guo, Alvin Kunyao; Tobiume, Kei; Wolf, Steven John; Kawauchi, Keiko

    2015-11-01

    Cancer cells possess unique characteristics such as invasiveness, the ability to undergo epithelial-mesenchymal transition, and an inherent stemness. Cell morphology is altered during these processes and this is highly dependent on actin cytoskeleton remodeling. Regulation of the actin cytoskeleton is, therefore, important for determination of cell fate. Mutations within the TP53 (tumor suppressor p53) gene leading to loss or gain of function (GOF) of the protein are often observed in aggressive cancer cells. Here, we highlight the roles of p53 and its GOF mutants in cancer cell invasion from the perspective of the actin cytoskeleton; in particular its reorganization and regulation by cell adhesion molecules such as integrins and cadherins. We emphasize the multiple functions of p53 in the regulation of actin cytoskeleton remodeling in response to the extracellular microenvironment, and oncogene activation. Such an approach provides a new perspective in the consideration of novel targets for anti-cancer therapy.

  6. 40 CFR 264.53 - Copies of contingency plan.

    Science.gov (United States)

    2010-07-01

    ... police departments, fire departments, hospitals, and State and local emergency response teams that may be called upon to provide emergency services. ... Contingency Plan and Emergency Procedures § 264.53 Copies of contingency plan. A copy of the contingency plan...

  7. 49 CFR 230.53 - Time of cleaning.

    Science.gov (United States)

    2010-10-01

    ... Water Glasses and Gauge Cocks § 230.53 Time of cleaning. The spindles of all water glass valves and of all gauge cocks shall be removed and valves and cocks thoroughly cleaned of scale and sediment at...

  8. 42 CFR 433.53 - State plan requirements.

    Science.gov (United States)

    2010-10-01

    ... the State; and (2) If there is local financial participation, lack of funds from local sources will... Financial Participation § 433.53 State plan requirements. A State plan must provide that— (a) State (as...

  9. p53 Abnormalities and Potential Therapeutic Targeting in Multiple Myeloma

    Directory of Open Access Journals (Sweden)

    P. J. Teoh

    2014-01-01

    Full Text Available p53 abnormalities are regarded as an independent prognostic marker in multiple myeloma. Patients harbouring this genetic anomaly are commonly resistant to standard therapy. Thus, various p53 reactivating agents have been developed in order to restore its tumour suppressive abilities. Small molecular compounds, especially, have gained popularity in its efficacy against myeloma cells. For instance, promising preclinical results have steered both nutlin-3 and PRIMA-1 into phase I/II clinical trials. This review summarizes different modes of p53 inactivation in myeloma and highlights the current p53-based therapies that are being utilized in the clinic. Finally, we discuss the potential and promise that the novel small molecules possess for clinical application in improving the treatment outcome of myeloma.

  10. Irradiation selects for p53-deficient hematopoietic progenitors.

    Directory of Open Access Journals (Sweden)

    Andriy Marusyk

    2010-03-01

    Full Text Available Identification and characterization of mutations that drive cancer evolution constitute a major focus of cancer research. Consequently, dominant paradigms attribute the tumorigenic effects of carcinogens in general and ionizing radiation in particular to their direct mutagenic action on genetic loci encoding oncogenes and tumor suppressor genes. However, the effects of irradiation are not limited to genetic loci that encode oncogenes and tumor suppressors, as irradiation induces a multitude of other changes both in the cells and their microenvironment which could potentially affect the selective effects of some oncogenic mutations. P53 is a key tumor suppressor, the loss of which can provide resistance to multiple genotoxic stimuli, including irradiation. Given that p53 null animals develop T-cell lymphomas with high penetrance and that irradiation dramatically accelerates lymphoma development in p53 heterozygous mice, we hypothesized that increased selection for p53-deficient cells contributes to the causal link between irradiation and induction of lymphoid malignancies. We sought to determine whether ionizing irradiation selects for p53-deficient hematopoietic progenitors in vivo using mouse models. We found that p53 disruption does not provide a clear selective advantage within an unstressed hematopoietic system or in previously irradiated BM allowed to recover from irradiation. In contrast, upon irradiation p53 disruption confers a dramatic selective advantage, leading to long-term expansion of p53-deficient clones and to increased lymphoma development. Selection for cells with disrupted p53 appears to be attributable to several factors: protection from acute irradiation-induced ablation of progenitor cells, prevention of irradiation-induced loss of clonogenic capacity for stem and progenitor cells, improved long-term maintenance of progenitor cell fitness, and the disabling/elimination of competing p53 wild-type progenitors. These studies

  11. Blocking of p53-Snail Binding, Promoted by Oncogenic K-Ras, Recovers p53 Expression and function

    OpenAIRE

    Lee, Sun-Hye; Lee, Su-Jin; Jung, Yeon Sang; Xu, Yongbin; Kang, Ho Sung; Ha, Nam-Chul; Park, Bum-Joon

    2009-01-01

    Differentially from other kinds of Ras, oncogenic K-Ras, which is mutated approximately 30% of human cancer, does not induce apoptosis and senescence. Here, we provide the evidence that oncogenic K-Ras abrogates p53 function and expression through induction of Ataxia telangiectasia-mutated and Rad3-related mediated Snail stabilization. Snail directly binds to DNA binding domain of p53 and diminishes the tumor-suppressive function of p53. Thus, elimination of Snail through si-RNA can induce p5...

  12. Regulation of Mammary Progenitor Cells by p53 and Parity

    Science.gov (United States)

    2011-01-01

    pregnancy early in reproductive life can reduce breast cancer incidence in women by up to 50% 4. The research in our lab has shown that the p53 tum or...13. SUPPLEMENTARY NOTES 14. ABSTRACT Breast cancer is the most common tumor among women with inherited mutations in the p53 gene (Li-Fraumeni...4 Introduction Breast cancer is the m ost frequent cancer am ong women in the United S tates1. Understanding the biological

  13. Super p53 for Treatment of Ovarian Cancer

    Science.gov (United States)

    2017-09-01

    ABSTRACT In this final report, we show gene therapy using re-engineered super p53 (p53-CC constructs) kills some ovarian cancer cell lines in vitro ...a lead construct. Technical skills gained in the proposal include cell culture , transfections, microscopy, apoptosis assays, transcriptional assays...able to create ovarian tumors in mice. Our polymer-adenovirus constructs were optimized in vitro and in vivo, and did not show gross signs of toxicity

  14. Super p53 for Treatment of Ovarian Cancer

    Science.gov (United States)

    2016-07-01

    as demonstrated by fluorescence microscopy. Preliminary studies indicate that p53-CC causes robust apoptosis in Kuramochi and ID8 cells as well...measured using the 7AAD assay (late stage apoptosis ). IC50 values for taxol have been determined in ID8 (and SKOV3) cells. In ID8 cells (which will...be used to implant into mice for the syngeneic animal study), p53-CCmut causes the highest levels of apoptosis regardless of whether taxol is added

  15. Stimulus-Specific Transcriptional Regulation Within the p53 Network

    Science.gov (United States)

    Donner, Aaron Joseph; Hoover, Jennifer Michelle; Szostek, Stephanie Aspen; Espinosa, Joaquín Maximiliano

    2010-01-01

    The p53 transcriptional network is composed of hundreds of effector genes involved in varied stress-response pathways, including cell cycle arrest and apoptosis. It is not clear how distinct p53 target genes are differentially activated to trigger stress-specific biological responses. We analyzed the p53 transcriptional program upon activation by two DNA-damaging agents, UVC and doxorubicin, versus the non-genotoxic molecule Nutlin-3. In colorectal cancer cells, UVC triggers apoptosis, doxorubicin induces transient cell cycle arrest followed by apoptosis, and Nutlin-3 leads to cell cycle arrest with no significant apoptosis. Quantitative gene expression analysis allowed us to group p53 target genes into three main classes according to their activation profiles in each scenario. The CDK-inhibitor p21 was classified as a Class I gene, being significantly activated under cell cycle arrest conditions (i.e., doxorubicin and Nutlin-3) but not during UVC-induced apoptosis. Chromatin immunoprecipitation analysis of the p21 locus indicates that the level of p53-dependent transcription is determined by the effects of stimulus-specific transcriptional coregulators acting downstream of p53 binding and histone acetylation. In particular, our analysis indicates that the subunits of the CDK-module of the human Mediator complex function as stimulus-specific positive coregulators of p21 transcription. PMID:17957141

  16. PERAN MUTASI GEN p53 PADA KARSINOGENESIS SEL BASAL KULIT

    Directory of Open Access Journals (Sweden)

    Kadek Pramesti Dewi

    2015-01-01

    Full Text Available Karsinoma sel basal (KSB merupakan keganasan kulit non-melanotik tersering dan mempunyai kaitan erat dengan paparan sinar ultra violet (UV. Keganasan ini berasal dari sel-sel pluripotensial stratum basalis epidermis maupun selubung akar folikel rambut. Gambaran klinis dan histopatologis terdiri dari KSB tipe klasik (noduler dan KSB varian (tipe superfisial, fibroepithelial, KSB dengan diferensiasi adneksal, basoskuamous, infiltrating, morpheaform.Kanker pada tubuh manusia muncul karena adanya mutasi genetik pada gen-gen yang terlibat dalamkontrol pertumbuhan sel, seperti onkogen, tumor suppressor gene, gen apoptosis, dan DNA repair gene.Pada kebanyakan kasus KSB, gen yang tersering mengalami mutasi adalah tumor suppressor genep53. Mutasi ini timbul akibat paparan langsung sinar UV, bergantung pada dosis, durasi dan intensitas paparan.Gen p53 dikenal dengan sebutan guardian of the genome, karena fungsinya sebagai sensor terhadapterjadinya kerusakan DNA. Adanya kerusakan DNA menginduksi aktivasi p53 untuk menghentikan siklus sel saat memasuki fase G1, sehingga memberikan kesempatan kepada DNA repair proteinbekerja memperbaiki kerusakan DNA. Lebih dari itu, p53 juga mengaktivasi gen GADD45 (growth arrest and DNA damage untuk membantu perbaikan DNA. Jika perbaikan gagal, p53 akanmengarahkan sel dengan DNA yang rusak ke mesin apoptosis.Pada sel-sel basal terpapar UV, gen p53 mengalami mutasi dan inaktivasi. Karena itu, sel-sel dengan DNA yang mengalami kerusakan non-lethal akan mengalami ekspansi klonal sehingga tumbuh menjadilesi pra kanker dan akhirnya kanker (KSB. [MEDICINA 2014;45:38-42

  17. TP53 Mutations in Nonsmall Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Akira Mogi

    2011-01-01

    Full Text Available The tumor suppressor gene TP53 is frequently mutated in human cancers. Abnormality of the TP53 gene is one of the most significant events in lung cancers and plays an important role in the tumorigenesis of lung epithelial cells. Human lung cancers are classified into two major types, small cell lung cancer (SCLC and nonsmall cell lung cancer (NSCLC. The latter accounts for approximately 80% of all primary lung cancers, and the incidence of NSCLC is increasing yearly. Most clinical studies suggest that NSCLC with TP53 alterations carries a worse prognosis and may be relatively more resistant to chemotherapy and radiation. A deep understanding of the role of TP53 in lung carcinogenesis may lead to a more reasonably targeted clinical approach, which should be exploited to enhance the survival rates of patients with lung cancer. This paper will focus on the role of TP53 in the molecular pathogenesis, epidemiology, and therapeutic strategies of TP53 mutation in NSCLC.

  18. Characterization of p53 expression in rainbow trout.

    Science.gov (United States)

    Liu, Michelle; Tee, Catherine; Zeng, Fanxing; Sherry, James P; Dixon, Brian; Bols, Niels C; Duncker, Bernard P

    2011-11-01

    The tumour suppressor protein p53 is a critical component of cell cycle checkpoint responses. It upregulates the expression of cyclin-dependent kinase inhibitors in response to DNA damage and other cellular perturbations, and promotes apoptosis when DNA repair pathways are overwhelmed. Given the high incidence of p53 mutations in human cancers, it has been extensively studied, though only a small fraction of these investigations have been in non-mammalian systems. For the present study, an anti-rainbow trout p53 polyclonal antibody was generated. A variety of rainbow trout (Oncorhynchus mykiss) tissues and cell lines were examined through western blot analysis of cellular protein extracts, which revealed relatively high p53 levels in brain and gills. To evaluate the checkpoint response of rainbow trout p53, RTbrain-W1 and RTgill-W1 cell lines were exposed to varying concentrations of the DNA damaging agent bleomycin and ribonucleotide reductase inhibitor hydroxyurea. In contrast to mammals, these checkpoint-inducing agents provoked no apparent increase in rainbow trout p53 levels. These results infer the presence of alternate DNA damage checkpoint mechanisms in rainbow trout cells. Copyright © 2011 Elsevier Inc. All rights reserved.

  19. p53-competent cells and p53-deficient cells display different susceptibility to oxygen functionalized graphene cytotoxicity and genotoxicity.

    Science.gov (United States)

    Petibone, Dayton M; Mustafa, Thikra; Bourdo, Shawn E; Lafont, Andersen; Ding, Wei; Karmakar, Alokita; Nima, Zeid A; Watanabe, Fumiya; Casciano, Daniel; Morris, Suzanne M; Dobrovolsky, Vasily N; Biris, Alexandru S

    2017-11-01

    Due to the distinctive physical, electrical, and chemical properties of graphene nanomaterials, numerous efforts pursuing graphene-based biomedical and industrial applications are underway. Oxidation of pristine graphene surfaces mitigates its otherwise hydrophobic characteristic thereby improving its biocompatibility and functionality. Yet, the potential widespread use of oxidized graphene derivatives raises concern about adverse impacts on human health. The p53 tumor suppressor protein maintains cellular and genetic stability after toxic exposures. Here, we show that p53 functional status correlates with oxygen functionalized graphene (f-G) cytotoxicity and genotoxicity in vitro. The f-G exposed p53-competent cells, but not p53-deficient cells, initiated G0 /G1 phase cell cycle arrest, suppressed reactive oxygen species, and entered apoptosis. There was p53-dependent f-G genotoxicity evident as increased structural chromosome damage, but not increased gene mutation or chromatin loss. In conclusion, the cytotoxic and genotoxic potential for f-G in exposed cells was dependent on the p53 functional status. These findings have broad implications for the safe and effective implementation of oxidized graphene derivatives into biomedical and industrial applications. Published 2017. This article has been contributed to by US Government employees and their work is in the public domain in the USA. Published 2017. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

  20. MG53-IRS-1 (Mitsugumin 53-Insulin Receptor Substrate-1) Interaction Disruptor Sensitizes Insulin Signaling in Skeletal Muscle.

    Science.gov (United States)

    Lee, Hyun; Park, Jung-Jin; Nguyen, Nga; Park, Jun Sub; Hong, Jin; Kim, Seung-Hyeob; Song, Woon Young; Kim, Hak Joong; Choi, Kwangman; Cho, Sungchan; Lee, Jae-Seon; Kim, Bong-Woo; Ko, Young-Gyu

    2016-12-23

    Mitsugumin 53 (MG53) is an E3 ligase that interacts with and ubiquitinates insulin receptor substrate-1 (IRS-1) in skeletal muscle; thus, an MG53-IRS-1 interaction disruptor (MID), which potentially sensitizes insulin signaling with an elevated level of IRS-1 in skeletal muscle, is an excellent candidate for treating insulin resistance. To screen for an MID, we developed a bimolecular luminescence complementation system using an N-terminal luciferase fragment fused with IRS-1 and a C-terminal luciferase fragment fused with an MG53 C14A mutant that binds to IRS-1 but does not have E3 ligase activity. An MID, which was discovered using the bimolecular luminescence complementation system, disrupted the molecular association of MG53 with IRS-1, thus abolishing MG53-mediated IRS-1 ubiquitination and degradation. Thus, the MID sensitized insulin signaling and increased insulin-elicited glucose uptake with an elevated level of IRS-1 in C2C12 myotubes. These data indicate that this MID holds promise as a drug candidate for treating insulin resistance. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  1. TP53 and Beta-catenin mutations in liver tumours

    Directory of Open Access Journals (Sweden)

    Pierre Hainaut

    2007-02-01

    Full Text Available

    HBV and HCV play key roles in the etiopathogenesis of Hepatocellular carcinoma (HCC . Studies mostly based on cases from Western countries suggest distinct genetic pathways of carcinogenesis involving either TP53 or CTTNB1 mutations. Inappropriate reactivation of Wnt pathway due to mutations in CTNNB1 (Beta-Catenin gene itself is also frequently reported. Mutant Beta-catenin escapes to ubiquitination and down regulation by GSK3-B, it accumulates and trans-activates variety of oncogenes involved in neoplasmic transformation mimicking Wnt pathway activation. Taking into consideration viral infection, chromosome instability and TP53 /Beta-catenin alterations, Laurent-Puig et al. described two distinct HCC profiles in a serie of 137 HCC cases , the first one associates HBV infection with frequent chromosomal alteration and distributes with TP53 mutations, the second would be observed in HBV negative large sized tumors and distributes with Beta-catenin mutations. We have investigated the status of HBV and HCV infections and of genetic alterations in TP53 and CTTNB1 in 26 patients with HCC from Thailand. In tumours, HBV DNA was found in 19 cases (73% and HCV RNA in 4 cases (15.4% cases, 3 of whom were co-infected. Among the 19 HBV positive cases, sequencing of S gene showed genotype C in 82% and genotype B in 18%. Furthermore, 5/19 cases were negative for HBsAg and were categorized as occult HBV infections. TP53 mutations were detected in 9 cases (34,6% including 7 mutations at codon 249 (AGG to AGT, arginine to serine, considered as ";fingerprint"; of mutagenesis by aflatoxin metabolites. All cases with 249ser mutation had overt HBV infection.

    CTNNB1 mutations were found in 6/26 cases (23%, 4 of whom also had TP53 mutation. There was no significant association between CTTNB1

  2. Microsatellite instability and p53 mutations in hepatocellular carcinoma.

    Science.gov (United States)

    Karachristos, A; Liloglou, T; Field, J K; Deligiorgi, E; Kouskouni, E; Spandidos, D A

    1999-01-01

    We have studied 27 hepatocellular carcinomas (HCCs) to identify possible relationships between microsatellite instability (MSI), p53 mutations, and HBV infection in hepatocarcinogenesis. MSI was assessed using 19 polymorphic markers and the poly(A) tract BAT-26. All coding regions of p53 were examined for mutations. Tumors were also examined for presence of hepatitis B virus (HBV) DNA sequences; 66.6% of the samples exhibit MSI in at least one microsatellite locus and 44% in two or three loci. None of the tumors examined showed alterations in BAT-26. Moreover, 73.3% of samples with indication of HBV infection showed instability in at least one marker. No association between MSI and pathological profile was found. Five (18.5%) samples harbored mutations in p53, three missense, and two insertions, all in exons 5 and 8 not previously reported. No mutations were detected in codon 249, which has been linked with dietary intake of aflatoxins. Our results support the hypothesis that HCC is a "low" MSI tumor. Only 1/5 samples with MSI in more than two markers harbored a mutation in p53. Although the number of samples is too small to support a statistical significance, this finding may indicate an inverse relationship between p53 mutations and MSI in HCC.

  3. p53 as a retrovirus-induced oxidative stress modulator.

    Science.gov (United States)

    Kim, Soo Jin; Wong, Paul K Y

    2015-01-01

    Infection of astrocytes by the neuropathogenic mutant of Moloney murine leukemia virus, ts1, exhibits increased levels of reactive oxygen species (ROS) and signs of oxidative stress compared with uninfected astrocytes. Previously, we have demonstrated that ts1 infection caused two separate events of ROS upregulation. The first upregulation occurs during early viral establishment in host cells and the second during the virus-mediated apoptotic process. In this study, we show that virus-mediated ROS upregulation activates the protein kinase, ataxia telangiectasia mutated, which in turn phosphorylates serine 15 on p53. This activation of p53 however, is unlikely associated with ts1-induced cell death. Rather p53 appears to be involved in suppressing intracellular ROS levels in astrocytes under oxidative stress. The activated p53 appears to delay retroviral gene expression by suppressing NADPH oxidase, a superoxide-producing enzyme. These results suggest that p53 plays a role as a retrovirus-mediated oxidative stress modulator. © 2015 The Authors.

  4. Number of rare germline CNVs and TP53 mutation types.

    Science.gov (United States)

    Silva, Amanda G; Achatz, Isabel Maria W; Krepischi, Ana Cv; Pearson, Peter L; Rosenberg, Carla

    2012-12-21

    The Li-Fraumeni syndrome (LFS), an inherited rare cancer predisposition syndrome characterized by a variety of early-onset tumors, is caused by different highly penetrant germline mutations in the TP53 gene; each separate mutation has dissimilar functional and phenotypic effects, which partially clarifies the reported heterogeneity between LFS families. Increases in copy number variation (CNV) have been reported in TP53 mutated individuals, and are also postulated to contribute to LFS phenotypic variability. The Brazilian p.R337H TP53 mutation has particular functional and regulatory properties that differ from most other common LFS TP53 mutations, by conferring a strikingly milder phenotype. We compared the CNV profiles of controls, and LFS individuals carrying either p.R337H or DNA binding domain (DBD) TP53 mutations by high resolution array-CGH. Although we did not find any significant difference in the frequency of CNVs between LFS patients and controls, our data indicated an increased proportion of rare CNVs per genome in patients carrying DBD mutations compared to both controls (p=0.0002***) and p.R337H (0.0156*) mutants. The larger accumulation of rare CNVs in DBD mutants may contribute to the reported anticipation and severity of the syndrome; likewise the fact that p.R337H individuals do not present the same magnitude of rare CNV accumulation may also explain the maintenance of this mutation at relatively high frequency in some populations.

  5. Number of rare germline CNVs and TP53 mutation types

    Directory of Open Access Journals (Sweden)

    Silva Amanda G

    2012-12-01

    Full Text Available Abstract Background The Li-Fraumeni syndrome (LFS, an inherited rare cancer predisposition syndrome characterized by a variety of early-onset tumors, is caused by different highly penetrant germline mutations in the TP53 gene; each separate mutation has dissimilar functional and phenotypic effects, which partially clarifies the reported heterogeneity between LFS families. Increases in copy number variation (CNV have been reported in TP53 mutated individuals, and are also postulated to contribute to LFS phenotypic variability. The Brazilian p.R337H TP53 mutation has particular functional and regulatory properties that differ from most other common LFS TP53 mutations, by conferring a strikingly milder phenotype. Methods We compared the CNV profiles of controls, and LFS individuals carrying either p.R337H or DNA binding domain (DBD TP53 mutations by high resolution array-CGH. Results Although we did not find any significant difference in the frequency of CNVs between LFS patients and controls, our data indicated an increased proportion of rare CNVs per genome in patients carrying DBD mutations compared to both controls (p=0.0002*** and p.R337H (0.0156* mutants. Conclusions The larger accumulation of rare CNVs in DBD mutants may contribute to the reported anticipation and severity of the syndrome; likewise the fact that p.R337H individuals do not present the same magnitude of rare CNV accumulation may also explain the maintenance of this mutation at relatively high frequency in some populations.

  6. Experimental Conditions: SE53_S01_M03_D03 [Metabolonote[Archive

    Lifescience Database Archive (English)

    Full Text Available using metabolomics for objective substantial equivalence assessment SE53_S01 Tomato SE53_S01_M03 14μg SE53_M...SE53_S01_M03_D03 SE53 Covering chemical diversity of genetically-modified tomatoes

  7. Experimental Conditions: SE53_S01_M02_D02 [Metabolonote[Archive

    Lifescience Database Archive (English)

    Full Text Available using metabolomics for objective substantial equivalence assessment SE53_S01 Tomato SE53_S01_M02 125μl SE53_...SE53_S01_M02_D02 SE53 Covering chemical diversity of genetically-modified tomatoes

  8. Protein 53 expression in a mixed Labrador subcutaneous lymphoma

    Directory of Open Access Journals (Sweden)

    Annahita Rezaie

    2012-06-01

    Full Text Available An 11 year – old mixed female Labrador was presented with two masses in trunk and neck. The tumoral masses were excised and sent for histopathological and immunohistochemical analyses. Histopathological examination of masses revealed diffuse infiltration of small sized lymphoid cells in subcutaneous tissue which were intense around the blood vessels. More than 10% lymphoid cells were CD3 positive in the immunohistochemical staining and most of them were accumulated around vessels. Protein 53 (p53 expression was detected by brown nuclei in immunohistochemical staining. Subcutaneous lymphoma was diagnosed according to histopathological results. After 6 months the case was referred with multicentric lymphoma and based on the owner request euthanasia was performed. These findings emphasize on poor prognosis for tumors with p53 mutation.

  9. Germline mutations of TP53 gene in breast cancer.

    Science.gov (United States)

    Damineni, Surekha; Rao, Vadlamudi Raghavendra; Kumar, Satish; Ravuri, Rajasekar Reddy; Kagitha, Sailaja; Dunna, Nageswara Rao; Digumarthi, Raghunadharao; Satti, Vishnupriya

    2014-09-01

    Germline alterations of the TP53 gene encoding the p53 protein have been observed in the majority of families with the Li-Fraumeni syndrome, a rare dominantly inherited disorder with breast cancer. Genomic DNA samples of 182 breast cancer cases and 186 controls were sequenced for TP53 mutations in the exon 5-9 and intervening introns 5, 7-9. Direct sequencing was done using Applied Biosystem 3730 DNA analyzer. In the present study, we observed nine mutations in the sequenced region, of which five were novel. Hardy-Weinberg equilibrium (HWE) was done for all the mutations; C14181T, T14201G, and G13203A have shown deviation from HWE. High linkage disequilibrium (LD) was observed between C14181T (rs129547788) and T14201G (rs12951053) (r (2) = 0.98.3; D' = 1.00), whereas other observed mutations do not show strong LD with any of the other mutations. None of the intronic mutations has shown significant association with the breast cancer, two exonic mutations G13203A (rs28934578) and A14572G are significantly (P = 0.04, P = 0.007) associated with breast cancer. Germline mutations observed in DNA-binding domain of the gene showed significant association with breast cancer. This study reports five novel germline mutations in the TP53 gene out of which one mutation may confer significant risk to the breast cancer. Mutations in DNA-binding domain of TP53 gene may play role in the early onset and prognosis of breast cancer. The population-based studies of germline mutations in DNA-binding domain of TP53 gene helps in identification of individuals and families who are at risk of developing cancers.

  10. Recent Improvements To The RELAP5-3D Code

    Energy Technology Data Exchange (ETDEWEB)

    Richard A. Riemke; Paul D. Bayless; S. Michael Modro

    2006-06-01

    The RELAP5-3D computer program has been recently improved. Changes were made as follows: (1) heat structures are allowed to be decoupled from hydrodynamic components, (2) built-in material properties for heat structures have been made consistent with those in MATPRO and the Nuclear Systems Materials Handbook (they are now documented in the RELAP5-3D manual, (3) Schrock's flow quality correlation is now used for a downward oriented junction from a horizontal volume for the stratification entrainment/pullthrough model.

  11. The 5'-3' Distance of RNA Secondary Structures

    DEFF Research Database (Denmark)

    Han, Hillary S W; Reidys, Christian

    2012-01-01

    Abstract Recently, Yoffe and colleagues observed that the average distances between 5'-3' ends of RNA molecules are very small and largely independent of sequence length. This observation is based on numerical computations as well as theoretical arguments maximizing certain entropy functionals....... In this article, we compute the exact distribution of 5'-3' distances of RNA secondary structures for any finite n. Furthermore, we compute the limit distribution and show that for n = 30 the exact distribution and the limit distribution are very close. Our results show that the distances of random RNA secondary...... structures are distinctively lower than those of minimum free energy structures of random RNA sequences....

  12. Morphological Heterogeneity of p53 Positive and p53 Negative Nuclei in Breast Cancers Stratified by Clinicopathological Variables

    Directory of Open Access Journals (Sweden)

    Katrin Friedrich

    1997-01-01

    Full Text Available The study was aimed to detect differences in nuclear morphology between nuclear populations as well as between tumours with different p53 expression in breast cancers with different clinicopathological features, which also reflect the stage of tumour progression. The p53 immunohistochemistry was performed on paraffin sections from 88 tumour samples. After the cells had been localised by means of an image cytometry workstation and their immunostaining had been categorised visually, the sections were destained and stained by the Feulgen protocol. The nuclei were relocated and measured cytometrically by the workstation.

  13. 46 CFR 310.53 - Nominations and vacancies.

    Science.gov (United States)

    2010-10-01

    ... Shipping MARITIME ADMINISTRATION, DEPARTMENT OF TRANSPORTATION TRAINING MERCHANT MARINE TRAINING Admission and Training of Midshipmen at the United States Merchant Marine Academy § 310.53 Nominations and... for each nominee to the Admissions Office, U.S. Merchant Marine Academy, Kings Point, Long Island, New...

  14. Profile of TP53 gene mutations in sinonasal cancer

    DEFF Research Database (Denmark)

    Holmila, Reetta; Bornholdt, Jette; Suitiala, Tuula

    2010-01-01

    Genetic alterations underlying the development of the cancer of the nose and paranasal sinuses (sinonasal cancer, SNC), a rare cancer that can be included in the group of head and neck cancers, are still largely unknown. We recently reported that TP53 mutations are a common feature of SNC, with a...

  15. Systematic and comprehensive analysis of mutant p53 proteins in ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    The gene p53 is a well-known tumour suppressor gene that prevents cancer formation. It is the most commonly mutated gene among individuals with a diagnosis of cancer. Through recent advances in DNA sequencing abilities, researchers are now in a position to take a patient's tumour and identify the exact mutation in ...

  16. A role for p53 in selenium-induced senescence

    Science.gov (United States)

    The tumor suppressor p53 and the ataxia-telangiectasia mutated (ATM) kinase play important roles in the senescence response to oncogene activation and DNA damage. We have previously shown that selenium-containing compounds can activate an ATM-dependent senescence response in MRC-5 normal fibroblasts...

  17. 27 CFR 53.114 - Use in further manufacture.

    Science.gov (United States)

    2010-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 2 2010-04-01 2010-04-01 false Use in further manufacture... further manufacture. For purposes of section 4218 and § 53.111, an article is used as material in the manufacture or production of, or as a component part of, another article, if it is incorporated in, or is a...

  18. 40 CFR 53.52 - Leak check test.

    Science.gov (United States)

    2010-07-01

    ... MONITORING REFERENCE AND EQUIVALENT METHODS Procedures for Testing Physical (Design) and Performance Characteristics of Reference Methods and Class I and Class II Equivalent Methods for PM2.5 or PM10â2.5 § 53.52... equipment. (1) Flow rate measurement device, range 70 mL/min to 130 mL/min, 2 percent certified accuracy...

  19. 30 CFR 47.53 - Alternative for hazardous waste.

    Science.gov (United States)

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Alternative for hazardous waste. 47.53 Section... waste. If the mine produces or uses hazardous waste, the operator must provide potentially exposed miners and designated representatives access to available information for the hazardous waste that— (a...

  20. Complete molar pregnancy in a 53-year-old woman

    African Journals Online (AJOL)

    Enrique

    43. SA JOURNAL OF RADIOLOGY • May 2004. CASE REPORT. Introduction. This case emphasises the role of sonography in the diagnosis of a com- plete molar pregnancy. Case report. A 53-year-old female, para 13 gravid 13, presented to the casualty department of Pretoria Academic. Hospital with a complaint of PV (per.

  1. Cellular inactivation of nitric oxide induces p53-dependent ...

    African Journals Online (AJOL)

    Results: c-PTIO and 1400W, alone or in combination, inhibited cell growth and promoted apoptosis via sub-G1 cell cycle arrest mediated by decrease in NO•. Apoptosis was delayed and greatly reduced in magnitude in SK mel-28 cells, underscoring the importance of p53 modulation of the response. In both cell types, ...

  2. 21 CFR 314.53 - Submission of patent information.

    Science.gov (United States)

    2010-04-01

    ... Cosmetic Act. This time-sensitive patent information is submitted pursuant to 21 CFR 314.53. I attest that... approved under section 505 of the Federal Food, Drug, and Cosmetic Act. This time-sensitive patent... information, an archival copy and a copy for the chemistry, manufacturing, and controls section of the review...

  3. 44 CFR 204.53 - Certifying costs and payments.

    Science.gov (United States)

    2010-10-01

    ... Procedures § 204.53 Certifying costs and payments. (a) By submitting applicants' Project Worksheets to us, the Grantee is certifying that all costs reported on applicant Project Worksheets were incurred for work that was performed in compliance with FEMA laws, regulations, policy and guidance applicable to...

  4. 8 CFR 280.53 - Civil monetary penalties inflation adjustment.

    Science.gov (United States)

    2010-01-01

    ... 8 Aliens and Nationality 1 2010-01-01 2010-01-01 false Civil monetary penalties inflation... REGULATIONS IMPOSITION AND COLLECTION OF FINES § 280.53 Civil monetary penalties inflation adjustment. (a) In general. In accordance with the requirements of the Federal Civil Penalties Inflation Adjustment Act of...

  5. The p53-Deficient Mouse as a Breast Cancer Model

    Science.gov (United States)

    1995-10-01

    Vogelstein, B. and Fornace, A.J., Jr. (1992). Cell 71:587-597. (6) Yonish-Rouach, E., Resnitsky, D., Lotem, J., Sachs, L., Kimchi , A., and Oren, M. (1991...Cell 70: 937-948. Yonish-Rouach, E., D. Resnitzky, J. Lotem, L. Sachs, A. Kimchi , and M. Oren. 1991. Wild-type p53 induces apoptosis of my- eloid

  6. Immunohistochemical detection of P53 and Mdm2 in vitiligo

    Directory of Open Access Journals (Sweden)

    Ola A Bakry

    2012-01-01

    Full Text Available Background: Vitiligo is a common depigmented skin disorder that is caused by selective destruction of melanocytes. It is generally accepted that the main function of melanin resides in the protection of skin cells against the deleterious effect of ultraviolet rays (UVRs. Association of vitiligo and skin cancer has been a subject of controversy. Occurrence of skin cancer in long-lasting vitiligo is rare despite multiple evidences of DNA damage in vitiliginous skin. Aim: To detect the expression of P53 and Mdm2 proteins in both depigmented and normally pigmented skin of vitiligo patients and to compare it to control subjects suffering from nonmelanoma skin cancer (NMSC. Materials and Methods: Thirty-four patients with vitiligo and 30 age and sex-matched patients with nodulo-ulcerative basal cell carcinoma (BCC as a control group were selected. Both patients and control subjects had outdoor occupations. Skin biopsies were taken from each case and control subjects. Histopathological examination of Hematoxylin and eosin-stained sections was done. Expression of P53 and Mdm2 proteins were examined immunohistochemically. Results: Both P53 and Mdm2 were strongly expressed in depigmented as well as normally pigmented skin of vitiligo patients. This expression involved the epidermis, skin adnexa and blood vessels with significant differences between cases and controls. Conclusions: The overexpression of P53 and Mdm2 proteins in both normally pigmented and depigmented skin of patients with vitiligo could contribute to the decreased occurrence of actinic damage and NMSC in these patients.

  7. Phenotype abnormality: 53 [Arabidopsis Phenome Database[Archive

    Lifescience Database Archive (English)

    Full Text Available 53 http://metadb.riken.jp/db/SciNetS_ria224i/cria224u1ria224u559i abnormal for trait of duration quality... of a process in organ named whole plant in period of organ development ... whole plant organ development ... abnormal ... duration quality of a process

  8. 36 CFR 910.53 - Building restriction line.

    Science.gov (United States)

    2010-07-01

    ... 36 Parks, Forests, and Public Property 3 2010-07-01 2010-07-01 false Building restriction line... PENNSYLVANIA AVENUE DEVELOPMENT AREA Glossary of Terms § 910.53 Building restriction line. Building restriction line means a line beyond which an exterior wall of any building of a development may not be constructed...

  9. Protecting the hedgerow: p53 and hedgehog pathway interactions.

    Science.gov (United States)

    Ho, Louisa; Alman, Benjamin

    2010-02-01

    A common environment for the Hedgehog (Subfamily: erinaceinae) is a row of shrubs and trees often used on farms for enclosing or separating fields, called a hedgerow. Maintenance of a continuous shrub border is important for shielding crops from weather damage, but also provides an ideal protective habitat for the hedgehog. Similar to its mammalian counterpart, the Hedgehog (Hh) signalling pathway requires a controlled environment to regulate proper functioning of the cell. When allowed to run wild, constitutive activation of the Hh pathway results in tumorigenesis in different tissues types, including brain, skin and cartilage. With an additional loss of p53 tumor suppressor activity, an increase in tumor incidence, size and metastasis have been observed. p53 has a number of functions that can suppress tumor formation and growth in most, if not all Hh-related cancers, such as the inhibition of cell cycle progression and cell survival. Furthermore, increasing evidence of an interaction between p53 and Hedgehog signalling pathways suggests a critical role for the tumor suppressor activity of p53 in "protecting the hedgerow".

  10. 46 CFR 53.01-5 - Scope (modifies HG-100).

    Science.gov (United States)

    2010-10-01

    ... Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) MARINE ENGINEERING HEATING BOILERS General Requirements § 53.01-5 Scope (modifies HG-100). (a) The regulations in this part apply to steam heating boilers, hot water boilers (which include hot water heating boilers and hot water supply boilers...

  11. 40 CFR 265.53 - Copies of contingency plan.

    Science.gov (United States)

    2010-07-01

    ...) Submitted to all local police departments, fire departments, hospitals, and State and local emergency response teams that may be called upon to provide emergency services. ... DISPOSAL FACILITIES Contingency Plan and Emergency Procedures § 265.53 Copies of contingency plan. A copy...

  12. 41 CFR 105-53.114 - General statement of organization.

    Science.gov (United States)

    2010-07-01

    ... description of each of GSA's major functions and organizational components is presented in subparts B and C. ... FUNCTIONS General § 105-53.114 General statement of organization. The General Services Administration is an independent agency in the executive branch of the Government. The work of the agency as a whole is directed by...

  13. 46 CFR 53.01-1 - Incorporation by reference.

    Science.gov (United States)

    2010-10-01

    .... (b) American Society of Mechanical Engineers (ASME) International, Three Park Avenue, New York, NY 10016-5990: (1) 2001 ASME Boiler and Pressure Vessel Code, Section I, Rules for Construction of Power Boilers (July 1, 2001) (“Section I of the ASME Boiler and Pressure Vessel Code”), 53.01-10. (2) 2004 ASME...

  14. 48 CFR 53.219 - Small Business Programs.

    Science.gov (United States)

    2010-10-01

    ... 48 Federal Acquisition Regulations System 2 2010-10-01 2010-10-01 false Small Business Programs... (CONTINUED) CLAUSES AND FORMS FORMS Prescription of Forms 53.219 Small Business Programs. (a) The following form may be used in reporting small disadvantaged business contracting data: OF 312 (10/00), Small...

  15. 26 CFR 53.4945-5 - Grants to organizations.

    Science.gov (United States)

    2010-04-01

    ... EXCISE TAXES (CONTINUED) FOUNDATION AND SIMILAR EXCISE TAXES Taxes on Taxable Expenditures § 53.4945-5... believe that certain organizations would derive benefits from such grant so long as the original grantee... to repay any portion not used for such purposes, provided that, with respect to equity investments...

  16. Phylogenetic analysis of human Tp53 gene using computational ...

    African Journals Online (AJOL)

    user

    2011-01-17

    Jan 17, 2011 ... their relations (Saccone et al., 2002; Waddell et al.,. 2001). Modern research strategies through manipulating the p53 pathway are emerging rapidly and one can pre- dict its extensive clinical use in the near future for the human benefit worldwide. This study was focused to explore the distribution pattern of ...

  17. TP53 gene polymorphism: Importance to cancer, ethnicity and birth ...

    Indian Academy of Sciences (India)

    Arg72Pro SNP of p53 has been associated with many types of cancer as well as with survival and longevity. We evaluated the Arg72Pro SNP frequencies of a Brazilian birth cohort and their association with current, demographic and birth epidemiological parameters available. In 1982, all hospital births of Pelotas, southern ...

  18. Artificial Macrocycles as Potent p53-MDM2 Inhibitors

    NARCIS (Netherlands)

    Estrada-Ortiz, Natalia; Neochoritis, Constantinos G.; Twarda-Clapa, Aleksandra; Musielak, Bogdan; Holak, Tad A.; Dömling, Alexander

    2017-01-01

    Based on a combination of an Ugi four component reaction and a ring closing metathesis, a library of novel artificial macrocyclic inhibitors of the p53-MDM2 interaction was designed and synthesized. These macrocycles, alternatively to stapled peptides, target for the first time the large hydrophobic

  19. 47 CFR 11.53 - Dissemination of Emergency Action Notification.

    Science.gov (United States)

    2010-10-01

    ... 47 Telecommunication 1 2010-10-01 2010-10-01 false Dissemination of Emergency Action Notification... SYSTEM (EAS) Emergency Operations § 11.53 Dissemination of Emergency Action Notification. Initiation of... levels. EAN dissemination arrangements at these levels originate from State and local governments in...

  20. 41 CFR 105-53.143 - Information Resources Management Service.

    Science.gov (United States)

    2010-07-01

    ... 41 Public Contracts and Property Management 3 2010-07-01 2010-07-01 false Information Resources... FUNCTIONS Central Offices § 105-53.143 Information Resources Management Service. (a) Creation and authority. The Information Resources Management Service (IRMS), headed by the Commissioner, Information Resources...

  1. The p53-MDM2 network: from oscillations to apoptosis

    Indian Academy of Sciences (India)

    2007-07-05

    Jul 5, 2007 ... Keywords. Apoptosis; cancer; cell cycle; MDM2 overexpression; tumour suppressor ... In this paper, we give an overview of our studies on the p53-MDM2 module and the associated pathways from a systems biology perspective. We discuss a number of key predictions, related to some specific aspects of ...

  2. RELAP5-3D Developer Guidelines and Programming Practices

    Energy Technology Data Exchange (ETDEWEB)

    Dr. George L Mesina

    2014-03-01

    Our ultimate goal is to create and maintain RELAP5-3D as the best software tool available to analyze nuclear power plants. This begins with writing excellent programming and requires thorough testing. This document covers development of RELAP5-3D software, the behavior of the RELAP5-3D program that must be maintained, and code testing. RELAP5-3D must perform in a manner consistent with previous code versions with backward compatibility for the sake of the users. Thus file operations, code termination, input and output must remain consistent in form and content while adding appropriate new files, input and output as new features are developed. As computer hardware, operating systems, and other software change, RELAP5-3D must adapt and maintain performance. The code must be thoroughly tested to ensure that it continues to perform robustly on the supported platforms. The coding must be written in a consistent manner that makes the program easy to read to reduce the time and cost of development, maintenance and error resolution. The programming guidelines presented her are intended to institutionalize a consistent way of writing FORTRAN code for the RELAP5-3D computer program that will minimize errors and rework. A common format and organization of program units creates a unifying look and feel to the code. This in turn increases readability and reduces time required for maintenance, development and debugging. It also aids new programmers in reading and understanding the program. Therefore, when undertaking development of the RELAP5-3D computer program, the programmer must write computer code that follows these guidelines. This set of programming guidelines creates a framework of good programming practices, such as initialization, structured programming, and vector-friendly coding. It sets out formatting rules for lines of code, such as indentation, capitalization, spacing, etc. It creates limits on program units, such as subprograms, functions, and modules. It

  3. Functional four-base A/T gap core sequence CATTAG of P53 response elements specifically bound tetrameric P53 differently than two-base A/T gap core sequence CATG bound both dimeric and tetrameric P53.

    Science.gov (United States)

    Cai, Bi-He; Chen, Jang-Yi; Lu, Mei-Hua; Chang, Li-Tze; Lin, Hwang-Chi; Chang, Yu-Ming; Chao, Chung-Faye

    2009-04-01

    The consensus sequence of p53 is repeated half sites of PuPuPuC(A/T)(A/T)GPyPyPy. GtAGCAttAGCCCAGACATGTCC is a 14-3-3sigma promoter p53 regulation site; the first core sequence is CAttAG, and the second is CATG. Both mutants GtAGgAttAGCCCAGACATGTCC and GtAGCAttAGCCCAGACATcTCC can be activated by p53 as a 1.5-fold half site. The original p53 regulated site on the 14-3-3sigma promoter is a whole site, and CATTAG is a functional core sequence. The p53-binding affinity and the activity of CATTAG were lower than for the mutant CATATG core sequence. Wild-type p53 acts as a tetramer to bind to the whole site; however, it also can bind to a half site by one of its dimers. Wild-type p53 can only bind to a half site with core sequence CATG but not to CATATG. The 1.5-fold half site or whole site with core sequence CATATG can be bound by wild-type p53. A p53 mutant, A344, forms dimeric p53; it can only bind to CATG, and not to CATATG. Therefore, tetrameric and dimeric p53 can bind to a two-base A/T gap core sequence, but only tetrameric p53 can bind to a four-base A/T gap core sequence.

  4. p53's choice of myocardial death or survival: Oxygen protects infarct myocardium by recruiting p53 on NOS3 promoter through regulation of p53-Lys118 acetylation

    Science.gov (United States)

    Gogna, Rajan; Madan, Esha; Khan, Mahmood; Pati, Uttam; Kuppusamy, Periannan

    2013-01-01

    Myocardial infarction, an irreversible cardiac tissue damage, involves progressive loss of cardiomyocytes due to p53-mediated apoptosis. Oxygenation is known to promote cardiac survival through activation of NOS3 gene. We hypothesized a dual role for p53, which, depending on oxygenation, can elicit apoptotic death signals or NOS3-mediated survival signals in the infarct heart. p53 exhibited a differential DNA-binding, namely, BAX-p53RE in the infarct heart or NOS3-p53RE in the oxygenated heart, which was regulated by oxygen-induced, post-translational modification of p53. In the infarct heart, p53 was heavily acetylated at Lys118 residue, which was exclusively reversed in the oxygenated heart, apparently regulated by oxygen-dependent expression of TIP60. The inhibition of Lys118 acetylation promoted the generation of NOS3-promoting prosurvival form of p53. Thus, oxygenation switches p53-DNA interaction by regulating p53 core-domain acetylation, promoting a prosurvival transcription activity of p53. Understanding this novel oxygen-p53 survival pathway will open new avenues in cardioprotection molecular therapy. PMID:24096875

  5. p53's choice of myocardial death or survival: Oxygen protects infarct myocardium by recruiting p53 on NOS3 promoter through regulation of p53-Lys(118) acetylation.

    Science.gov (United States)

    Gogna, Rajan; Madan, Esha; Khan, Mahmood; Pati, Uttam; Kuppusamy, Periannan

    2013-11-01

    Myocardial infarction, an irreversible cardiac tissue damage, involves progressive loss of cardiomyocytes due to p53-mediated apoptosis. Oxygenation is known to promote cardiac survival through activation of NOS3 gene. We hypothesized a dual role for p53, which, depending on oxygenation, can elicit apoptotic death signals or NOS3-mediated survival signals in the infarct heart. p53 exhibited a differential DNA-binding, namely, BAX-p53RE in the infarct heart or NOS3-p53RE in the oxygenated heart, which was regulated by oxygen-induced, post-translational modification of p53. In the infarct heart, p53 was heavily acetylated at Lys(118) residue, which was exclusively reversed in the oxygenated heart, apparently regulated by oxygen-dependent expression of TIP60. The inhibition of Lys(118) acetylation promoted the generation of NOS3-promoting prosurvival form of p53. Thus, oxygenation switches p53-DNA interaction by regulating p53 core-domain acetylation, promoting a prosurvival transcription activity of p53. Understanding this novel oxygen-p53 survival pathway will open new avenues in cardioprotection molecular therapy. © 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO.

  6. Cytoskeleton-Anchoring of Conformational Mutant-Like p53, but Not Shorter Isoforms p53β and p47 (ΔN40p53) in Senescent Human Fibroblasts.

    Science.gov (United States)

    Nishio, Koji

    2017-01-01

    Cytoskeleton anchoring of conformational mutant-like p53 is prominent in human senescent cells. The present research investigated the structural basis of vimentin cytoskeleton- anchoring of human p53. GFP-fused wild type p53, mutant p53, those of the various truncated isoforms including p53β and p47, were expressed in the vimentin-expressing cells: mouse fibroblasts, COS-7 cells, young and senescent human fibroblasts, and HeLa cells (non-vimentin-expressing). A cancer-specific mutant p53V143A-GFP expressed in mouse fibroblasts, exclusively anchored on the vimentin cytoskeleton. Class I mutant p53R175C-GFP and class II mutant p53R175S-GFP localized in the nuclei of COS-7 cells. A class III mutant p53R175X-GFP (X: D, F, W or Y), cancer-specific mutant p53V143A-GFP and p53R249S-GFP, exclusively anchored on the vimentin cytoskeleton of COS-7 cells. The deletions of p53R249S and p53V143A at the Cterminus (ΔC63) exclusively promoted the nuclear import of the deleted mutant p53 in COS-7 and HeLa cells, whereas the deletions at the N-terminus (ΔN40) or C-terminus (ΔC33) were ineffective. Thus, the cancer-specific mutant p53R249S and p53V143A adopt distinct mutant conformation and thereby the C-terminal region (aa331-360) potently interacts with the vimentin cytoskeleton and HeLa cells' cytoskeleton. Wild type p53-GFP exclusively localized in the nuclei of growing young fibroblast, in contrast to the significant cytoplasmic retention in senescent human fibroblasts. The deletion of p53 at the N-terminus or at the C-terminus (ΔN40 or ΔC63) results in a significant nuclear import of the shorter isoforms, p53β and p47. Senescent fibroblasts promote p53 to adopt a hotspot mutant like-conformation which significantly overrides the nuclear import due to the potent cytoskeleton-anchoring. Interestingly, the shorter p53 isoforms can escape from the cytoskeleton-anchoring. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  7. The IARC TP53 mutation database: a resource for studying the significance of TP53 mutations in human cancers

    Directory of Open Access Journals (Sweden)

    Magali Olivier

    2007-02-01

    Full Text Available

    The tumor suppressor gene TP53 is frequently inactivated by gene mutations in many types of human sporadic cancers, and inherited TP53 mutations predispose to a wide spectrum of early-onset tumors (Li-Fraumeni et Li-Fraumenilike Syndromes. All TP53 gene variations (somatic and germline mutations, as well as polymorphisms that are reported in the scientific literature or in SNP databases are compiled in the IARC TP53 Database. This database provides structured data and analysis tools to study mutation patterns in human cancers and cell-lines and to investigate the clinical impact of mutations. It contains annotations related to the clinical and pathological characteristics of tumors, as well as the demographics and carcinogen exposure of patients. The IARC TP53 web site (53.iarc.fr/">http://www-p53.iarc.fr/ provides a search interface for the core database and includes a comprehensive user guide, a slideshow on TP53 mutations in human cancer, protocols and references for sequencing TP53 gene, and links to relevant publications and bioinformatics databases. The database interface allows download of entire data sets and propose various tools for the selection, analysis and downloads of specific sets of data according to user's query.

    Recently, new annotations on the functional properties of mutant p53 proteins have been integrated in this database. Indeed, the most frequent TP53 alterations observed in cancers (75% are missense mutations that result in the production of a mutant protein that differ from the wildtype by one single amino-acid. The characterization of the biological activities of these mutant proteins is thus very important. Over the last ten years, a great amount of systematic data has been generated from experimental assays performed in

  8. The structure formed by inverted repeats in p53 response elements determines the transactivation activity of p53 protein

    Czech Academy of Sciences Publication Activity Database

    Brázda, Václav; Čechová, Jana; Battistin, M.; Coufal, Jan; Jagelská, Eva; Raimondi, I.; Inga, A.

    2017-01-01

    Roč. 483, č. 1 (2017), s. 516-521 ISSN 0006-291X R&D Projects: GA ČR GA15-21855S Institutional support: RVO:68081707 Keywords : tumor-suppressor p53 * cruciform structures * dna-conformation Subject RIV: CE - Biochemistry Impact factor: 2.466, year: 2016

  9. Construction of a triple modified p53 containing DNA vaccine to enhance processing and presentation of the p53 antigen

    NARCIS (Netherlands)

    Hospers, Geke A. P.; Meijer, Coby; Dam, Wendy A.; Roossink, Frank; Mulder, Nanno H.

    2009-01-01

    More effective and less toxic treatments are urgently needed in the treatment of patients with cancer. The turnout suppressor protein p53 is a tumour-associated antigen that could serve that purpose when applied in an immunologic approval to cancer. It is mutated in similar to 50% of the tumours

  10. Lung tumors with distinct p53 mutations respond similarly to p53 targeted therapy but exhibit genotype-specific statin sensitivity

    Science.gov (United States)

    Turrell, Frances K.; Kerr, Emma M.; Gao, Meiling; Thorpe, Hannah; Doherty, Gary J.; Cridge, Jake; Shorthouse, David; Speed, Alyson; Samarajiwa, Shamith; Hall, Benjamin A.; Griffiths, Meryl; Martins, Carla P.

    2017-01-01

    Lung adenocarcinoma accounts for ∼40% of lung cancers, the leading cause of cancer-related death worldwide, and current therapies provide only limited survival benefit. Approximately half of lung adenocarcinomas harbor mutations in TP53 (p53), making these mutants appealing targets for lung cancer therapy. As mutant p53 remains untargetable, mutant p53-dependent phenotypes represent alternative targeting opportunities, but the prevalence and therapeutic relevance of such effects (gain of function and dominant-negative activity) in lung adenocarcinoma are unclear. Through transcriptional and functional analysis of murine KrasG12D-p53null, -p53R172H (conformational), and -p53R270H (contact) mutant lung tumors, we identified genotype-independent and genotype-dependent therapeutic sensitivities. Unexpectedly, we found that wild-type p53 exerts a dominant tumor-suppressive effect on mutant tumors, as all genotypes were similarly sensitive to its restoration in vivo. These data show that the potential of p53 targeted therapies is comparable across all p53-deficient genotypes and may explain the high incidence of p53 loss of heterozygosity in mutant tumors. In contrast, mutant p53 gain of function and their associated vulnerabilities can vary according to mutation type. Notably, we identified a p53R270H-specific sensitivity to simvastatin in lung tumors, and the transcriptional signature that underlies this sensitivity was also present in human lung tumors, indicating that this therapeutic approach may be clinically relevant. PMID:28790158

  11. Binding kinetics of mutant p53R175H with wild type p53 and p63: A Surface Plasmon Resonance and Atomic Force Spectroscopy study.

    Science.gov (United States)

    Moscetti, Ilaria; Bizzarri, Anna Rita; Cannistraro, Salvatore

    2017-09-01

    The oncogenic mutant p53R175H, one of the most frequently occurring in human cancers and usually associated with poor prognosis and chemo resistance, can exert a dominant negative effect over p53 family members, namely wild type p53, p63 and p73, inhibiting their oncosuppressive function. Novel anticancer strategies based on drugs able to prevent the formation of complexes between p53R175H and the p53 family members call for a deeper knowledge on the molecular mechanisms of their interaction. To this aim, p53R175H/p63 and p53R175H/p53 complexes were investigated in vitro by using Surface Plasmon Resonance and Atomic Force Spectroscopy, two emerging and complementary techniques able to provide interaction kinetic information, in near physiological conditions and without any labelling. Both approaches show that p53R175H forms a very specific and highly stable bimolecular complex with both p63 and p53; with these interactions being characterized by a very high affinity with equilibrium dissociation constant, KD, of about 10-9M. These kinetics results, discussed also in connection with those previously reported for the interaction of p53R175H with p73, could inspire the design of suitable anticancer drugs able to antagonize the interaction of p53R175H with the p53 family members, by restoring then their anti-tumour function. Copyright © 2017. Published by Elsevier B.V.

  12. Paracrine Apoptotic Effect of p53 Mediated by Tumor Suppressor Par-4

    Directory of Open Access Journals (Sweden)

    Ravshan Burikhanov

    2014-01-01

    Full Text Available The guardian of the genome, p53, is often mutated in cancer and may contribute to therapeutic resistance. Given that p53 is intact and functional in normal tissues, we harnessed its potential to inhibit the growth of p53-deficient cancer cells. Specific activation of p53 in normal fibroblasts selectively induced apoptosis in p53-deficient cancer cells. This paracrine effect was mediated by p53-dependent secretion of the tumor suppressor Par-4. Accordingly, the activation of p53 in normal mice, but not p53−/− or Par-4−/− mice, caused systemic elevation of Par-4, which induced apoptosis of p53-deficient tumor cells. Mechanistically, p53 induced Par-4 secretion by suppressing the expression of its binding partner, UACA, which sequesters Par-4. Thus, normal cells can be empowered by p53 activation to induce Par-4 secretion for the inhibition of therapy-resistant tumors.

  13. In vivo footprinting and DNA affinity chromatography for analysis of p53 DNA binding ability.

    Science.gov (United States)

    Molina, Maria Patricia; Cain, Christine; Bargonetti, Jill

    2003-01-01

    p53 is a sequence-specific DNA binding protein. The p53 consensus is two copies of 5'- RRRC(A/T)(T/A)GYYY-3'. The interaction of p53 with specific DNA binding sites (DBS) has been analyzed extensively using electrophoretic mobility shift analysis (EMSA). These studies do not address the interaction of p53 with nuclear chromatin or the stability of p53-DBS interactions. In vivo footprinting examines the dynamic interactions of p53 protein in nuclear chromatin. p53 DBS affinity chromatography compares the stability of p53 from different cellular extracts with different DBS. Isogenic strains expressing high p53 levels, and deleted for p53, are required for controlled experiments using both methods. Different systems can be used to generate sufficient p53 protein (including DNA damage), and this results in the analysis of different forms of p53. A comparison of different cellular sources of high levels of p53 (in the presence and absence of DNA damage) vs different p53 DBS is required to appreciate the complexity of the regulation. Methods for comparing p53 from three different cellular sources with different DBS are presented here. The p53 research community needs to expand this analysis to complete the picture of how p53 differentially regulates transcription of target genes in nuclear chromatin.

  14. Expression of full-length p53 and its isoform Δp53 in breast carcinomas in relation to mutation status and clinical parameters

    Directory of Open Access Journals (Sweden)

    Deppert Wolfgang

    2006-10-01

    Full Text Available Abstract Background The tumor suppressor gene p53 (TP53 controls numerous signaling pathways and is frequently mutated in human cancers. Novel p53 isoforms suggest alternative splicing as a regulatory feature of p53 activity. Results In this study we have analyzed mRNA expression of both wild-type and mutated p53 and its respective Δp53 isoform in 88 tumor samples from breast cancer in relation to clinical parameters and molecular subgroups. Three-dimensional structure differences for the novel internally deleted p53 isoform Δp53 have been predicted. We confirmed the expression of Δp53 mRNA in tumors using quantitative real-time PCR technique. The mRNA expression levels of the two isoforms were strongly correlated in both wild-type and p53-mutated tumors, with the level of the Δp53 isoform being approximately 1/3 of that of the full-length p53 mRNA. Patients expressing mutated full-length p53 and non-mutated (wild-type Δp53, "mutational hybrids", showed a slightly higher frequency of patients with distant metastasis at time of diagnosis compared to other patients with p53 mutations, but otherwise did not differ significantly in any other clinical parameter. Interestingly, the p53 wild-type tumors showed a wide range of mRNA expression of both p53 isoforms. Tumors with mRNA expression levels in the upper or lower quartile were significantly associated with grade and molecular subtypes. In tumors with missense or in frame mutations the mRNA expression levels of both isoforms were significantly elevated, and in tumors with nonsense, frame shift or splice mutations the mRNA levels were significantly reduced compared to those expressing wild-type p53. Conclusion Expression of p53 is accompanied by the functionally different isoform Δp53 at the mRNA level in cell lines and human breast tumors. Investigations of "mutational hybrid" patients highlighted that wild-type Δp53 does not compensates for mutated p53, but rather may be associated with a

  15. Design of pneumatic proportional flow valve type 5/3

    Science.gov (United States)

    Laski, P. A.; Pietrala, D. S.; Zwierzchowski, J.; Czarnogorski, K.

    2017-08-01

    In this paper the 5/3-way pneumatic, proportional flow valve was designed and made. Stepper linear actuator was used to move the spool. The valve is controlled by the controlled based on a AVR microcontroller. Virtual model of the valve was created in CAD. The real element was made based on a standard 5/3-way manually actuated valve with hand lever, which was dismounted and replaced by linear stepper motor. All the elements was mounted in a specially made housing. The controller consists of microcontroller Atmega16, integrated circuit L293D, display, two potentiometers, three LEDs and six buttons. Series of research was also conducted. Simulation research were performed using CFD by the Flow Simulation addition to SolidWorks. During the experiments the valve characteristics of flow and pressure was determined.

  16. TA53:19 Reverb Chamber Quick-Look

    Energy Technology Data Exchange (ETDEWEB)

    Bishofberger, Kip A. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2016-05-19

    Within Building 19 of TA-53, a screen room has been evaluated for use as a reverb chamber (with deep gratitude to Dale Dalmas and Greg Dale for their assistance). With minimal additional sealing of the chamber, we expect the Q to increase even more, and thus field levels for the same RF source power. Future studies need to determine leakage field levels, which will define maximum achievable field levels.

  17. Detection of an exon 53 polymorphism in the dystrophin gene.

    Science.gov (United States)

    Prior, T W; Papp, A C; Snyder, P J; Sedra, M S

    1993-10-01

    We utilized a heteroduplex method to screen for small mutations in Duchenne muscular dystrophy patients who did not have deletions or duplications. A dystrophin exon 53 heteroduplex band was identified in 14.4% of the affected patients. Direct sequencing of the amplified product from DNA producing the heteroduplex revealed the presence of a polymorphism in the coding region. The codon for asparagine was converted from AAT to AAC.

  18. The CH-53K: Are We Purchasing the Right Amount?

    Science.gov (United States)

    2009-01-01

    QUOTATION FROM, ABSTRACTION FROM, OR REPRODUCTION OF ALL OR ANY PART OF THIS DOCUMENT IS PERMITTED PROVIDED PROPER ACKNOWLEDGEMENT IS MADE. 2 Table of...address how either modified or new equipment will operate under this new environment. In January 2006, Colonel Paul Croisetiere of Program Manager , Air...In August 1962, the Marine Corps was in search for a new heavy lift helicopter and placed its initial order for the CH-53A Sea Stallion (Figure A). At

  19. South of Sahara | Page 53 | IDRC - International Development ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    49 · 50 · 51 · 52; 53; 54 · 55 · 56 · 57 … next › · last » · What we do · Funding · Resources · About IDRC. Knowledge. Innovation. Solutions. Careers · Contact Us · Site map · Copyright · Open access policy · Privacy policy · Research ethics · Transparency · Website usage. Follow us; Facebook · Twitter · Youtube · Linked In ...

  20. 46 CFR 32.53-1 - Application-T/ALL.

    Science.gov (United States)

    2010-10-01

    ... REQUIREMENTS Inert Gas System § 32.53-1 Application—T/ALL. (a) Except as provided in paragraphs (b) and (c) of this section, this subpart applies to: (1) A U.S. crude oil tanker or product carrier of 100,000 DWT... laying date on or after January 1, 1975. (2) A new (as defined in 46 U.S.C. 3701) crude oil tanker or...

  1. Mutasi Gen P53: Faktor Prediktif Kanker Payudara?

    OpenAIRE

    Suyanto, Putri Y; Utomo, Ahmad R; Sandra, Ferry

    2008-01-01

    Farmakogenetik dalam terapi kanker adalah pemberian terapi kepada pasien berdasarkan status atau profil genetik dari sel kanker. Dengan demikian, pemberian kemoterapi diharapkan bisa lebih efektif dan meningkatkan kualitas hidup pasien dengan menghindari terapi yang diketahui secara genetik tidak memberikan keuntungan klinis. Pemeriksaan DNA gen p53 sebagai salah satu tumor suppresor gene yang termutasi pada hampir sebagian besar tumor diharapkan mampu menjadi faktor prediktif ketika dilakuka...

  2. Integrative genome analysis of somatic p53 mutant osteosarcomas identifies Ets2-dependent regulation of small nucleolar RNAs by mutant p53 protein.

    Science.gov (United States)

    Pourebrahim, Rasoul; Zhang, Yun; Liu, Bin; Gao, Ruli; Xiong, Shunbin; Lin, Patrick P; McArthur, Mark J; Ostrowski, Michael C; Lozano, Guillermina

    2017-09-15

    TP53 is the most frequently mutated gene in human cancer. Many mutant p53 proteins exert oncogenic gain-of-function (GOF) properties that contribute to metastasis, but the mechanisms mediating these functions remain poorly defined in vivo. To elucidate how mutant p53 GOF drives metastasis, we developed a traceable somatic osteosarcoma mouse model that is initiated with either a single p53 mutation (p53R172H) or p53 loss in osteoblasts. Our study confirmed that p53 mutant mice developed osteosarcomas with increased metastasis as compared with p53-null mice. Comprehensive transcriptome RNA sequencing (RNA-seq) analysis of 16 tumors identified a cluster of small nucleolar RNAs (snoRNAs) that are highly up-regulated in p53 mutant tumors. Regulatory element analysis of these deregulated snoRNA genes identified strong enrichment of a common Ets2 transcription factor-binding site. Homozygous deletion of Ets2 in p53 mutant mice resulted in strong down-regulation of snoRNAs and reversed the prometastatic phenotype of mutant p53 but had no effect on osteosarcoma development, which remained 100% penetrant. In summary, our studies identify Ets2 inhibition as a potential therapeutic vulnerability in p53 mutant osteosarcomas. © 2017 Pourebrahim et al.; Published by Cold Spring Harbor Laboratory Press.

  3. Induction of p53-Specific Immunity by a p53 Synthetic Long Peptide Vaccine in Patients Treated for Metastatic Colorectal Cancer

    NARCIS (Netherlands)

    Speetjens, Frank M.; Kuppen, PeterJ. K.; Welters, Marij. J. P.; Essahsah, Farah; van den Brink, Anne Marie E. G. Voet; Lantrua, M. Graziella Kallenberg; Valentijn, A. Rob P. M.; Oostendorp, Jaap; Fathers, Lorraine M.; Nijman, Hans W.; Drijfhout, Jan W.; van de Velde, Cornelis J. H.; Melief, Cornelis J. M.; van der Burg, Sjoerd H.

    2009-01-01

    Purpose: The tumor-associated self-antigen p53 is commonly overexpressed in cancer, including colorectal cancer, and can serve as a target for immunotherapy. The safety and immunogenicity of a p53 synthetic long peptide (p53-SLP) vaccine were investigated in patients treated for metastatic

  4. Biological activity and safety of adenoviral vector-expressed wild-type p53 after intratumoral injection in melanoma and breast cancer patients with p53-overexpressing tumors

    NARCIS (Netherlands)

    Dummer, R; Bergh, J; Karlsson, Y; Horovitz, JA; Mulder, NH; Huinin, DT; Burg, G; Hofbauer, G; Osanto, S

    p53 mutations are common genetic alterations in human cancer. Gene transfer of a wild-type (wt) p53 gene reverses the loss of normal p53 function in vitro and in vivo. A phase I dose escalation study of single intratumoral (i.t.) injection of a replication-defective adenoviral expression vector

  5. The Inherited p53 Mutation in the Brazilian Population.

    Science.gov (United States)

    Achatz, Maria Isabel; Zambetti, Gerard P

    2016-12-01

    A common criticism of studying rare diseases is the often-limited relevance of the findings to human health. Here, we review ∼15 years of research into an unusual germline TP53 mutation (p.R337H) that began with its detection in children with adrenocortical carcinoma (ACC), a remarkably rare childhood cancer that is associated with poor prognosis. We have come to learn that the p.R337H mutation exists at a very high frequency in Southern and Southeastern Brazil, occurring in one of 375 individuals within a total population of ∼100 million. Moreover, it has been determined that carriers of this founder mutation display variable tumor susceptibility, ranging from isolated cases of pediatric ACC to Li-Fraumeni or Li-Fraumeni-like (LFL) syndromes, thus representing a significant medical issue for this country. Studying the biochemical and molecular consequences of this mutation on p53 tumor-suppressor activity, as well as the putative additional genetic alterations that cooperate with this mutation, is advancing our understanding of how p53 functions in tumor suppression in general. These studies, which originated with a rare childhood tumor, are providing important information for guiding genetic counselors and physicians in treating their patients and are already providing clinical benefit. Copyright © 2016 Cold Spring Harbor Laboratory Press; all rights reserved.

  6. Phenotype Specific Analyses Reveal Distinct Regulatory Mechanism for Chronically Activated p53

    Science.gov (United States)

    Cairns, Jonathan M.; Menon, Suraj; Pérez-Mancera, Pedro A.; Tomimatsu, Kosuke; Bermejo-Rodriguez, Camino; Ito, Yoko; Chandra, Tamir; Narita, Masako; Lyons, Scott K.; Lynch, Andy G.; Kimura, Hiroshi; Ohbayashi, Tetsuya; Tavaré, Simon; Narita, Masashi

    2015-01-01

    The downstream functions of the DNA binding tumor suppressor p53 vary depending on the cellular context, and persistent p53 activation has recently been implicated in tumor suppression and senescence. However, genome-wide information about p53-target gene regulation has been derived mostly from acute genotoxic conditions. Using ChIP-seq and expression data, we have found distinct p53 binding profiles between acutely activated (through DNA damage) and chronically activated (in senescent or pro-apoptotic conditions) p53. Compared to the classical ‘acute’ p53 binding profile, ‘chronic’ p53 peaks were closely associated with CpG-islands. Furthermore, the chronic CpG-island binding of p53 conferred distinct expression patterns between senescent and pro-apoptotic conditions. Using the p53 targets seen in the chronic conditions together with external high-throughput datasets, we have built p53 networks that revealed extensive self-regulatory ‘p53 hubs’ where p53 and many p53 targets can physically interact with each other. Integrating these results with public clinical datasets identified the cancer-associated lipogenic enzyme, SCD, which we found to be directly repressed by p53 through the CpG-island promoter, providing a mechanistic link between p53 and the ‘lipogenic phenotype’, a hallmark of cancer. Our data reveal distinct phenotype associations of chronic p53 targets that underlie specific gene regulatory mechanisms. PMID:25790137

  7. Mutant Mice Lacking the p53 C-Terminal Domain Model Telomere Syndromes

    NARCIS (Netherlands)

    Simeonova, I.; Jaber, S.; Draskovic, I.; Bardot, B.; Fang, M.; Bouarich-Bourimi, R.; Lejour, V.; Charbonnier, L.; Soudais, C.; Bourdon, J.C.; Huerre, M.; Londono-Vallejo, A.; Toledo, F.

    2013-01-01

    Mutations in p53, although frequent in human cancers, have not been implicated in telomere-related syndromes. Here, we show that homozygous mutant mice expressing p53(Delta31), a p53 lacking the C-terminal domain, exhibit increased p53 activity and suffer from aplastic anemia and pulmonary fibrosis,

  8. Experimental Conditions: SE53_S01_M01_D01 [Metabolonote[Archive

    Lifescience Database Archive (English)

    Full Text Available using metabolomics for objective substantial equivalence assessment SE53_S01 Tomato SE53_S01_M01 An equivale...SE53_S01_M01_D01 SE53 Covering chemical diversity of genetically-modified tomatoes

  9. Release of targeted p53 from the mitochondrion as an early signal during mitochondrial dysfunction

    Science.gov (United States)

    Increased accumulation of p53 tumor suppressor protein is an early response to low-level stressors. To investigate the fate of mitochondrial-sequestered p53, mouse embryonic fibroblast cells (MEFs) on a p53-deficient genetic background were transfected with p53-EGFP fusion protei...

  10. Evidence for allosteric variants of wild-type p53, a tumour suppressor protein.

    OpenAIRE

    Cook, A.; Milner, J.

    1990-01-01

    A tumour suppressor function for p53 is indicated in human lung cancer and in carcinoma of the colorectum. Loss of suppressor function, by mutation of the p53 gene, is associated with activation of p53 as an oncogene. The suppressor (wild type) and oncogenic (mutant) forms of the murine p53 protein are distinguishable at the molecular level by reactivity with anti-p53 monoclonal antibodies. For example, activated mutant p53 fails to react with PAb246 (p53-246 degrees). We now demonstrate that...

  11. Mutant p53 accumulates in cycling and proliferating cells in the normal tissues of p53 R172H mutant mice

    Science.gov (United States)

    Leushacke, Marc; Li, Ling; Wong, Julin S.; Chiam, Poh Cheang; Rahmat, Siti Aishah Binte; Mann, Michael B.; Mann, Karen M.; Barker, Nick; Lozano, Guillermina; Terzian, Tamara; Lane, David P.

    2015-01-01

    The tumour suppressor p53 is regulated primarily at the protein level. In normal tissues its levels are maintained at a very low level by the action of specific E3 ligases and the ubiquitin proteosome pathway. The mutant p53 protein contributes to transformation, metastasis and drug resistance. High levels of mutant p53 can be found in tumours and the accumulation of mutant p53 has previously been reported in pathologically normal cells in human skin. We show for the first time that similarly elevated levels of mutant p53 can be detected in apparently normal cells in a mutant p53 knock-in mouse model. In fact, in the small intestine, mutant p53 spontaneously accumulates in a manner dependent on gene dosage and cell type. Mutant p53 protein is regulated similarly to wild type p53, which can accumulate rapidly after induction by ionising radiation or Mdm2 inhibitors, however, the clearance of mutant p53 protein is much slower than wild type p53. The accumulation of the protein in the murine small intestine is limited to the cycling, crypt base columnar cells and proliferative zone and is lost as the cells differentiate and exit the cell cycle. Loss of Mdm2 results in even higher levels of p53 expression but p53 is still restricted to proliferating cells in the small intestine. Therefore, the small intestine of these p53 mutant mice is an experimental system in which we can dissect the molecular pathways leading to p53 accumulation, which has important implications for cancer prevention and therapy. PMID:26255629

  12. COMPLETION REPORT FOR WELL CLUSTER ER-5-3

    Energy Technology Data Exchange (ETDEWEB)

    BECHTEL NEVADA

    2005-12-01

    Well Cluster ER-5-3 was drilled for the U.S. Department of Energy, National Nuclear Security Administration Nevada Site Office in support of the Nevada Environmental Restoration Project at the Nevada Test Site, Nye County, Nevada. This cluster of 3 wells was drilled in 2000 and 2001 as part of a hydrogeologic investigation program in Frenchman Flat. The first borehole in the cluster, Well ER-5-3, was drilled in February and March 2000. A 47.0-centimeter surface hole was drilled and cased off to the depth of 374.8 meters. The hole diameter was decreased to 31.1 centimeters for drilling to a total depth of 794.3 meters within welded ash-flow tuff. A piezometer string with 1 slotted interval was installed in the annulus of the surface casing, open to the saturated alluvium. A completion string with 2 slotted intervals was installed in the main hole, open to saturated alluvium and to the welded tuff aquifer. A second piezometer string with 1 slotted interval open to the welded-tuff aquifer was installed outside the completion string. Well ER-5-3 No.2 was drilled about 30 meters west of the first borehole in March 2000, and was recompleted in March 2001. A 66.0-centimeter hole was drilled and cased off to the depth of 613.8 meters. The hole diameter was decreased to 44.5 centimeters and the borehole was drilled and cased off to the depth of 849.0 meters. The hole diameter was decreased once more to 31.1 centimeters for drilling to a total depth of 1,732.2 meters in dolomite. A completion string open to the dolomite (lower carbonate aquifer) was installed. Well ER-5-3 No.3 was drilled approximately 30 meters north of the first 2 boreholes in February 2001. A 66.0-centimeter hole was drilled and cased off to the depth of 36.6 meters, then the main 25.1-centimeter-diameter hole was drilled to a total depth of 548.6 meters in alluvium. A slotted stainless-steel tubing string was installed in the saturated alluvium. A preliminary composite, static water level was measured at

  13. Gene expression profiles resulting from stable loss of p53 mirrors its role in tissue differentiation.

    Directory of Open Access Journals (Sweden)

    Oliver Couture

    Full Text Available The tumor suppressor gene p53 is involved in a variety of cellular activities such as cellular stress responses, cell cycle regulation and differentiation. In our previous studies we have shown p53's transcription activating role to be important in osteoblast differentiation. There is still a debate in the literature as to whether p53 inhibits or promotes differentiation. We have found p53 heterozygous mice to show a p53 dependency on some bone marker gene expression that is absent in knockout mice. Mice heterozygous for p53 also show a higher incidence of osteosarcomas than p53 knockout mice. This suggests that p53 is able to modify the environment within osteoblasts. In this study we compare changes in gene expression resulting after either a transient or stable reduction in p53. Accordingly we reduced p53 levels transiently and stably in C2C12 cells, which are capable of both myoblast and osteoblast differentiation, and compared the changes in gene expression of candidate genes regulated by the p53 pathway. Using a PCR array to assay for p53 target genes, we have found different expression profiles when comparing stable versus transient knockdown of p53. As expected, several genes with profound changes after transient p53 loss were related to apoptosis and cell cycle regulation. In contrast, stable p53 loss produced a greater change in MyoD and other transcription factors with tissue specific roles, suggesting that long term loss of p53 affects tissue homeostasis to a greater degree than changes resulting from acute loss of p53. These differences in gene expression were validated by measuring promoter activity of different pathway specific genes involved in differentiation. These studies suggest that an important role for p53 is context dependent, with a stable reduction in p53 expression affecting normal tissue physiology more than acute loss of p53.

  14. Ninjurin 1 has two opposing functions in tumorigenesis in a p53-dependent manner.

    Science.gov (United States)

    Yang, Hee Jung; Zhang, Jin; Yan, Wensheng; Cho, Seong-Jun; Lucchesi, Christopher; Chen, Mingyi; Huang, Eric C; Scoumanne, Ariane; Zhang, Weici; Chen, Xinbin

    2017-10-24

    WT p53 is critical for tumor suppression, whereas mutant p53 promotes tumor progression. Nerve injury-induced protein 1 (Ninj1) is a target of p53 and forms a feedback loop with p53 by repressing p53 mRNA translation. Here, we show that loss of Ninj1 increased mutant p53 expression and, subsequently, enhanced cell growth and migration in cells carrying a mutant p53. In contrast, loss of Ninj1 inhibited cell growth and migration in cells carrying a WT p53. To explore the biological significance of Ninj1, we generated a cohort of Ninj1-deficient mice and found that Ninj1+/- mice were prone to systemic inflammation and insulitis, but not to spontaneous tumors. We also found that loss of Ninj1 altered the tumor susceptibility in both mutant p53 and p53-null background. Specifically, in a mutant p53(R270H) background, Ninj1 deficiency shortened the lifespan, altered the tumor spectrum, and increased tumor burden, likely via enhanced expression of mutant p53. In a p53-null background, Ninj1 deficiency significantly increased the incidence of T-lymphoblastic lymphoma. Taken together, our data suggest that depending on p53 genetic status, Ninj1 has two opposing functions in tumorigenesis and that the Ninj1-p53 loop may be targeted to manage inflammatory diseases and cancer. Published under the PNAS license.

  15. Identification of p53 and Its Isoforms in Human Breast Carcinoma Cells

    Directory of Open Access Journals (Sweden)

    Zorka Milićević

    2014-01-01

    Full Text Available In breast carcinoma, disruption of the p53 pathway is one of the most common genetic alterations. The observation that the p53 can express multiple protein isoforms adds a novel level of complexity to the outcome of p53 mutations. p53 expression was analysed by Western immunoblotting and immunohistochemistry using monoclonal antibodies DO-7, Pab240, and polyclonal antiserum CM-1. The more frequently p53-positive nuclear staining has been found in the invasive breast tumors. One of the most intriguing findings is that mutant p53 appears as discrete dot-shaped regions within the nucleus of breast cancer cells. In many malignant cells, the nucleolar sequestration of p53 is evident. These observations support the view that the nucleolus is involved directly in the mediation of p53 function or indirectly by the control of the localization of p53 interplayers. p53 expressed in the nuclear fraction of breast cancer cells revealed a wide spectrum of isoforms. p53 isoforms ΔNp53 (47 kDa and Δ133p53β (35 kDa, known as dominant-negative repressors of p53 function, were detected as the most predominant variants in nuclei of invasive breast carcinoma cells. The isoforms expressed also varied between individual tumors, indicating potential roles of these p53 variants in human breast cancer.

  16. Discrimination of p53 immunohistochemistry-positive tumors by its staining pattern in gastric cancer

    Science.gov (United States)

    Ando, Koji; Oki, Eiji; Saeki, Hiroshi; Yan, Zhao; Tsuda, Yasuo; Hidaka, Gen; Kasagi, Yuta; Otsu, Hajime; Kawano, Hiroyuki; Kitao, Hiroyuki; Morita, Masaru; Maehara, Yoshihiko

    2015-01-01

    Immunohistochemistry staining of p53 is a cheap and simple method to detect aberrant function of p53. However, there are some discrepancies between the result of immunohistochemistry staining and mutation analysis. This study attempted to find a new definition of p53 staining by its staining pattern. Immunohistochemistry staining of p53 and TP53 gene mutation analysis were performed in 148 gastric cancer patients. Also SNP-CGH array analysis was conducted to four cases. Positive staining of p53 was observed in 88 (59.5%) tumors. Tumors with positive p53 staining showed malignant features compared to negative tumors. Mutation of TP53 gene was observed in 29 (19.6%) tumors with higher age and differentiated type. In positive p53 tumors, two types could be distinguished; aberrant type and scattered type. With comparison to TP53 gene mutation analysis, all the scattered type had wild-type TP53 gene (P = 0.0003). SNP-CGH array showed that scattered-type tumors had no change in the structure of chromosome 17. P53-scattered-type staining tumors may reflect a functionally active nonmutated TP53 gene. In interpretation of p53 immunohistochemistry staining, distinguishing p53-positive tumors by their staining pattern may be important in gastric cancer. PMID:25354498

  17. Inhibition of p53-Dependent, but Not p53-Independent, Cell Death by U19 Protein from Human Herpesvirus 6B

    Science.gov (United States)

    Kofod-Olsen, Emil; Møller, Janni M. L.; Schleimann, Mariane H.; Bundgaard, Bettina; Bak, Rasmus O.; Øster, Bodil; Mikkelsen, Jacob G.; Hupp, Ted; Höllsberg, Per

    2013-01-01

    Infection with human herpesvirus (HHV)-6B alters cell cycle progression and stabilizes tumor suppressor protein p53. In this study, we have analyzed the activity of p53 after stimulation with p53-dependent and -independent DNA damaging agents during HHV-6B infection. Microarray analysis, Western blotting and confocal microscopy demonstrated that HHV-6B-infected cells were resistant to p53-dependent arrest and cell death after γ irradiation in both permissive and non-permissive cell lines. In contrast, HHV-6B-infected cells died normally through p53-independet DNA damage induced by UV radiation. Moreover, we identified a viral protein involved in inhibition of p53 during HHV-6B-infection. The protein product from the U19 ORF was able to inhibit p53-dependent signaling following γ irradiation in a manner similar to that observed during infection. Similar to HHV-6B infection, overexpression of U19 failed to rescue the cells from p53-independent death induced by UV radiation. Hence, infection with HHV-6B specifically blocks DNA damage-induced cell death associated with p53 without inhibiting the p53-independent cell death response. This block in p53 function can in part be ascribed to the activities of the viral U19 protein. PMID:23555634

  18. Specific TP53 Mutants Overrepresented in Ovarian Cancer Impact CNV, TP53 Activity, Responses to Nutlin-3a, and Cell Survival

    Directory of Open Access Journals (Sweden)

    Lisa K. Mullany

    2015-10-01

    Full Text Available Evolutionary Action analyses of The Cancer Gene Atlas data sets show that many specific p53 missense and gain-of-function mutations are selectively overrepresented and functional in high-grade serous ovarian cancer (HGSC. As homozygous alleles, p53 mutants are differentially associated with specific loss of heterozygosity (R273; chromosome 17; copy number variation (R175H; chromosome 9; and up-stream, cancer-related regulatory pathways. The expression of immune-related cytokines was selectively related to p53 status, showing for the first time that specific p53 mutants impact, and are related to, the immune subtype of ovarian cancer. Although the majority (31% of HGSCs exhibit loss of heterozygosity, a significant number (24% maintain a wild-type (WT allele and represent another HGSC subtype that is not well defined. Using human and mouse cell lines, we show that specific p53 mutants differentially alter endogenous WT p53 activity; target gene expression; and responses to nutlin-3a, a small molecular that activates WT p53 leading to apoptosis, providing “proof of principle” that ovarian cancer cells expressing WT and mutant alleles represent a distinct ovarian cancer subtype. We also show that siRNA knock down of endogenous p53 in cells expressing homozygous mutant alleles causes apoptosis, whereas cells expressing WT p53 (or are heterozygous for WT and mutant p53 alleles are highly resistant. Therefore, despite different gene regulatory pathways associated with specific p53 mutants, silencing mutant p53 might be a suitable, powerful, global strategy for blocking ovarian cancer growth in those tumors that rely on mutant p53 functions for survival. Knowing p53 mutational status in HGSC should permit new strategies tailored to control this disease.

  19. p53 gene mutations and expression of p53 and mdm2 proteins in invasive breast carcinoma. A comparative analysis with clinico-pathological factors.

    Science.gov (United States)

    Günther, T; Schneider-Stock, R; Rys, J; Niezabitowski, A; Roessner, A

    1997-01-01

    The aim of the study was to analyze p53 gene mutations and the expression of p53 and mdm2 proteins in 31 randomly selected invasive breast carcinomas. The results were then correlated with tumor grade, stage, estrogen receptor status, nodal status, and DNA ploidy. The expression of the proteins p53 and mdm2 was determined immunohistochemically using formalin-fixed, paraffin-embedded material. Screening for p53 mutation involved analysis of the highly conserved regions of the p53 gene (exons 5-9) by the polymerase chain reaction/ single-strand conformation polymorphism (PCR-SSCP) technique. PCR products with band shifts were directly sequenced. Immunohistochemical staining of p53 was positive in 9 cases (29.0%), only 2 of which showed a p53 gene mutation. These were identified as a C-->G transversion at the second position of codon 278 in exon 8 and an A-->G transition at the second position of codon 205 in exon 6. A third case with a mutation was observed (C-->T transition, position 1 of codon 250 in exon 7) that did not show p53 immunohistochemically. Of the 9 p53-positive tumors, 2 were moderately differentiated (grade II). The remaining tumors were poorly differentiated (7/9). By contrast, p53-negative carcinomas were well differentiated (grade I) in most cases (P = 0.02). DNA cytometry in 8 of the 9 p53-positive carcinomas revealed an aneuploid stem line. The majority of the p53-negative tumors were diploid (P = 0.01). Mdm2 oncoprotein was detected in 10 tumors (32.2%), 4 of which were p53-positive, including the 3 with mutations. The grading of the mdm2-positive tumors was moderate or poor, G1 carcinomas were always noted to be mdm2-negative (P = 0.04). Overexpression of p53 protein is a complex mechanism and does not merely indicate the detection of mutations in the p53 gene. This study has shown that p53 expression correlates with tumor grade and DNA ploidy. Mdm2 expression was also associated with the tumor grade. Immunohistological demonstration of the p53

  20. Serum p53 antibody as a potential tumor marker in extrahepatic cholangiocarcinoma.

    Science.gov (United States)

    Okada, Rei; Shimada, Hideaki; Otsuka, Yuichiro; Tsuchiya, Masaru; Ishii, Jun; Katagiri, Toshio; Maeda, Tetsuya; Kubota, Yoshihisa; Nemoto, Tetsuo; Kaneko, Hironori

    2017-12-01

    Only a few studies have evaluated the clinicopathological significance of the p53 protein expression and s-p53-Abs level in patients with cholangiocarcinoma. We therefore analyzed the clinicopathological and prognostic significance of s-p53-Abs in patients with extrahepatic cholangiocarcinoma. We prospectively evaluated s-p53-Abs levels before and after surgery in 61 patients with extrahepatic cholangiocarcinoma to determine the relationship between clinicopathological factors and the prognostic significance of s-p53-Abs. Among a total of 61 primary extrahepatic cholangiocarcinoma cases, 23% were positive for s-p53-Abs. Combination of s-p53-Abs with the conventional serum markers carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) significantly increased the rate of positive extrahepatic cholangiocarcinoma cases (57% for CEA and/or CA19-9 vs. 75% for CEA and/or CA19-9 and/or s-p53-Abs, P = 0.035). There were no significant differences in clinicopathological factors between the p53-seropositive and p53-seronegative patients. An immunohistochemical analysis showed the presence of significant associations between the intensity (P = 0.003) and extent (P = 0.001) of p53 immunoreactivity and p53-seropositivitly. Although s-p53-Abs was not a significant prognostic factor for the survival in either univariate or multivariate analyses, p53 immunoreactivity was independently associated with a poor survival. Among patients positive for s-p53-Abs before surgery, the s-p53-Abs levels were reduced after surgery in most. These findings suggested that s-p53-Abs might be associated with p53 immunoreactivity. In addition, s-p53-Abs may be useful for a diagnosis, but was not useful for predicting tumor recurrence or the survival. This study was registered as UMIN000014530.

  1. Ctenopharyngodon idella p53 mediates between NF-κB and PKR at the transcriptional level.

    Science.gov (United States)

    Huang, Qingli; Xie, Dingkun; Mao, Huiling; Wang, Haizhou; Wu, Zhen; Huang, Keyi; Wan, Yiqi; Xu, Qun; Hu, Chengyu

    2017-10-01

    p53, NF-κB and PKR are well-known to be involved in antiviral response. Although p53 has been reported in fish, its role in the regulation of NF-κB and PKR is not well understood. Here, we cloned and characterized the full length of cDNA sequence of grass carp (Ctenopharyngodon idella) p53 (Cip53) and its promoter sequence. The full length cDNA of Cip53 was 1879 bp with an ORF of 1116 bp encoding a polypeptide of 371 amino acids. Phylogenetic tree analysis revealed that Cip53 shares high homology with Dario rerio p53 (Drp53). Similar to those of Cip65 and CiPKR, the expression of Cip53 in CIK cells was significantly up-regulated after stimulation with poly I:C. To further understand the roles of fish p53 in the transcriptional control of NF-κB and PKR, Cip53 and Cip65 were expressed in E. coli BL21 and purified by affinity chromatography with the Ni-NTA His-Bind resin. In vitro, gel mobility shift assays demonstrated that the high affinity interaction between Cip65 and Cip53 promoter. Similarly, Cip53 bound to CiPKR promoter with high affinity. Dual-luciferase reporter assays showed that Cip65 activated Cip53 promoter and Cip53 activated CiPKR promoter, respectively. In addition, the role of p53 in p65-p53-PKR transcription pathway was explored. When Cip53 was knockdown in CIK cells, the mRNA levels of Cip65 and CiPKR were decreased. Taken together, p53 may play pivotal roles in transcription pathway of NF-κB and PKR in fish. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. Streamlining of the RELAP5-3D Code

    Energy Technology Data Exchange (ETDEWEB)

    Mesina, George L; Hykes, Joshua; Guillen, Donna Post

    2007-11-01

    RELAP5-3D is widely used by the nuclear community to simulate general thermal hydraulic systems and has proven to be so versatile that the spectrum of transient two-phase problems that can be analyzed has increased substantially over time. To accommodate the many new types of problems that are analyzed by RELAP5-3D, both the physics and numerical methods of the code have been continuously improved. In the area of computational methods and mathematical techniques, many upgrades and improvements have been made decrease code run time and increase solution accuracy. These include vectorization, parallelization, use of improved equation solvers for thermal hydraulics and neutron kinetics, and incorporation of improved library utilities. In the area of applied nuclear engineering, expanded capabilities include boron and level tracking models, radiation/conduction enclosure model, feedwater heater and compressor components, fluids and corresponding correlations for modeling Generation IV reactor designs, and coupling to computational fluid dynamics solvers. Ongoing and proposed future developments include improvements to the two-phase pump model, conversion to FORTRAN 90, and coupling to more computer programs. This paper summarizes the general improvements made to RELAP5-3D, with an emphasis on streamlining the code infrastructure for improved maintenance and development. With all these past, present and planned developments, it is necessary to modify the code infrastructure to incorporate modifications in a consistent and maintainable manner. Modifying a complex code such as RELAP5-3D to incorporate new models, upgrade numerics, and optimize existing code becomes more difficult as the code grows larger. The difficulty of this as well as the chance of introducing errors is significantly reduced when the code is structured. To streamline the code into a structured program, a commercial restructuring tool, FOR_STRUCT, was applied to the RELAP5-3D source files. The

  3. Uncertainty Analysis of RELAP5-3D

    Energy Technology Data Exchange (ETDEWEB)

    Alexandra E Gertman; Dr. George L Mesina

    2012-07-01

    As world-wide energy consumption continues to increase, so does the demand for the use of alternative energy sources, such as Nuclear Energy. Nuclear Power Plants currently supply over 370 gigawatts of electricity, and more than 60 new nuclear reactors have been commissioned by 15 different countries. The primary concern for Nuclear Power Plant operation and lisencing has been safety. The safety of the operation of Nuclear Power Plants is no simple matter- it involves the training of operators, design of the reactor, as well as equipment and design upgrades throughout the lifetime of the reactor, etc. To safely design, operate, and understand nuclear power plants, industry and government alike have relied upon the use of best-estimate simulation codes, which allow for an accurate model of any given plant to be created with well-defined margins of safety. The most widely used of these best-estimate simulation codes in the Nuclear Power industry is RELAP5-3D. Our project focused on improving the modeling capabilities of RELAP5-3D by developing uncertainty estimates for its calculations. This work involved analyzing high, medium, and low ranked phenomena from an INL PIRT on a small break Loss-Of-Coolant Accident as wall as an analysis of a large break Loss-Of- Coolant Accident. Statistical analyses were performed using correlation coefficients. To perform the studies, computer programs were written that modify a template RELAP5 input deck to produce one deck for each combination of key input parameters. Python scripting enabled the running of the generated input files with RELAP5-3D on INL’s massively parallel cluster system. Data from the studies was collected and analyzed with SAS. A summary of the results of our studies are presented.

  4. Distinct pattern of p53 mutations in bladder cancer

    DEFF Research Database (Denmark)

    Spruck, C H; Rideout, W M; Olumi, A F

    1993-01-01

    double mutations, four of which were tandem mutations on the same allele. No double mutations were found in tumors from nonsmoking patients. None of the mutations in smokers were G:C-->T:A transversions, which would be anticipated for exposure to the suspected cigarette smoke carcinogen 4-aminobiphenyl....... The results suggest that, although cigarette smoke exposure may not significantly alter the kinds of mutations sustained in the p53 gene, it may act to increase the extent of DNA damage per mutagenic event....

  5. A dynamic p53-mdm2 model with distributed delay

    Science.gov (United States)

    Horhat, Raluca; Horhat, Raul Florin

    2014-12-01

    Specific activator and repressor transcription factors which bind to specific regulator DNA sequences, play an important role in gene activity control. Interactions between genes coding such transcripion factors should explain the different stable or sometimes oscillatory gene activities characteristic for different tissues. In this paper, the dynamic P53-Mdm2 interaction model with distributed delays is investigated. Both weak and Dirac kernels are taken into consideration. For Dirac case, the Hopf bifurcation is investigated. Some numerical examples are finally given for justifying the theoretical results.

  6. Agaritine content of 53 Agaricus species collected from nature

    DEFF Research Database (Denmark)

    Schulzova, V.; Hajslova, J.; Peroutka, R.

    2009-01-01

    carcinogen. There was a huge variation in agaritine content between species, but less variation between samples of a species. Whereas the cultivated mushroom Agaricus bisporus commonly contain 200-500 mg agaritine kg-1 fresh weight, no less than 24 of the 53 species contained agaritine levels above 1000 mg...... strain development of Agaricus mushrooms for cultivation. No correlation could be observed between agaritine content and size of the mushroom, week of the year when collected, year of collection, or site of collection. Besides occurring in the genus Agaricus, some species of the genera Leucoagaricus...

  7. Cross-regulation of protein stability by p53 and nuclear receptor SHP.

    Directory of Open Access Journals (Sweden)

    Zhihong Yang

    Full Text Available We report here a novel interplay between tumor suppressor p53 and nuclear receptor SHP that controls p53 and SHP stability. Overexpression of p53 causes rapid SHP protein degradation, which does not require the presence of Mdm2 and is mediated by the proteosome pathway. Overexpressing SHP alone does not affect p53 stability. However, SHP destabilizes p53 by augmentation of Mdm2 ubiquitin ligase activity toward p53. The single amino acid substitution in the SHP protein SHPK170R increases SHP binding to p53 relative to SHP wild-type, whereas SHPG171A variant shows a diminished p53 binding. As a result of the cross-regulation, the tumor suppressor function of p53 and SHP in inhibition of colon cancer growth is compromised. Our findings reveal a unique scenario for a cross-inhibition between two tumor suppressors to keep their expression and function in check.

  8. Nutlin-3 downregulates p53 phosphorylation on serine392 and induces apoptosis in hepatocellular carcinoma cells.

    Science.gov (United States)

    Shi, Xinli; Liu, Jingli; Ren, Laifeng; Mao, Nan; Tan, Fang; Ding, Nana; Yang, Jing; Li, Mingyuan

    2014-04-01

    Drug-resistance and imbalance of apoptotic regulation limit chemotherapy clinical application for the human hepatocellular carcinoma (HCC) treatment. The reactivation of p53 is an attractive therapeutic strategy in cancer with disrupted-p53 function. Nutlin-3, a MDM2 antagonist, has antitumor activity in various cancers. The post-translational modifications of p53 are a hot topic, but there are some controversy ideas about the function of phospho-Ser392-p53 protein in cancer cell lines in response to Nutlin-3. Therefore, we investigated the relationship between Nutlin-3 and phospho-Ser392-p53 protein expression levels in SMMC-7721 (wild-type TP53) and HuH-7 cells (mutant TP53). We demonstrated that Nutlin-3 induced apoptosis through down-regulation phospho-Ser392-p53 in two HCC cells. The result suggests that inhibition of p53 phosphorylation on Ser392 presents an alternative for HCC chemotherapy.

  9. Long Noncoding RNA PURPL Suppresses Basal p53 Levels and Promotes Tumorigenicity in Colorectal Cancer.

    Science.gov (United States)

    Li, Xiao Ling; Subramanian, Murugan; Jones, Matthew F; Chaudhary, Ritu; Singh, Deepak K; Zong, Xinying; Gryder, Berkley; Sindri, Sivasish; Mo, Min; Schetter, Aaron; Wen, Xinyu; Parvathaneni, Swetha; Kazandjian, Dickran; Jenkins, Lisa M; Tang, Wei; Elloumi, Fathi; Martindale, Jennifer L; Huarte, Maite; Zhu, Yuelin; Robles, Ana I; Frier, Susan M; Rigo, Frank; Cam, Maggie; Ambs, Stefan; Sharma, Sudha; Harris, Curtis C; Dasso, Mary; Prasanth, Kannanganattu V; Lal, Ashish

    2017-09-05

    Basal p53 levels are tightly suppressed under normal conditions. Disrupting this regulation results in elevated p53 levels to induce cell cycle arrest, apoptosis, and tumor suppression. Here, we report the suppression of basal p53 levels by a nuclear, p53-regulated long noncoding RNA that we termed PURPL (p53 upregulated regulator of p53 levels). Targeted depletion of PURPL in colorectal cancer cells results in elevated basal p53 levels and induces growth defects in cell culture and in mouse xenografts. PURPL associates with MYBBP1A, a protein that binds to and stabilizes p53, and inhibits the formation of the p53-MYBBP1A complex. In the absence of PURPL, MYBBP1A interacts with and stabilizes p53. Silencing MYBBP1A significantly rescues basal p53 levels and proliferation in PURPL-deficient cells, suggesting that MYBBP1A mediates the effect of PURPL in regulating p53. These results reveal a p53-PURPL auto-regulatory feedback loop and demonstrate a role for PURPL in maintaining basal p53 levels. Published by Elsevier Inc.

  10. A Novel p53 Phosphorylation Site within the MDM2 Ubiquitination Signal

    Science.gov (United States)

    Fraser, Jennifer A.; Madhumalar, Arumugam; Blackburn, Elizabeth; Bramham, Janice; Walkinshaw, Malcolm D.; Verma, Chandra; Hupp, Ted R.

    2010-01-01

    The p53 DNA-binding domain harbors a conformationally flexible multiprotein binding site that regulates p53 ubiquitination. A novel phosphorylation site exists within this region at Ser269, whose phosphomimetic mutation inactivates p53. The phosphomimetic p53 (S269D) exhibits characteristics of mutant p53: stable binding to Hsp70 in vivo, elevated ubiquitination in vivo, inactivity in DNA binding and transcription, increased thermoinstability using thermal shift assays, and λmax of intrinsic tryptophan fluorescence at 403 nm rather than 346 nm, characteristic of wild type p53. These data indicate that p53 conformational stability is regulated by a phosphoacceptor site within an exposed flexible surface loop and that this can be destabilized by phosphorylation. To test whether other motifs within p53 have similarly evolved, we analyzed the effect of Ser215 mutation on p53 function because Ser215 is another inactivating phosphorylation site in the conformationally flexible PAb240 epitope. The p53S215D protein is inactive like p53S269D, whereas p53S215A is as active as p53S269A. However, the double mutant p53S215A/S269A was transcriptionally inactive and more thermally unstable than either individual Ser-Ala loop mutant. Molecular dynamics simulations suggest that (i) solvation of phospho-Ser215 and phospho-Ser269 by positive charged residues or solvent water leads to local unfolding, which is accompanied by local destabilization of the N-terminal loop and global destabilization of p53, and (ii) the double alanine 215/269 mutation disrupts hydrogen bonding normally stabilized by both Ser215 and Ser269. These data indicate that p53 has evolved two serine phosphoacceptor residues within conformationally flexible epitopes that normally stabilize the p53 DNA-binding domain but whose phosphorylation induces a mutant conformation to wild type p53. PMID:20847049

  11. p53 modulates the AMPK inhibitor compound C induced apoptosis in human skin cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Huang, Shi-Wei [Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan (China); Wu, Chun-Ying [Division of Gastroenterology and Hepatology, Taichung Veterans General Hospital, Taichung, Taiwan (China); Wang, Yen-Ting [Department of Medical Research and Education, Cheng Hsin General Hospital, Taipei, Taiwan (China); Kao, Jun-Kai [Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan (China); Department of Pediatrics, Children' s Hospital, Changhua Christian Hospital, Changhua, Taiwan (China); Lin, Chi-Chen; Chang, Chia-Che; Mu, Szu-Wei; Chen, Yu-Yu [Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan (China); Chiu, Husan-Wen [Institute of Biotechnology, National Cheng-Kung University, Tainan, Taiwan (China); Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan (China); Chang, Chuan-Hsun [Department of Surgical Oncology, Cheng Hsin General Hospital, Taipei, Taiwan (China); Department of Nutrition Therapy, Cheng Hsin General Hospital, Taipei, Taiwan (China); School of Nutrition and Health Sciences, Taipei Medical University, Taipei, Taiwan (China); Liang, Shu-Mei [Institute of Biotechnology, National Cheng-Kung University, Tainan, Taiwan (China); Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan (China); Chen, Yi-Ju [Department of Dermatology, Taichung Veterans General Hospital, Taichung, Taiwan (China); Huang, Jau-Ling [Department of Bioscience Technology, Chang Jung Christian University, Tainan, Taiwan (China); Shieh, Jeng-Jer, E-mail: shiehjj@vghtc.gov.tw [Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan (China); Department of Education and Research, Taichung Veterans General Hospital, Taichung, Taiwan (China)

    2013-02-15

    Compound C, a well-known inhibitor of the intracellular energy sensor AMP-activated protein kinase (AMPK), has been reported to cause apoptotic cell death in myeloma, breast cancer cells and glioma cells. In this study, we have demonstrated that compound C not only induced autophagy in all tested skin cancer cell lines but also caused more apoptosis in p53 wildtype skin cancer cells than in p53-mutant skin cancer cells. Compound C can induce upregulation, phosphorylation and nuclear translocalization of the p53 protein and upregulate expression of p53 target genes in wildtype p53-expressing skin basal cell carcinoma (BCC) cells. The changes of p53 status were dependent on DNA damage which was caused by compound C induced reactive oxygen species (ROS) generation and associated with activated ataxia-telangiectasia mutated (ATM) protein. Using the wildtype p53-expressing BCC cells versus stable p53-knockdown BCC sublines, we present evidence that p53-knockdown cancer cells were much less sensitive to compound C treatment with significant G2/M cell cycle arrest and attenuated the compound C-induced apoptosis but not autophagy. The compound C induced G2/M arrest in p53-knockdown BCC cells was associated with the sustained inactive Tyr15 phosphor-Cdc2 expression. Overall, our results established that compound C-induced apoptosis in skin cancer cells was dependent on the cell's p53 status. - Highlights: ► Compound C caused more apoptosis in p53 wildtype than p53-mutant skin cancer cells. ► Compound C can upregulate p53 expression and induce p53 activation. ► Compound C induced p53 effects were dependent on ROS induced DNA damage pathway. ► p53-knockdown attenuated compound C-induced apoptosis but not autophagy. ► Compound C-induced apoptosis in skin cancer cells was dependent on p53 status.

  12. High incidence of protein-truncating TP53 mutations in BRCA1-related breast cancer.

    Science.gov (United States)

    Holstege, Henne; Joosse, Simon A; van Oostrom, Conny Th M; Nederlof, Petra M; de Vries, Annemieke; Jonkers, Jos

    2009-04-15

    Approximately half of all hereditary breast cancers are compromised in their DNA repair mechanisms due to loss of BRCA1 or BRCA2 function. Previous research has found a strong correlation between BRCA mutation and TP53 mutation. However, TP53 mutation status is often indirectly assessed by immunohistochemical staining of accumulated p53 protein. We sequenced TP53 exons 2 to 9 in 21 BRCA1-related breast cancers and 37 sporadic breast tumors. Strikingly, all BRCA1-related breast tumors contained TP53 mutations, whereas only half of these tumors stained positive for p53 accumulation. Positive p53 staining correlates with the presence of TP53 hotspot mutations in both BRCA1-related and sporadic breast tumors. However, whereas the majority of sporadic breast tumors that stained negative for p53 accumulation had wild-type TP53, the majority of BRCA1-associated breast tumors that stained negative for p53 accumulation had protein-truncating TP53 mutations (nonsense, frameshift, and splice mutations). Therefore, the strong selection for p53 loss in BRCA1-related tumors is achieved by an increase of protein-truncating TP53 mutations rather than hotspot mutations. Hence, immunohistochemical detection of TP53 mutation could lead to misdiagnosis in approximately half of all BRCA1-related tumors. The presence of deleterious TP53 mutations in most, if not all, BRCA1-related breast cancers suggests that p53 loss of function is essential for BRCA1-associated tumorigenesis. BRCA1-related tumors may therefore be treated not only with drugs that target BRCA1 deficiency [e.g., poly(ADP-ribose) polymerase inhibitors] but also with drugs that selectively target p53-deficient cells. This raises interesting possibilities for combination therapies against BRCA1-deficient breast cancers and BRCA1-like tumors with homologous recombination deficiency.

  13. Lung tumors with distinct p53 mutations respond similarly to p53 targeted therapy but exhibit genotype-specific statin sensitivity.

    Science.gov (United States)

    Turrell, Frances K; Kerr, Emma M; Gao, Meiling; Thorpe, Hannah; Doherty, Gary J; Cridge, Jake; Shorthouse, David; Speed, Alyson; Samarajiwa, Shamith; Hall, Benjamin A; Griffiths, Meryl; Martins, Carla P

    2017-08-08

    Lung adenocarcinoma accounts for ∼40% of lung cancers, the leading cause of cancer-related death worldwide, and current therapies provide only limited survival benefit. Approximately half of lung adenocarcinomas harbor mutations in TP53 (p53), making these mutants appealing targets for lung cancer therapy. As mutant p53 remains untargetable, mutant p53-dependent phenotypes represent alternative targeting opportunities, but the prevalence and therapeutic relevance of such effects (gain of function and dominant-negative activity) in lung adenocarcinoma are unclear. Through transcriptional and functional analysis of murine Kras(G12D) -p53(null) , -p53(R172H) (conformational), and -p53(R270H) (contact) mutant lung tumors, we identified genotype-independent and genotype-dependent therapeutic sensitivities. Unexpectedly, we found that wild-type p53 exerts a dominant tumor-suppressive effect on mutant tumors, as all genotypes were similarly sensitive to its restoration in vivo. These data show that the potential of p53 targeted therapies is comparable across all p53-deficient genotypes and may explain the high incidence of p53 loss of heterozygosity in mutant tumors. In contrast, mutant p53 gain of function and their associated vulnerabilities can vary according to mutation type. Notably, we identified a p53(R270H) -specific sensitivity to simvastatin in lung tumors, and the transcriptional signature that underlies this sensitivity was also present in human lung tumors, indicating that this therapeutic approach may be clinically relevant. © 2017 Turrell et al.; Published by Cold Spring Harbor Laboratory Press.

  14. Proteasomal degradation of p53 by human papillomavirus E6 oncoprotein relies on the structural integrity of p53 core domain.

    Directory of Open Access Journals (Sweden)

    Xavier Bernard

    Full Text Available The E6 oncoprotein produced by high-risk mucosal HPV stimulates ubiquitinylation and proteasome-dependent degradation of the tumour suppressor p53 via formation of a trimeric complex comprising E6, p53, and E6-AP. p53 is also degraded by its main cellular regulator MDM2. The main binding site of p53 to MDM2 is situated in the natively unfolded N-terminal region of p53. By contrast, the regions of p53 implicated in the degradation by viral E6 are not fully identified to date. Here we generated a series of mutations (Y103G, Y107G, T155A, T155V, T155D, L264A, L265A targeting the central folded core domain of p53 within a region opposite to its DNA-binding site. We analysed by in vitro and in vivo assays the impact of these mutations on p53 degradation mediated by viral E6 oncoprotein. Whereas all mutants remained susceptible to MDM2-mediated degradation, several of them (Y103G, Y107G, T155D, L265A became resistant to E6-mediated degradation, confirming previous works that pointed to the core domain as an essential region for the degradation of p53. In parallel, we systematically checked the impact of the mutations on the transactivation activity of p53 as well as on the conformation of p53, analysed by Nuclear Magnetic Resonance (NMR, circular dichroism (CD, and antibody probing. These measurements suggested that the conformational integrity of the core domain is an essential parameter for the degradation of p53 by E6, while it is not essential for the degradation of p53 by MDM2. Thus, the intracellular stability of a protein may or may not rely on its biophysical stability depending on the degradation pathway taken into consideration.

  15. AdDelta24 and the p53-expressing variant AdDelta24-p53 achieve potent anti-tumor activity in glioma when combined with radiotherapy.

    Science.gov (United States)

    Idema, Sander; Lamfers, Martine L M; van Beusechem, Victor W; Noske, David P; Heukelom, Stan; Moeniralm, Sharif; Gerritsen, Winald R; Vandertop, W Peter; Dirven, Clemens M F

    2007-12-01

    The conditionally replicating adenovirus (CRAd) AdDelta24-p53 replicates selectively in Rb mutant cells, and encodes the p53 suppressor protein. It has shown improved oncolytic potency compared to the parental control AdDelta24. As exogenous p53 has been shown to enhance radiosensitivity, the combination of AdDelta24-p53 and AdDelta24 with radiotherapy was assessed in vitro and in vivo against the therapy resistant gliomas. In glioma cells, multicellular spheroids and animal xenografts the efficacy of combination therapy was assessed. P53 phosphorylation, induction of apoptosis and viral replication were determined following single or combination therapies. In vitro, AdDelta24-p53 was more effective against glioma cells than the control AdDelta24. Addition of irradiation equally increased the efficacy of both AdDelta24-p53 and AdDelta24 resulting in improved oncolysis compared to single agent treatment. Radiotherapy did not significantly change the replication kinetics of AdDelta24-p53 or AdDelta24. No detectable increase in p53 phosphorylation was observed but combination of radiotherapy and AdDelta24-p53 caused an increase in the percentage of apoptotic cells. In vivo, combination therapy with either AdDelta24 or AdDelta24-p53 significantly increased the number of mice demonstrating tumor regression (100%) as well as long-term survival (50%). No differences between viruses were noted. Exogenous p53 expression does not appear to increase the synergistic interaction of CRAds combined with radiotherapy. These results however do indicate that radiotherapy provides the time frame in which AdDelta24 and AdDelta24-p53 can eradicate established tumors that would otherwise escape treatment, and establishes the need to combine these modalities to form an effective anti-cancer treatment.

  16. AUTOMATED, HIGHLY ACCURATE VERIFICATION OF RELAP5-3D

    Energy Technology Data Exchange (ETDEWEB)

    George L Mesina; David Aumiller; Francis Buschman

    2014-07-01

    Computer programs that analyze light water reactor safety solve complex systems of governing, closure and special process equations to model the underlying physics. In addition, these programs incorporate many other features and are quite large. RELAP5-3D[1] has over 300,000 lines of coding for physics, input, output, data management, user-interaction, and post-processing. For software quality assurance, the code must be verified and validated before being released to users. Verification ensures that a program is built right by checking that it meets its design specifications. Recently, there has been an increased importance on the development of automated verification processes that compare coding against its documented algorithms and equations and compares its calculations against analytical solutions and the method of manufactured solutions[2]. For the first time, the ability exists to ensure that the data transfer operations associated with timestep advancement/repeating and writing/reading a solution to a file have no unintended consequences. To ensure that the code performs as intended over its extensive list of applications, an automated and highly accurate verification method has been modified and applied to RELAP5-3D. Furthermore, mathematical analysis of the adequacy of the checks used in the comparisons is provided.

  17. Heterogeneous Hydration of p53/MDM2 Complex

    Science.gov (United States)

    2015-01-01

    Water-mediated interactions play critical roles in biomolecular recognition processes. Explicit solvent molecular dynamics (MD) simulations and the variational implicit-solvent model (VISM) are used to study those hydration properties during binding for the biologically important p53/MDM2 complex. Unlike simple model solutes, in such a realistic and heterogeneous solute–solvent system with both geometrical and chemical complexity, the local water distribution sensitively depends on nearby amino acid properties and the geometric shape of the protein. We show that the VISM can accurately describe the locations of high and low density solvation shells identified by the MD simulations and can explain them by a local coupling balance of solvent–solute interaction potentials and curvature. In particular, capillary transitions between local dry and wet hydration states in the binding pocket are captured for interdomain distance between 4 to 6 Å, right at the onset of binding. The underlying physical connection between geometry and polarity is illustrated and quantified. Our study offers a microscopic and physical insight into the heterogeneous hydration behavior of the biologically highly relevant p53/MDM2 system and demonstrates the fundamental importance of hydrophobic effects for biological binding processes. We hope our study can help to establish new design rules for drugs and medical substances. PMID:24803860

  18. p53 mutations occur in aggressive breast cancer.

    Science.gov (United States)

    Mazars, R; Spinardi, L; BenCheikh, M; Simony-Lafontaine, J; Jeanteur, P; Theillet, C

    1992-07-15

    Using a polymerase chain reaction-single strand conformation polymorphism approach we analyzed 96 human primary breast tumors for the presence of mutations in exons 2, 5, 6, 7, 8, and 9 of the p53 gene. These exons have been shown to comprise highly conserved sequences and the portion including exons 5 through 9 is believed to be the target for over 90% of the acquired mutations in human cancer. Eighteen tumors of the 96 (18.7%) tested showed reproducibly a variant band indicative of a mutation. Most (15 tumors) of the mutations were single nucleotide substitutions and G:C to A:T transitions were prevalent (6 tumors), G:C to T:A transversions came next (4 tumors), and guanines were always on the nontranscribed strand. Concomitant loss of the wild type allele and mutation of the other copy was observed in only 3 of 18 mutated cases; this is consistent with the heterogeneous cellular composition of breast tumors. Furthermore p53 mutations were correlated to estrogen and/or progesterone receptor negative tumors, thus indicating their relationships to aggressive breast cancer. No association could be observed with DNA amplification events in these tumors.

  19. First determination of ground state electromagnetic moments of 53Fe

    Science.gov (United States)

    Miller, A. J.; Minamisono, K.; Rossi, D. M.; Beerwerth, R.; Brown, B. A.; Fritzsche, S.; Garand, D.; Klose, A.; Liu, Y.; Maaß, B.; Mantica, P. F.; Müller, P.; Nörtershäuser, W.; Pearson, M. R.; Sumithrarachchi, C.

    2017-11-01

    The hyperfine coupling constants of neutron deficient 53Fe were deduced from the atomic hyperfine spectrum of the 3 d64 s25D4↔3 d64 s 4 p 5F5 transition, measured using the bunched-beam collinear laser spectroscopy technique. The low-energy 53Fe beam was produced by projectile-fragmentation reactions followed by gas stopping, and used for the first time for laser spectroscopy. Ground state magnetic-dipole and electric-quadrupole moments were determined as μ =-0.65 (1 ) μN and Q =+35 (15 ) e2fm2 , respectively. The multiconfiguration Dirac-Fock method was used to calculate the electric field gradient to deduce Q from the quadrupole hyperfine coupling constant, since the quadrupole coupling constant has not been determined for any Fe isotopes. Both experimental values agree well with nuclear shell model calculations using the GXPF1A effective interaction performed in a full f p shell model space, which support the soft nature of the 56Ni nucleus.

  20. P53 Mutations Change Phosphatidylinositol Acyl Chain Composition

    Directory of Open Access Journals (Sweden)

    Adam Naguib

    2015-01-01

    Full Text Available Phosphatidylinositol phosphate (PIP second messengers relay extracellular growth cues through the phosphorylation status of the inositol sugar, a signal transduction system that is deregulated in cancer. In stark contrast to PIP inositol head-group phosphorylation, changes in phosphatidylinositol (PI lipid acyl chains in cancer have remained ill-defined. Here, we apply a mass-spectrometry-based method capable of unbiased high-throughput identification and quantification of cellular PI acyl chain composition. Using this approach, we find that PI lipid chains represent a cell-specific fingerprint and are unperturbed by serum-mediated signaling in contrast to the inositol head group. We find that mutation of Trp53 results in PIs containing reduced-length fatty acid moieties. Our results suggest that the anchoring tails of lipid second messengers form an additional layer of PIP signaling in cancer that operates independently of PTEN/PI3-kinase activity but is instead linked to p53.

  1. Gastrointestinal injuries in childhood: analysis of 53 patients.

    Science.gov (United States)

    Grosfeld, J L; Rescorla, F J; West, K W; Vane, D W

    1989-06-01

    Gastrointestinal injuries were noted in 53 children. Blunt trauma was responsible for 51 cases, and penetrating wounds in two. There were 42 boys and 11 girls (mean age, 8.1 years). The site of injury was the stomach (2), duodenum (17), jejunum (19), and ileum (15). Types of injury included two gastric perforations, 16 duodenal hematomas, one duodenal laceration, 27 jejunoileal perforations, five mesenteric avulsions, one abdominal wall laceration and evisceration, and one entrapment necrosis between lumbar vertebrae. Diagnosis was accomplished by observing free air on x-ray, with contrast (duodenal haematoma), computed tomography, and frequent examination (noting peritoneal irritation). Thirty-four associated injuries occurred in 21 patients (40%) including the liver (6), pancreas (6), skeletal injury (6), head trauma (5), diaphragm (4), lung (3), spleen (2), and kidney (2). Nine of 16 duodenal hematomas resolved non-operatively, while seven were evacuated during other procedures. Twenty-three of 30 perforations had simple closure, while seven (jejunoileal) were resected. Mesenteric avulsions required resection in five cases--the eviscerated bowel was replaced and the entrapped bowel resected. Twenty complications occurred in 13 patients, including atelectases (6), pseudocyst (5), sepsis (4), wound infection (2), subhepatic abscess (1), subglottic stenosis (1), and short bowel syndrome (1). One infant (aged 2 months) with a duodenal laceration died of head injuries (1/53 = 1.8% mortality). Prompt recognition and appropriate treatment result in improved survival.

  2. 53BP1 mediates productive and mutagenic DNA repair through distinct phosphoprotein interactions

    DEFF Research Database (Denmark)

    Callen, E.; Wong, N.; Chen, H.-T.

    2013-01-01

    The DNA damage response (DDR) protein 53BP1 protects DNA ends from excessive resection in G1, and thereby favors repair by nonhomologous end-joining (NHEJ) as opposed to homologous recombination (HR). During S phase, BRCA1 antagonizes 53BP1 to promote HR. The pro-NHEJ and antirecombinase functions...... deficiency by restoring genome stability in BRCA1-deficient cells yet behaves like wild-type 53BP1 with respect to immunoglobulin class switch recombination (CSR). 53BP1 recruits RIF1 but fails to recruit the DDR protein PTIP to DSBs, and disruption of PTIP phenocopies 53BP1. We conclude that 53BP1 promotes...

  3. Both p53-PUMA/NOXA-Bax-mitochondrion and p53-p21cip1 pathways are involved in the CDglyTK-mediated tumor cell suppression

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Zhendong, E-mail: zdyu@hotmail.com [Department of Clinical laboratory, Peking University Shenzhen Hospital, Guangdong (China); Wang, Hao [Department of pathology, The Chinese University of Hong Kong, Hong Kong (China); Zhang, Libin; Tang, Aifa; Zhai, Qinna; Wen, Jianxiang; Yao, Li [Department of Clinical laboratory, Peking University Shenzhen Hospital, Guangdong (China); Li, Pengfei, E-mail: lipengfei@cuhk.edu.hk [Department of pathology, The Chinese University of Hong Kong, Hong Kong (China)

    2009-09-04

    CDglyTK fusion suicide gene has been well characterized to effectively kill tumor cells. However, the exact mechanism and downstream target genes are not fully understood. In our study, we found that CDglyTK/prodrug treatment works more efficiently in p53 wild-type (HONE1) cells than in p53 mutant (CNE1) cells. We then used adenovirus-mediated gene delivery system to either knockdown or overexpress p53 and its target genes in these cells. Consistent results showed that both p53-PUMA/NOXA/Bcl2-Bax and p53-p21 pathways contribute to the CDglyTK induced tumor cell suppression. Our work for the first time addressed the role of p53 related genes in the CDglyTK/prodrug system.

  4. Mutant p53 promotes cell spreading and migration via ARHGAP44.

    Science.gov (United States)

    Xu, Jinjin; Jiao, Jian; Xu, Wei; Ji, Lei; Jiang, Dongjie; Xie, Shaofang; Kubra, Syeda; Li, Xiaotao; Fu, Junjiang; Xiao, Jianru; Zhang, Bianhong

    2017-09-01

    The tumor suppressor p53 protein is either lost or mutated in about half of all human cancers. Loss of p53 function is well known to influence cell spreading, migration and invasion. While expression of mutant p53 is not equivalent to p53 loss, mutant p53 can acquire new functions to drive cell spreading and migration via different mechanisms. In our study, we found that mutant p53 significantly increased cell spreading and migration when comparing with p53-null cells. RNA-Seq analysis suggested that Rho GTPase activating protein 44 (ARHGAP44) is a new target of mutant p53, which suppressed ARHGAP44 transcription. ARHGAP44 has GAP activity and catalyze GTP hydrolysis on Cdc42. Higher level of GTP-Cdc42 was correlated with increase expression of mutant p53 and reduced ARHGAP44. Importantly, wt-ARHGAP44 but not mutant ARHGAP44 (R291A) suppressed mutant p53 mediated cell spreading and migration. Bioinformatics analysis indicated lower expression of ARHGAP44 in lung carcinoma compared with normal tissues, which was verified by RT-qPCR using specimens from patients. More interestingly, ARHGAP44 mRNA level was lower in tumors with mutant p53 than those with normal p53. Collectively, our results disclose a new mechanism by which mutant p53 stimulates cell spreading and migration.

  5. An adaptive molecular timer in p53-meidated cell fate decision

    Science.gov (United States)

    Zhang, Xiao-Peng; Wang, Ping; Liu, Feng; Wang, Wei

    The tumor suppressor p53 decides cellular outcomes in the DNA damage response. It is intriguing to explore the link between p53 dynamics and cell fates. We developed a theoretical model of p53 signaling network to clarify the mechanism of cell fate decision mediated by its dynamics. We found that the interplay between p53-Mdm2 negative feedback loop and p53-PTEN-Mdm2 positive feedback loop shapes p53 dynamics. Depending on the intensity of DNA damage, p53 shows three modes of dynamics: persistent pulses, two-phase dynamics with pulses followed by sustained high levels and straightforward high levels. Especially, p53 shows two-phase dynamics upon moderated damage and the required number of p53 pulses before apoptosis induction decreases with increasing DNA damage. Our results suggested there exists an adaptive molecular timer that determines whether and when the apoptosis switch should be triggered. We clarified the mechanism behind the switching of p53 dynamical modes by bifurcation analysis. Moreover, we reproduced the experimental results that drug additions alter p53 pulses to sustained p53 activation and leads to senescence. Our work may advance the understanding the significance of p53 dynamics in tumor suppression. This work was supported by National Natural Science Foundation of China (Nos. 11175084, 11204126 and 31361163003).

  6. The critical role of catalase in prooxidant and antioxidant function of p53

    Science.gov (United States)

    Kang, M Y; Kim, H-B; Piao, C; Lee, K H; Hyun, J W; Chang, I-Y; You, H J

    2013-01-01

    The tumor suppressor p53 is an important regulator of intracellular reactive oxygen species (ROS) levels, although downstream mediators of p53 remain to be elucidated. Here, we show that p53 and its downstream targets, p53-inducible ribonucleotide reductase (p53R2) and p53-inducible gene 3 (PIG3), physically and functionally interact with catalase for efficient regulation of intracellular ROS, depending on stress intensity. Under physiological conditions, the antioxidant functions of p53 are mediated by p53R2, which maintains increased catalase activity and thereby protects against endogenous ROS. After genotoxic stress, high levels of p53 and PIG3 cooperate to inhibit catalase activity, leading to a shift in the oxidant/antioxidant balance toward an oxidative status, which could augment apoptotic cell death. These results highlight the essential role of catalase in p53-mediated ROS regulation and suggest that the p53/p53R2–catalase and p53/PIG3–catalase pathways are critically involved in intracellular ROS regulation under physiological conditions and during the response to DNA damage, respectively. PMID:22918438

  7. Knockdown of p53 suppresses Nanog expression in embryonic stem cells

    Energy Technology Data Exchange (ETDEWEB)

    Abdelalim, Essam Mohamed, E-mail: emohamed@qf.org.qa [Qatar Biomedical Research Institute, Qatar Foundation, Doha 5825 (Qatar); Molecular Neuroscience Research Center, Shiga University of Medical Science, Setatsukinowa-cho, Otsu, Shiga 520-2192 (Japan); Department of Cytology and Histology, Faculty of Veterinary Medicine, Suez Canal University, Ismailia (Egypt); Tooyama, Ikuo [Molecular Neuroscience Research Center, Shiga University of Medical Science, Setatsukinowa-cho, Otsu, Shiga 520-2192 (Japan)

    2014-01-10

    Highlights: •We investigate the role of p53 in ESCs in the absence of DNA damage. •p53 knockdown suppresses ESC proliferation. •p53 knockdown downregulates Nanog expression. •p53 is essential for mouse ESC self-renewal. -- Abstract: Mouse embryonic stem cells (ESCs) express high levels of cytoplasmic p53. Exposure of mouse ESCs to DNA damage leads to activation of p53, inducing Nanog suppression. In contrast to earlier studies, we recently reported that chemical inhibition of p53 suppresses ESC proliferation. Here, we confirm that p53 signaling is involved in the maintenance of mouse ESC self-renewal. RNA interference-mediated knockdown of p53 induced downregulation of p21 and defects in ESC proliferation. Furthermore, p53 knockdown resulted in a significant downregulation in Nanog expression at 24 and 48 h post-transfection. p53 knockdown also caused a reduction in Oct4 expression at 48 h post-transfection. Conversely, exposure of ESCs to DNA damage caused a higher reduction of Nanog expression in control siRNA-treated cells than in p53 siRNA-treated cells. These data show that in the absence of DNA damage, p53 is required for the maintenance of mouse ESC self-renewal by regulating Nanog expression.

  8. Inactivation and inducible oncogenic mutation of p53 in gene targeted pigs.

    Directory of Open Access Journals (Sweden)

    Simon Leuchs

    Full Text Available Mutation of the tumor suppressor p53 plays a major role in human carcinogenesis. Here we describe gene-targeted porcine mesenchymal stem cells (MSCs and live pigs carrying a latent TP53(R167H mutant allele, orthologous to oncogenic human mutant TP53(R175H and mouse Trp53(R172H, that can be activated by Cre recombination. MSCs carrying the latent TP53(R167H mutant allele were analyzed in vitro. Homozygous cells were p53 deficient, and on continued culture exhibited more rapid proliferation, anchorage independent growth, and resistance to the apoptosis-inducing chemotherapeutic drug doxorubicin, all characteristic of cellular transformation. Cre mediated recombination activated the latent TP53(R167H allele as predicted, and in homozygous cells expressed mutant p53-R167H protein at a level ten-fold greater than wild-type MSCs, consistent with the elevated levels found in human cancer cells. Gene targeted MSCs were used for nuclear transfer and fifteen viable piglets were produced carrying the latent TP53(R167H mutant allele in heterozygous form. These animals will allow study of p53 deficiency and expression of mutant p53-R167H to model human germline, or spontaneous somatic p53 mutation. This work represents the first inactivation and mutation of the gatekeeper tumor suppressor gene TP53 in a non-rodent mammal.

  9. RELAP5-3D Restart and Backup Verification Testing

    Energy Technology Data Exchange (ETDEWEB)

    Mesina, George L. [Idaho National Lab. (INL), Idaho Falls, ID (United States)

    2013-09-01

    Existing testing methodology for RELAP5-3D employs a set of test cases collected over two decades to test a variety of code features and run on a Linux or Windows platform. However, this set has numerous deficiencies in terms of code coverage, detail of comparison, running time, and testing fidelity of RELAP5-3D restart and backup capabilities. The test suite covers less than three quarters of the lines of code in the relap directory and just over half those in the environmental library. Even in terms of code features, many are not covered. Moreover, the test set runs many problems long past the point necessary to test the relevant features. It requires standard problems to run to completion. This is unnecessary for features can be tested in a short-running problem. For example, many trips and controls can be tested in the first few time steps, as can a number of fluid flow options. The testing system is also inaccurate. For the past decade, the diffem script has been the primary tool for checking that printouts from two different RELAP5-3D executables agree. This tool compares two output files to verify that all characters are the same except for those relating to date, time and a few other excluded items. The variable values printed on the output file are accurate to no more than eight decimal places. Therefore, calculations with errors in decimal places beyond those printed remain undetected. Finally, fidelity of restart is not tested except in the PVM sub-suite and backup is not specifically tested at all. When a restart is made from any midway point of the base-case transient, the restart must produce the same values. When a backup condition occurs, the code repeats advancements with the same time step. A perfect backup can be tested by forcing RELAP5 to perform a backup by falsely setting a backup condition flag at a user-specified-time. Comparison of the calculations of that run and those produced by the same input w/o the spurious condition should be

  10. Mitochondrial localization of the low level p53 protein in proliferative cells

    Energy Technology Data Exchange (ETDEWEB)

    Ferecatu, Ioana; Bergeaud, Marie; Rodriguez-Enfedaque, Aida; Le Floch, Nathalie [Laboratoire de Genetique et Biologie Cellulaire - CNRS UMR 8159, Universite de Versailles Saint-Quentin-en-Yvelines, Versailles, France and Laboratoire de Genetique Moleculaire et Physiologique, Ecole Pratique des Hautes Etudes, Versailles (France); Oliver, Lisa [INSERM U601, Universite de Nantes, Faculte de Medecine, Nantes Cedex (France); Rincheval, Vincent; Renaud, Flore [Laboratoire de Genetique et Biologie Cellulaire - CNRS UMR 8159, Universite de Versailles Saint-Quentin-en-Yvelines, Versailles, France and Laboratoire de Genetique Moleculaire et Physiologique, Ecole Pratique des Hautes Etudes, Versailles (France); Vallette, Francois M. [INSERM U601, Universite de Nantes, Faculte de Medecine, Nantes Cedex (France); Mignotte, Bernard [Laboratoire de Genetique et Biologie Cellulaire - CNRS UMR 8159, Universite de Versailles Saint-Quentin-en-Yvelines, Versailles, France and Laboratoire de Genetique Moleculaire et Physiologique, Ecole Pratique des Hautes Etudes, Versailles (France); Vayssiere, Jean-Luc, E-mail: jean-luc.vayssiere@uvsq.fr [Laboratoire de Genetique et Biologie Cellulaire - CNRS UMR 8159, Universite de Versailles Saint-Quentin-en-Yvelines, Versailles, France and Laboratoire de Genetique Moleculaire et Physiologique, Ecole Pratique des Hautes Etudes, Versailles (France)

    2009-10-02

    p53 protein plays a central role in suppressing tumorigenesis by inducing cell cycle arrest or apoptosis through transcription-dependent and -independent mechanisms. Emerging publications suggest that following stress, a fraction of p53 translocates to mitochondria to induce cytochrome c release and apoptosis. However, the localization of p53 under unstressed conditions remains largely unexplored. Here we show that p53 is localized at mitochondria in absence of apoptotic stimuli, when cells are proliferating, localization observed in various cell types (rodent and human). This is also supported by acellular assays in which p53 bind strongly to mitochondria isolated from rat liver. Furthermore, the mitochondria subfractionation study and the alkaline treatment of the mitochondrial p53 revealed that the majority of mitochondrial p53 is present in the membranous compartments. Finally, we identified VDAC, a protein of the mitochondrial outer-membrane, as a putative partner of p53 in unstressed/proliferative cells.

  11. 48 CFR 53.236 - Construction and architect-engineer contracts.

    Science.gov (United States)

    2010-10-01

    ... 48 Federal Acquisition Regulations System 2 2010-10-01 2010-10-01 false Construction and architect-engineer contracts. 53.236 Section 53.236 Federal Acquisition Regulations System FEDERAL ACQUISITION...-engineer contracts. ...

  12. Mutant p53 drives pancreatic cancer metastasis through cell-autonomous PDGF receptor β signaling

    National Research Council Canada - National Science Library

    Weissmueller, Susann; Manchado, Eusebio; Saborowski, Michael; Morris, 4th, John P; Wagenblast, Elvin; Davis, Carrie A; Moon, Sung-Hwan; Pfister, Neil T; Tschaharganeh, Darjus F; Kitzing, Thomas; Aust, Daniela; Markert, Elke K; Wu, Jianmin; Grimmond, Sean M; Pilarsky, Christian; Prives, Carol; Biankin, Andrew V; Lowe, Scott W

    2014-01-01

    ...) as both necessary and sufficient to mediate these effects. Mutant p53 induced PDGFRb through a cell-autonomous mechanism involving inhibition of a p73/NF-Y complex that represses PDGFRb expression in p53-deficient, noninvasive cells...

  13. Substrate phosphorylation and feedback regulation in JFK-promoted p53 destabilization

    National Research Council Canada - National Science Library

    Sun, Luyang; Shi, Lei; Wang, Feng; Huangyang, Peiwei; Si, Wenzhe; Yang, Jie; Yao, Zhi; Shang, Yongfeng

    2011-01-01

    .... Previously, we reported that JFK, the only Kelch domain-containing F-box protein in human, promotes ubiquitination and degradation of p53 and that unlike the other E3 ligases for p53, all of which...

  14. Development and Application of RELAP5-3D

    Energy Technology Data Exchange (ETDEWEB)

    Coryell, Eric Wesley; Harvego, Edwin Allan; Siefken, Larry James

    2002-04-01

    The SCDAP-3D computer code (Coryell 2001) has been developed at the Idaho National Engineering and Environmental Laboratory (INEEL) for the analysis of severe reactor accidents. A prominent feature of SCDAP-3D relative to other versions of the code is its linkage to the state-of-the-art thermal/hydraulic analysis capabilities of RELAP5-3D. Enhancements to the severe accident models include the ability to simulate high burnup and alternative fuel, as well as modifications to support advanced reactor analyses, such as those described by the Department of Energy's Generation IV (GenIV) initiative. Initial development of SCDAP-3D is complete and two widely varying but successful applications of the code are summarized. The first application is to large break loss of coolant accident analysis performed for a reactor with alternative fuel, and the second is a calculation of International Standard Problem 45 (ISP-45) or the QUENCH 6 experiment.

  15. Radiosensitivity in lung cancer with focus on p53

    CERN Document Server

    Bergqvist, M

    2002-01-01

    In Sweden approximately 2800 new lung cancer patients are diagnosed every year. Radiotherapy is used with curative intention in certain groups of patients. The aim of this thesis is to study the basis of differences in radioresistance and the possibility to predict response to radiotherapy. In the first study we investigated, using the comet assay, four lung cancer cell lines with different sensitivity towards radiation. A clear dose-response relationship for radiation-induced DNA single strand and double strand breaks were found. All cell lines showed a remarkably efficient repair of both the DNA single strand and double strand breaks one hour after irradiation. However, further studies in one radioresistant and one radiosensitive cell line demonstrated that repair during the first 15 min had the best accordance with radiosensitivity measured as surviving fraction. In the second and third study, sequencing studies of the p53 gene were performed on cell lines as well as on tumour material. Cell lines that wer...

  16. -5/3 Kolmogorov Turbulent Behaviour and Intermittent Sustainable Energies

    Science.gov (United States)

    Calif, Rudy; Schmitt, François G.; Medina, O. Durán

    2016-12-01

    he massive integration of sustainable energies into electrical grids (non-interconnected or connected) is a major problem due to their stochastic character revealed by strong fluctuations at all scales. In this paper, the scaling behaviour or power law correlations and the nature of scaling behaviour of sustainable resource data such as flow velocity, atmospheric wind speed, solar global solar radiation and sustainable energy such as, wind power output, are highlighted. For the first time, Fourier power spectral densities are estimated for each dataset. We show that the power spectrum densities obtained are close to the 5/3 Kolmogorov spectrum. Furthermore, the multifractal and intermittent properties of sustainable resource and energy data have been revealed by the concavity of the scaling exponent function. The proposed analysis frame allows a full description of fluctuations of processes considered. A good knowledge of the dynamic of fluctuations is crucial to manageme! nt of the integration of sustainable energies into a grid.

  17. 5/3 Kolmogorov Turbulent Behaviour and Intermittent Sustainable Energies

    Science.gov (United States)

    Calif, Rudy; Schmitt, François G.; Medina, O. Durán

    2016-12-01

    The massive integration of sustainable energies into electrical grids (non-interconnected or connected) is a major problem due to their stochastic character revealed by strong fluctuations at all scales. In this paper, the scaling behaviour or power law correlations and the nature of scaling behaviour of sustainable resource data such as flow velocity, atmospheric wind speed, solar global solar radiation and sustainable energy such as, wind power output, are highlighted. For the first time, Fourier power spectral densities are estimated for each dataset. We show that the power spectrum densities obtained are close to the 5/3 Kolmogorov spectrum. Furthermore, the multifractal and intermittent properties of sustainable resource and energy data have been revealed by the concavity of the scaling exponent function. The proposed analysis frame allows a full description of fluctuations of processes considered. A good knowledge of the dynamic of fluctuations is crucial to management of the integration of sustainable energies into a grid.

  18. Drosophila p53 controls Notch expression and balances apoptosis and proliferation.

    Science.gov (United States)

    Simón, Rocío; Aparicio, Ricardo; Housden, Ben E; Bray, Sarah; Busturia, Ana

    2014-10-01

    A balance between cell proliferation and apoptosis is important for normal development and tissue homeostasis. Under stress conditions, the conserved tumor suppressor and transcription factor Dp53 induces apoptosis to contribute to the maintenance of homeostasis. However, in some cases Dp53-induced apoptosis results in the proliferation of surrounding non-apoptotic cells. To gain insight into the Dp53 function in the control of apoptosis and proliferation, we studied the interaction between the Drosophila Dp53 and Notch genes. We present evidence that simultaneous reduction of Dp53 and Notch function synergistically increases the wing phenotype of Notch heterozygous mutant flies. Further, we found that a Notch cis-regulatory element is responsive to loss and gain of Dp53 function and that over-expression of Dp53 up-regulates Notch mRNA and protein expression. These findings suggest not only that Dp53 and Notch act together to control wing development but also indicate that Dp53 transcriptionally regulates Notch expression. Moreover, using Notch  gain and loss of function mutations we examined the relevance of Dp53 and Notch interactions in the process of Dp53-apoptosis induced proliferation. Results show that proliferation induced by Dp53 over-expression is dependent on Notch, thus identifying Notch as a new player in Dp53-induced proliferation. Interestingly, we found that Dp53-induced Notch activation and proliferation occurs even under conditions where apoptosis was inhibited. Our findings highlight the conservation between flies and vertebrates of the Dp53 and Notch cross-talk and suggest that Dp53 has a dual role regulating cell death and proliferation gene networks to control the homeostatic balance between apoptosis and proliferation.

  19. Toca-1 is suppressed by p53 to limit breast cancer cell invasion and tumor metastasis.

    Science.gov (United States)

    Chander, Harish; Brien, Colin D; Truesdell, Peter; Watt, Kathleen; Meens, Jalna; Schick, Colleen; Germain, Doris; Craig, Andrew W B

    2014-12-30

    Transducer of Cdc42-dependent actin assembly-1 (Toca-1) recruits actin regulatory proteins to invadopodia, and promotes breast tumor metastasis. Since metastatic breast tumors frequently harbor mutations in the tumor suppressor p53, we tested whether p53 regulates Toca-1 expression. Normal mammary epithelial cells (HBL-100, MCF10A) and breast cancer cell lines expressing wild-type (WT) p53 (DU4475, MTLn3) were treated with camptothecin or Nutlin-3 to stabilize p53 to test effects on Toca-1 mRNA and protein levels. Chromatin immunoprecipitation (ChIP) assays were performed to identify p53 binding site in Toca-1 gene. Stable silencing of p53 and Toca-1 were performed in MTLn3 cells to test effects on invadopodia and cell invasion in vitro, and tumor metastasis in vivo. We observed that breast cancer cell lines with mutant p53 have high levels of Toca-1 compared to those with WT p53. Stabilization of WT p53 led to further reduction in Toca-1 mRNA and protein levels in normal breast epithelial cells and breast cancer cells. ChIP assays revealed p53 binding within intron 2 of toca1, and reduced histone acetylation within its promoter region upon p53 upregulation or activation. Stable silencing of WT p53 in MTLn3 cells led to increased extracellular matrix degradation and cell invasion compared to control cells. Interestingly, the combined silencing of p53 and Toca-1 led to a partial rescue of these effects of p53 silencing in vitro and reduced lung metastases in mice. In human breast tumors, Toca-1 levels were high in subtypes with frequent p53 mutations, and high Toca-1 transcript levels correlated with increased risk of relapse. Based on these findings, we conclude that loss of p53 tumor suppressor function in breast cancers leads to upregulation of Toca-1, and results in enhanced risk of developing metastatic disease.

  20. Das Tumorsuppressorprotein p53 - Rolle bei der Induktion von Apoptose und bei der Replikation von Adenoviren

    OpenAIRE

    Koch, Philipp

    2003-01-01

    Das Tumorsuppressorgen p53 gehört zu den zentralen Steuereinheiten von Proliferation und Wachstum in der Zelle. Mutationen und funktioneller Verlust bei diesem Protein ist eng mit der Entstehung maligner Tumoren assoziiert. So kann man in über 50% aller soliden Tumoren Mutationen von p53 nachweisen. Es vermittelt seine Funktion hauptsächlich durch transkriptionelle Aktivierung p53-responsiver Gene. Folge der Aktivierung von p53 is...

  1. Targeting the p53 signaling pathway in cancer therapy - The promises, challenges, and perils

    Science.gov (United States)

    Stegh, Alexander H.

    2012-01-01

    Introduction Research over the past three decades has identified p53 as a multifunctional transcription factor, which regulates the expression of >2,500 target genes. p53 impacts myriad, highly diverse cellular processes, including the maintenance of genomic stability and fidelity, metabolism, longevity, and represents one of the most important and extensively studied tumor suppressors. Activated by various stresses, foremost genotoxic damage, hypoxia, heat shock and oncogenic assault, p53 blocks cancer progression by provoking transient or permanent growth arrest, by enabling DNA repair or by advancing cellular death programs. This potent and versatile anti-cancer activity profile, together with genomic and mutational analyses documenting inactivation of p53 in more than 50% of human cancers, motivated drug development efforts to (re-) activate p53 in established tumors. Areas covered In this review the complexities of p53 signaling in cancer are summarized. Current strategies and challenges to restore p53’s tumor suppressive function in established tumors, i.e. adenoviral gene transfer and small molecules to activate p53, to inactivate p53 inhibitors and to restore wild type function of p53 mutant proteins are discussed. Expert opinion It is indubitable that p53 represents an attractive target for the development of anti-cancer therapies. Whether p53 is ‘druggable’, however, remains an area of active research and discussion, as p53 has pro-survival functions and chronic p53 activation accelerates aging, which may compromise the long-term homeostasis of an organism. Thus, the complex biology and dual functions of p53 in cancer prevention and age-related cellular responses pose significant challenges on the development of p53-targeting cancer therapies. PMID:22239435

  2. Analysis of P53 mutations and their expression in 56 colorectal cancer cell lines

    DEFF Research Database (Denmark)

    Liu, Ying; Bodmer, Walter F

    2006-01-01

    A comprehensive analysis of the TP53 gene and its protein status was carried out on a panel of 56 colorectal cancer cell lines. This analysis was based on a combination of denaturing HPLC mutation screening of all exons of the p53 gene, sequencing the cDNA, and assessing the function of the p53...

  3. The p53 codon 72 polymorphism and association to prostate cancer ...

    African Journals Online (AJOL)

    Jane

    2011-10-05

    Oct 5, 2011 ... Tp53 is an important tumor suppressor gene, which induces cell growth arrest or apoptosis when subjected to cytotoxic stimuli. Association has been reported between various cancers and p53 codon. 72 polymorphism. Our objective was to investigate the possible association between p53 at codon 72.

  4. 7 CFR 1124.53 - Announcement of class prices, component prices, and advanced pricing factors.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 9 2010-01-01 2009-01-01 true Announcement of class prices, component prices, and advanced pricing factors. 1124.53 Section 1124.53 Agriculture Regulations of the Department of Agriculture... Announcement of class prices, component prices, and advanced pricing factors. See § 1000.53. ...

  5. 7 CFR 1030.53 - Announcement of class prices, component prices, and advanced pricing factors.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 9 2010-01-01 2009-01-01 true Announcement of class prices, component prices, and advanced pricing factors. 1030.53 Section 1030.53 Agriculture Regulations of the Department of Agriculture... of class prices, component prices, and advanced pricing factors. See § 1000.53. ...

  6. 7 CFR 1033.53 - Announcement of class prices, component prices, and advanced pricing factors.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 9 2010-01-01 2009-01-01 true Announcement of class prices, component prices, and advanced pricing factors. 1033.53 Section 1033.53 Agriculture Regulations of the Department of Agriculture... class prices, component prices, and advanced pricing factors. See § 1000.53. ...

  7. 7 CFR 1006.53 - Announcement of class prices, component prices, and advanced pricing factors.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 9 2010-01-01 2009-01-01 true Announcement of class prices, component prices, and advanced pricing factors. 1006.53 Section 1006.53 Agriculture Regulations of the Department of Agriculture... class prices, component prices, and advanced pricing factors. See § 1000.53. ...

  8. 7 CFR 1005.53 - Announcement of class prices, component prices, and advanced pricing factors.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 9 2010-01-01 2009-01-01 true Announcement of class prices, component prices, and advanced pricing factors. 1005.53 Section 1005.53 Agriculture Regulations of the Department of Agriculture... class prices, component prices, and advanced pricing factors. See § 1000.53. ...

  9. 7 CFR 1032.53 - Announcement of class prices, component prices, and advanced pricing factors.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 9 2010-01-01 2009-01-01 true Announcement of class prices, component prices, and advanced pricing factors. 1032.53 Section 1032.53 Agriculture Regulations of the Department of Agriculture... class prices, component prices, and advanced pricing factors. See § 1000.53. ...

  10. 7 CFR 1131.53 - Announcement of class prices, component prices, and advanced pricing factors.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 9 2010-01-01 2009-01-01 true Announcement of class prices, component prices, and advanced pricing factors. 1131.53 Section 1131.53 Agriculture Regulations of the Department of Agriculture... class prices, component prices, and advanced pricing factors. See § 1000.53. ...

  11. 7 CFR 1126.53 - Announcement of class prices, component prices, and advanced pricing factors.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 9 2010-01-01 2009-01-01 true Announcement of class prices, component prices, and advanced pricing factors. 1126.53 Section 1126.53 Agriculture Regulations of the Department of Agriculture... class prices, component prices, and advanced pricing factors. See § 1000.53. ...

  12. 7 CFR 1001.53 - Announcement of class prices, component prices, and advanced pricing factors.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 9 2010-01-01 2009-01-01 true Announcement of class prices, component prices, and advanced pricing factors. 1001.53 Section 1001.53 Agriculture Regulations of the Department of Agriculture... class prices, component prices, and advanced pricing factors. See § 1000.53. ...

  13. 7 CFR 1007.53 - Announcement of class prices, component prices, and advanced pricing factors.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 9 2010-01-01 2009-01-01 true Announcement of class prices, component prices, and advanced pricing factors. 1007.53 Section 1007.53 Agriculture Regulations of the Department of Agriculture... class prices, component prices, and advanced pricing factors. See § 1000.53. ...

  14. 41 CFR 105-53.130-4 - Office of Small and Disadvantaged Business Utilization.

    Science.gov (United States)

    2010-07-01

    ... Disadvantaged Business Utilization. 105-53.130-4 Section 105-53.130-4 Public Contracts and Property Management... ORGANIZATION AND FUNCTIONS Central Offices § 105-53.130-4 Office of Small and Disadvantaged Business Utilization. (a) Creation and authority. Public Law 95-507, October 14, 1978, an amendment to the Small...

  15. FGFR3 and P53 characterize alternative genetic pathways in the pathogenesis of urothelial cell carcinoma

    NARCIS (Netherlands)

    B.W. van Rhijn (Bas); Th.H. van der Kwast (Theo); A.N. Vis (André); W.J. Kirkels (Wim); E.R. Boeve; A.C. Jobsis; E.C. Zwarthoff (Ellen)

    2004-01-01

    textabstractFibroblast growth factor receptor 3 (FGFR3) and P53 mutations are frequently observed in bladder cancer. We here describe the distribution of FGFR3 mutations and P53 overexpression in 260 primary urothelial cell carcinomas. FGFR3 mutations were observed in 59% and P53

  16. 27 CFR 53.143 - Special rules relating to further manufacture.

    Science.gov (United States)

    2010-04-01

    ... further manufacture. 53.143 Section 53.143 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX... AND AMMUNITION Exemptions, Registration, Etc. § 53.143 Special rules relating to further manufacture... the Code for use by it in further manufacture shall be treated as the manufacturer or producer of such...

  17. 10 CFR 1.53 - Use of NRC seal or replicas.

    Science.gov (United States)

    2010-01-01

    ... 10 Energy 1 2010-01-01 2010-01-01 false Use of NRC seal or replicas. 1.53 Section 1.53 Energy NUCLEAR REGULATORY COMMISSION STATEMENT OF ORGANIZATION AND GENERAL INFORMATION NRC Seal and Flag § 1.53 Use of NRC seal or replicas. (a) The use of the seal or replicas is restricted to the following: (1...

  18. Suppression of p53 activity through the cooperative action of Ski and histone deacetylase SIRT1.

    Science.gov (United States)

    Inoue, Yasumichi; Iemura, Shun-ichiro; Natsume, Tohru; Miyazawa, Keiji; Imamura, Takeshi

    2011-02-25

    Ski was originally identified as an oncogene based on the fact that Ski overexpression transformed chicken and quail embryo fibroblasts. Consistent with these proposed oncogenic roles, Ski is overexpressed in various human tumors. However, whether and how Ski functions in mammalian tumorigenesis has not been fully investigated. Here, we show that Ski interacts with p53 and attenuates the biological functions of p53. Ski overexpression attenuated p53-dependent transactivation, whereas Ski knockdown enhanced the transcriptional activity of p53. Interestingly, Ski bound to the histone deacetylase SIRT1 and stabilized p53-SIRT1 interaction to promote p53 deacetylation, which subsequently decreased the DNA binding activity of p53. Consistent with the ability of Ski to inactivate p53, overexpressing Ski desensitized cells to genotoxic drugs and Nutlin-3, a small-molecule antagonist of Mdm2 that stabilizes p53 and activates the p53 pathway, whereas knocking down Ski increased the cellular sensitivity to these agents. These results indicate that Ski negatively regulates p53 and suggest that the p53-Ski-SIRT1 axis is an attractive target for cancer therapy.

  19. The role of p53.S389 phosphorylation in DNA damage response pathways and tumorigenesis

    NARCIS (Netherlands)

    Bruins, Wendy

    2007-01-01

    The results presented in this thesis provide new information on the role of the p53.S389A point mutation in chemical-induced tumorigenesis. After DNA damage, p53 protein levels increase due to several post-translational activation processes. Phosphorylation of p53.S389 seems to be partly required

  20. 48 CFR 53.301-294 - Subcontracting Report for Individual Contracts.

    Science.gov (United States)

    2010-10-01

    ... 48 Federal Acquisition Regulations System 2 2010-10-01 2010-10-01 false Subcontracting Report for Individual Contracts. 53.301-294 Section 53.301-294 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION (CONTINUED) CLAUSES AND FORMS FORMS Illustrations of Forms 53.301-294 Subcontracting...