Activation and activities of the p53 tumour suppressor protein (original) (raw)

Abstract

The p53 tumour suppressor protein inhibits malignant progression by mediating cell cycle arrest, apoptosis or repair following cellular stress. One of the major regulators of p53 function is the MDM2 protein, and multiple forms of cellular stress activate p53 by inhibiting the MDM2-mediated degradation of p53. Mutations in p53, or disruption of the pathways that allow activation of p53, seem to be a general feature of all cancers. Here we review recent advances in our understanding of the pathways that regulate p53 and the pathways that are induced by p53, as well as their implications for cancer therapy. © 2001 Cancer Research Campaign http://www.bjcancer.com

Full Text

The Full Text of this article is available as a PDF (165.8 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abrahamson J. L., Lee J. M., Bernstein A. Regulation of p53-mediated apoptosis and cell cycle arrest by Steel factor. Mol Cell Biol. 1995 Dec;15(12):6953–6960. doi: 10.1128/mcb.15.12.6953. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Agarwal M. L., Agarwal A., Taylor W. R., Stark G. R. p53 controls both the G2/M and the G1 cell cycle checkpoints and mediates reversible growth arrest in human fibroblasts. Proc Natl Acad Sci U S A. 1995 Aug 29;92(18):8493–8497. doi: 10.1073/pnas.92.18.8493. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Albrechtsen N., Dornreiter I., Grosse F., Kim E., Wiesmüller L., Deppert W. Maintenance of genomic integrity by p53: complementary roles for activated and non-activated p53. Oncogene. 1999 Dec 13;18(53):7706–7717. doi: 10.1038/sj.onc.1202952. [DOI] [PubMed] [Google Scholar]
  4. Almog N., Rotter V. Involvement of p53 in cell differentiation and development. Biochim Biophys Acta. 1997 Aug 8;1333(1):F1–27. doi: 10.1016/s0304-419x(97)00012-7. [DOI] [PubMed] [Google Scholar]
  5. An W. G., Kanekal M., Simon M. C., Maltepe E., Blagosklonny M. V., Neckers L. M. Stabilization of wild-type p53 by hypoxia-inducible factor 1alpha. Nature. 1998 Mar 26;392(6674):405–408. doi: 10.1038/32925. [DOI] [PubMed] [Google Scholar]
  6. Arriola E. L., Lopez A. R., Chresta C. M. Differential regulation of p21waf-1/cip-1 and Mdm2 by etoposide: etoposide inhibits the p53-Mdm2 autoregulatory feedback loop. Oncogene. 1999 Jan 28;18(4):1081–1091. doi: 10.1038/sj.onc.1202391. [DOI] [PubMed] [Google Scholar]
  7. Ashcroft M., Kubbutat M. H., Vousden K. H. Regulation of p53 function and stability by phosphorylation. Mol Cell Biol. 1999 Mar;19(3):1751–1758. doi: 10.1128/mcb.19.3.1751. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Ashcroft M., Taya Y., Vousden K. H. Stress signals utilize multiple pathways to stabilize p53. Mol Cell Biol. 2000 May;20(9):3224–3233. doi: 10.1128/mcb.20.9.3224-3233.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Ashcroft M., Vousden K. H. Regulation of p53 stability. Oncogene. 1999 Dec 13;18(53):7637–7643. doi: 10.1038/sj.onc.1203012. [DOI] [PubMed] [Google Scholar]
  10. Ashkenazi A., Dixit V. M. Death receptors: signaling and modulation. Science. 1998 Aug 28;281(5381):1305–1308. doi: 10.1126/science.281.5381.1305. [DOI] [PubMed] [Google Scholar]
  11. Atencio I. A., Ramachandra M., Shabram P., Demers G. W. Calpain inhibitor 1 activates p53-dependent apoptosis in tumor cell lines. Cell Growth Differ. 2000 May;11(5):247–253. [PubMed] [Google Scholar]
  12. Bachelder R. E., Ribick M. J., Marchetti A., Falcioni R., Soddu S., Davis K. R., Mercurio A. M. p53 inhibits alpha 6 beta 4 integrin survival signaling by promoting the caspase 3-dependent cleavage of AKT/PKB. J Cell Biol. 1999 Nov 29;147(5):1063–1072. doi: 10.1083/jcb.147.5.1063. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Barak Y., Juven T., Haffner R., Oren M. mdm2 expression is induced by wild type p53 activity. EMBO J. 1993 Feb;12(2):461–468. doi: 10.1002/j.1460-2075.1993.tb05678.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Bates S., Phillips A. C., Clark P. A., Stott F., Peters G., Ludwig R. L., Vousden K. H. p14ARF links the tumour suppressors RB and p53. Nature. 1998 Sep 10;395(6698):124–125. doi: 10.1038/25867. [DOI] [PubMed] [Google Scholar]
  15. Bates S., Ryan K. M., Phillips A. C., Vousden K. H. Cell cycle arrest and DNA endoreduplication following p21Waf1/Cip1 expression. Oncogene. 1998 Oct 1;17(13):1691–1703. doi: 10.1038/sj.onc.1202104. [DOI] [PubMed] [Google Scholar]
  16. Bell D. W., Varley J. M., Szydlo T. E., Kang D. H., Wahrer D. C., Shannon K. E., Lubratovich M., Verselis S. J., Isselbacher K. J., Fraumeni J. F. Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science. 1999 Dec 24;286(5449):2528–2531. doi: 10.1126/science.286.5449.2528. [DOI] [PubMed] [Google Scholar]
  17. Bennett M., Macdonald K., Chan S. W., Luzio J. P., Simari R., Weissberg P. Cell surface trafficking of Fas: a rapid mechanism of p53-mediated apoptosis. Science. 1998 Oct 9;282(5387):290–293. doi: 10.1126/science.282.5387.290. [DOI] [PubMed] [Google Scholar]
  18. Blander G., Zalle N., Leal J. F., Bar-Or R. L., Yu C. E., Oren M. The Werner syndrome protein contributes to induction of p53 by DNA damage. FASEB J. 2000 Nov;14(14):2138–2140. doi: 10.1096/fj.00-0171fje. [DOI] [PubMed] [Google Scholar]
  19. Blattner C., Tobiasch E., Litfen M., Rahmsdorf H. J., Herrlich P. DNA damage induced p53 stabilization: no indication for an involvement of p53 phosphorylation. Oncogene. 1999 Mar 4;18(9):1723–1732. doi: 10.1038/sj.onc.1202480. [DOI] [PubMed] [Google Scholar]
  20. Bossy-Wetzel E., Green D. R. Apoptosis: checkpoint at the mitochondrial frontier. Mutat Res. 1999 Jul 30;434(3):243–251. doi: 10.1016/s0921-8777(99)00032-4. [DOI] [PubMed] [Google Scholar]
  21. Bouvet M., Ellis L. M., Nishizaki M., Fujiwara T., Liu W., Bucana C. D., Fang B., Lee J. J., Roth J. A. Adenovirus-mediated wild-type p53 gene transfer down-regulates vascular endothelial growth factor expression and inhibits angiogenesis in human colon cancer. Cancer Res. 1998 Jun 1;58(11):2288–2292. [PubMed] [Google Scholar]
  22. Boyd M. T., Vlatkovic N., Haines D. S. A novel cellular protein (MTBP) binds to MDM2 and induces a G1 arrest that is suppressed by MDM2. J Biol Chem. 2000 Oct 13;275(41):31883–31890. doi: 10.1074/jbc.M004252200. [DOI] [PubMed] [Google Scholar]
  23. Boyd S. D., Tsai K. Y., Jacks T. An intact HDM2 RING-finger domain is required for nuclear exclusion of p53. Nat Cell Biol. 2000 Sep;2(9):563–568. doi: 10.1038/35023500. [DOI] [PubMed] [Google Scholar]
  24. Brugarolas J., Chandrasekaran C., Gordon J. I., Beach D., Jacks T., Hannon G. J. Radiation-induced cell cycle arrest compromised by p21 deficiency. Nature. 1995 Oct 12;377(6549):552–557. doi: 10.1038/377552a0. [DOI] [PubMed] [Google Scholar]
  25. Buckbinder L., Talbott R., Velasco-Miguel S., Takenaka I., Faha B., Seizinger B. R., Kley N. Induction of the growth inhibitor IGF-binding protein 3 by p53. Nature. 1995 Oct 19;377(6550):646–649. doi: 10.1038/377646a0. [DOI] [PubMed] [Google Scholar]
  26. Butz K., Denk C., Ullmann A., Scheffner M., Hoppe-Seyler F. Induction of apoptosis in human papillomaviruspositive cancer cells by peptide aptamers targeting the viral E6 oncoprotein. Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6693–6697. doi: 10.1073/pnas.110538897. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Bálint E., Bates S., Vousden K. H. Mdm2 binds p73 alpha without targeting degradation. Oncogene. 1999 Jul 8;18(27):3923–3929. doi: 10.1038/sj.onc.1202781. [DOI] [PubMed] [Google Scholar]
  28. Böttger A., Böttger V., Sparks A., Liu W. L., Howard S. F., Lane D. P. Design of a synthetic Mdm2-binding mini protein that activates the p53 response in vivo. Curr Biol. 1997 Nov 1;7(11):860–869. doi: 10.1016/s0960-9822(06)00374-5. [DOI] [PubMed] [Google Scholar]
  29. Canman C. E., Gilmer T. M., Coutts S. B., Kastan M. B. Growth factor modulation of p53-mediated growth arrest versus apoptosis. Genes Dev. 1995 Mar 1;9(5):600–611. doi: 10.1101/gad.9.5.600. [DOI] [PubMed] [Google Scholar]
  30. Chan T. A., Hermeking H., Lengauer C., Kinzler K. W., Vogelstein B. 14-3-3Sigma is required to prevent mitotic catastrophe after DNA damage. Nature. 1999 Oct 7;401(6753):616–620. doi: 10.1038/44188. [DOI] [PubMed] [Google Scholar]
  31. Chao C., Saito S., Kang J., Anderson C. W., Appella E., Xu Y. p53 transcriptional activity is essential for p53-dependent apoptosis following DNA damage. EMBO J. 2000 Sep 15;19(18):4967–4975. doi: 10.1093/emboj/19.18.4967. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Chehab N. H., Malikzay A., Appel M., Halazonetis T. D. Chk2/hCds1 functions as a DNA damage checkpoint in G(1) by stabilizing p53. Genes Dev. 2000 Feb 1;14(3):278–288. [PMC free article] [PubMed] [Google Scholar]
  33. Chen L., Lu W., Agrawal S., Zhou W., Zhang R., Chen J. Ubiquitous induction of p53 in tumor cells by antisense inhibition of MDM2 expression. Mol Med. 1999 Jan;5(1):21–34. [PMC free article] [PubMed] [Google Scholar]
  34. Chen X., Ko L. J., Jayaraman L., Prives C. p53 levels, functional domains, and DNA damage determine the extent of the apoptotic response of tumor cells. Genes Dev. 1996 Oct 1;10(19):2438–2451. doi: 10.1101/gad.10.19.2438. [DOI] [PubMed] [Google Scholar]
  35. Crook T., Marston N. J., Sara E. A., Vousden K. H. Transcriptional activation by p53 correlates with suppression of growth but not transformation. Cell. 1994 Dec 2;79(5):817–827. doi: 10.1016/0092-8674(94)90071-x. [DOI] [PubMed] [Google Scholar]
  36. Crook T., Wrede D., Tidy J. A., Mason W. P., Evans D. J., Vousden K. H. Clonal p53 mutation in primary cervical cancer: association with human-papillomavirus-negative tumours. Lancet. 1992 May 2;339(8801):1070–1073. doi: 10.1016/0140-6736(92)90662-m. [DOI] [PubMed] [Google Scholar]
  37. Damalas A., Ben-Ze'ev A., Simcha I., Shtutman M., Leal J. F., Zhurinsky J., Geiger B., Oren M. Excess beta-catenin promotes accumulation of transcriptionally active p53. EMBO J. 1999 Jun 1;18(11):3054–3063. doi: 10.1093/emboj/18.11.3054. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Dameron K. M., Volpert O. V., Tainsky M. A., Bouck N. Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1. Science. 1994 Sep 9;265(5178):1582–1584. doi: 10.1126/science.7521539. [DOI] [PubMed] [Google Scholar]
  39. Dobbelstein M., Wienzek S., König C., Roth J. Inactivation of the p53-homologue p73 by the mdm2-oncoprotein. Oncogene. 1999 Mar 25;18(12):2101–2106. doi: 10.1038/sj.onc.1202512. [DOI] [PubMed] [Google Scholar]
  40. Donehower L. A. The p53-deficient mouse: a model for basic and applied cancer studies. Semin Cancer Biol. 1996 Oct;7(5):269–278. doi: 10.1006/scbi.1996.0035. [DOI] [PubMed] [Google Scholar]
  41. Elenbaas B., Dobbelstein M., Roth J., Shenk T., Levine A. J. The MDM2 oncoprotein binds specifically to RNA through its RING finger domain. Mol Med. 1996 Jul;2(4):439–451. [PMC free article] [PubMed] [Google Scholar]
  42. Esteller M. Epigenetic lesions causing genetic lesions in human cancer: promoter hypermethylation of DNA repair genes. Eur J Cancer. 2000 Dec;36(18):2294–2300. doi: 10.1016/s0959-8049(00)00303-8. [DOI] [PubMed] [Google Scholar]
  43. Fang S., Jensen J. P., Ludwig R. L., Vousden K. H., Weissman A. M. Mdm2 is a RING finger-dependent ubiquitin protein ligase for itself and p53. J Biol Chem. 2000 Mar 24;275(12):8945–8951. doi: 10.1074/jbc.275.12.8945. [DOI] [PubMed] [Google Scholar]
  44. Ferbeyre G., de Stanchina E., Querido E., Baptiste N., Prives C., Lowe S. W. PML is induced by oncogenic ras and promotes premature senescence. Genes Dev. 2000 Aug 15;14(16):2015–2027. [PMC free article] [PubMed] [Google Scholar]
  45. Fogal V., Gostissa M., Sandy P., Zacchi P., Sternsdorf T., Jensen K., Pandolfi P. P., Will H., Schneider C., Del Sal G. Regulation of p53 activity in nuclear bodies by a specific PML isoform. EMBO J. 2000 Nov 15;19(22):6185–6195. doi: 10.1093/emboj/19.22.6185. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Ford J. M., Hanawalt P. C. Li-Fraumeni syndrome fibroblasts homozygous for p53 mutations are deficient in global DNA repair but exhibit normal transcription-coupled repair and enhanced UV resistance. Proc Natl Acad Sci U S A. 1995 Sep 12;92(19):8876–8880. doi: 10.1073/pnas.92.19.8876. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Foster B. A., Coffey H. A., Morin M. J., Rastinejad F. Pharmacological rescue of mutant p53 conformation and function. Science. 1999 Dec 24;286(5449):2507–2510. doi: 10.1126/science.286.5449.2507. [DOI] [PubMed] [Google Scholar]
  48. Freedman D. A., Levine A. J. Nuclear export is required for degradation of endogenous p53 by MDM2 and human papillomavirus E6. Mol Cell Biol. 1998 Dec;18(12):7288–7293. doi: 10.1128/mcb.18.12.7288. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Freedman D. A., Wu L., Levine A. J. Functions of the MDM2 oncoprotein. Cell Mol Life Sci. 1999 Jan;55(1):96–107. doi: 10.1007/s000180050273. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Fuchs S. Y., Adler V., Buschmann T., Yin Z., Wu X., Jones S. N., Ronai Z. JNK targets p53 ubiquitination and degradation in nonstressed cells. Genes Dev. 1998 Sep 1;12(17):2658–2663. doi: 10.1101/gad.12.17.2658. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Gaiddon C., Moorthy N. C., Prives C. Ref-1 regulates the transactivation and pro-apoptotic functions of p53 in vivo. EMBO J. 1999 Oct 15;18(20):5609–5621. doi: 10.1093/emboj/18.20.5609. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Garkavtsev I., Grigorian I. A., Ossovskaya V. S., Chernov M. V., Chumakov P. M., Gudkov A. V. The candidate tumour suppressor p33ING1 cooperates with p53 in cell growth control. Nature. 1998 Jan 15;391(6664):295–298. doi: 10.1038/34675. [DOI] [PubMed] [Google Scholar]
  53. Geyer R. K., Yu Z. K., Maki C. G. The MDM2 RING-finger domain is required to promote p53 nuclear export. Nat Cell Biol. 2000 Sep;2(9):569–573. doi: 10.1038/35023507. [DOI] [PubMed] [Google Scholar]
  54. Gostissa M., Hengstermann A., Fogal V., Sandy P., Schwarz S. E., Scheffner M., Del Sal G. Activation of p53 by conjugation to the ubiquitin-like protein SUMO-1. EMBO J. 1999 Nov 15;18(22):6462–6471. doi: 10.1093/emboj/18.22.6462. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Gottlieb E., Haffner R., von Rüden T., Wagner E. F., Oren M. Down-regulation of wild-type p53 activity interferes with apoptosis of IL-3-dependent hematopoietic cells following IL-3 withdrawal. EMBO J. 1994 Mar 15;13(6):1368–1374. doi: 10.1002/j.1460-2075.1994.tb06390.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Grossman S. R., Perez M., Kung A. L., Joseph M., Mansur C., Xiao Z. X., Kumar S., Howley P. M., Livingston D. M. p300/MDM2 complexes participate in MDM2-mediated p53 degradation. Mol Cell. 1998 Oct;2(4):405–415. doi: 10.1016/s1097-2765(00)80140-9. [DOI] [PubMed] [Google Scholar]
  57. Gu W., Roeder R. G. Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell. 1997 Aug 22;90(4):595–606. doi: 10.1016/s0092-8674(00)80521-8. [DOI] [PubMed] [Google Scholar]
  58. Guerra B., Götz C., Wagner P., Montenarh M., Issinger O. G. The carboxy terminus of p53 mimics the polylysine effect of protein kinase CK2-catalyzed MDM2 phosphorylation. Oncogene. 1997 Jun 5;14(22):2683–2688. doi: 10.1038/sj.onc.1201112. [DOI] [PubMed] [Google Scholar]
  59. Guo A., Salomoni P., Luo J., Shih A., Zhong S., Gu W., Pandolfi P. P. The function of PML in p53-dependent apoptosis. Nat Cell Biol. 2000 Oct;2(10):730–736. doi: 10.1038/35036365. [DOI] [PubMed] [Google Scholar]
  60. Götz C., Kartarius S., Scholtes P., Nastainczyk W., Montenarh M. Identification of a CK2 phosphorylation site in mdm2. Eur J Biochem. 1999 Dec;266(2):493–501. doi: 10.1046/j.1432-1327.1999.00882.x. [DOI] [PubMed] [Google Scholar]
  61. Hainaut P., Hollstein M. p53 and human cancer: the first ten thousand mutations. Adv Cancer Res. 2000;77:81–137. doi: 10.1016/s0065-230x(08)60785-x. [DOI] [PubMed] [Google Scholar]
  62. Harper J. W., Adami G. R., Wei N., Keyomarsi K., Elledge S. J. The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell. 1993 Nov 19;75(4):805–816. doi: 10.1016/0092-8674(93)90499-g. [DOI] [PubMed] [Google Scholar]
  63. Haupt Y., Maya R., Kazaz A., Oren M. Mdm2 promotes the rapid degradation of p53. Nature. 1997 May 15;387(6630):296–299. doi: 10.1038/387296a0. [DOI] [PubMed] [Google Scholar]
  64. Hay T. J., Meek D. W. Multiple sites of in vivo phosphorylation in the MDM2 oncoprotein cluster within two important functional domains. FEBS Lett. 2000 Jul 28;478(1-2):183–186. doi: 10.1016/s0014-5793(00)01850-0. [DOI] [PubMed] [Google Scholar]
  65. Hermeking H., Lengauer C., Polyak K., He T. C., Zhang L., Thiagalingam S., Kinzler K. W., Vogelstein B. 14-3-3sigma is a p53-regulated inhibitor of G2/M progression. Mol Cell. 1997 Dec;1(1):3–11. doi: 10.1016/s1097-2765(00)80002-7. [DOI] [PubMed] [Google Scholar]
  66. Hietanen S., Lain S., Krausz E., Blattner C., Lane D. P. Activation of p53 in cervical carcinoma cells by small molecules. Proc Natl Acad Sci U S A. 2000 Jul 18;97(15):8501–8506. doi: 10.1073/pnas.97.15.8501. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Hirao A., Kong Y. Y., Matsuoka S., Wakeham A., Ruland J., Yoshida H., Liu D., Elledge S. J., Mak T. W. DNA damage-induced activation of p53 by the checkpoint kinase Chk2. Science. 2000 Mar 10;287(5459):1824–1827. doi: 10.1126/science.287.5459.1824. [DOI] [PubMed] [Google Scholar]
  68. Hollander M. C., Sheikh M. S., Bulavin D. V., Lundgren K., Augeri-Henmueller L., Shehee R., Molinaro T. A., Kim K. E., Tolosa E., Ashwell J. D. Genomic instability in Gadd45a-deficient mice. Nat Genet. 1999 Oct;23(2):176–184. doi: 10.1038/13802. [DOI] [PubMed] [Google Scholar]
  69. Honda R., Tanaka H., Yasuda H. Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. FEBS Lett. 1997 Dec 22;420(1):25–27. doi: 10.1016/s0014-5793(97)01480-4. [DOI] [PubMed] [Google Scholar]
  70. Honda R., Yasuda H. Association of p19(ARF) with Mdm2 inhibits ubiquitin ligase activity of Mdm2 for tumor suppressor p53. EMBO J. 1999 Jan 4;18(1):22–27. doi: 10.1093/emboj/18.1.22. [DOI] [PMC free article] [PubMed] [Google Scholar]
  71. Hsieh J. K., Chan F. S., O'Connor D. J., Mittnacht S., Zhong S., Lu X. RB regulates the stability and the apoptotic function of p53 via MDM2. Mol Cell. 1999 Feb;3(2):181–193. doi: 10.1016/s1097-2765(00)80309-3. [DOI] [PubMed] [Google Scholar]
  72. Hupp T. R., Meek D. W., Midgley C. A., Lane D. P. Regulation of the specific DNA binding function of p53. Cell. 1992 Nov 27;71(5):875–886. doi: 10.1016/0092-8674(92)90562-q. [DOI] [PubMed] [Google Scholar]
  73. Irwin M., Marin M. C., Phillips A. C., Seelan R. S., Smith D. I., Liu W., Flores E. R., Tsai K. Y., Jacks T., Vousden K. H. Role for the p53 homologue p73 in E2F-1-induced apoptosis. Nature. 2000 Oct 5;407(6804):645–648. doi: 10.1038/35036614. [DOI] [PubMed] [Google Scholar]
  74. Ishida S., Yamashita T., Nakaya U., Tokino T. Adenovirus-mediated transfer of p53-related genes induces apoptosis of human cancer cells. Jpn J Cancer Res. 2000 Feb;91(2):174–180. doi: 10.1111/j.1349-7006.2000.tb00929.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  75. Ito A., Lai C. H., Zhao X., Saito S., Hamilton M. H., Appella E., Yao T. P. p300/CBP-mediated p53 acetylation is commonly induced by p53-activating agents and inhibited by MDM2. EMBO J. 2001 Mar 15;20(6):1331–1340. doi: 10.1093/emboj/20.6.1331. [DOI] [PMC free article] [PubMed] [Google Scholar]
  76. Jackson M. W., Berberich S. J. MdmX protects p53 from Mdm2-mediated degradation. Mol Cell Biol. 2000 Feb;20(3):1001–1007. doi: 10.1128/mcb.20.3.1001-1007.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  77. Jacobs J. J., Keblusek P., Robanus-Maandag E., Kristel P., Lingbeek M., Nederlof P. M., van Welsem T., van de Vijver M. J., Koh E. Y., Daley G. Q. Senescence bypass screen identifies TBX2, which represses Cdkn2a (p19(ARF)) and is amplified in a subset of human breast cancers. Nat Genet. 2000 Nov;26(3):291–299. doi: 10.1038/81583. [DOI] [PubMed] [Google Scholar]
  78. Jacobs J. J., Scheijen B., Voncken J. W., Kieboom K., Berns A., van Lohuizen M. Bmi-1 collaborates with c-Myc in tumorigenesis by inhibiting c-Myc-induced apoptosis via INK4a/ARF. Genes Dev. 1999 Oct 15;13(20):2678–2690. doi: 10.1101/gad.13.20.2678. [DOI] [PMC free article] [PubMed] [Google Scholar]
  79. Jayaraman L., Moorthy N. C., Murthy K. G., Manley J. L., Bustin M., Prives C. High mobility group protein-1 (HMG-1) is a unique activator of p53. Genes Dev. 1998 Feb 15;12(4):462–472. doi: 10.1101/gad.12.4.462. [DOI] [PMC free article] [PubMed] [Google Scholar]
  80. Jayaraman L., Murthy K. G., Zhu C., Curran T., Xanthoudakis S., Prives C. Identification of redox/repair protein Ref-1 as a potent activator of p53. Genes Dev. 1997 Mar 1;11(5):558–570. doi: 10.1101/gad.11.5.558. [DOI] [PubMed] [Google Scholar]
  81. Jayaraman L., Prives C. Covalent and noncovalent modifiers of the p53 protein. Cell Mol Life Sci. 1999 Jan;55(1):76–87. doi: 10.1007/s000180050271. [DOI] [PMC free article] [PubMed] [Google Scholar]
  82. Jimenez G. S., Nister M., Stommel J. M., Beeche M., Barcarse E. A., Zhang X. Q., O'Gorman S., Wahl G. M. A transactivation-deficient mouse model provides insights into Trp53 regulation and function. Nat Genet. 2000 Sep;26(1):37–43. doi: 10.1038/79152. [DOI] [PubMed] [Google Scholar]
  83. Joazeiro C. A., Weissman A. M. RING finger proteins: mediators of ubiquitin ligase activity. Cell. 2000 Sep 1;102(5):549–552. doi: 10.1016/s0092-8674(00)00077-5. [DOI] [PubMed] [Google Scholar]
  84. Jones S. N., Roe A. E., Donehower L. A., Bradley A. Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53. Nature. 1995 Nov 9;378(6553):206–208. doi: 10.1038/378206a0. [DOI] [PubMed] [Google Scholar]
  85. Juan L. J., Shia W. J., Chen M. H., Yang W. M., Seto E., Lin Y. S., Wu C. W. Histone deacetylases specifically down-regulate p53-dependent gene activation. J Biol Chem. 2000 Jul 7;275(27):20436–20443. doi: 10.1074/jbc.M000202200. [DOI] [PubMed] [Google Scholar]
  86. Juven-Gershon T., Shifman O., Unger T., Elkeles A., Haupt Y., Oren M. The Mdm2 oncoprotein interacts with the cell fate regulator Numb. Mol Cell Biol. 1998 Jul;18(7):3974–3982. doi: 10.1128/mcb.18.7.3974. [DOI] [PMC free article] [PubMed] [Google Scholar]
  87. Kamijo T., Weber J. D., Zambetti G., Zindy F., Roussel M. F., Sherr C. J. Functional and physical interactions of the ARF tumor suppressor with p53 and Mdm2. Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):8292–8297. doi: 10.1073/pnas.95.14.8292. [DOI] [PMC free article] [PubMed] [Google Scholar]
  88. Kamijo T., Zindy F., Roussel M. F., Quelle D. E., Downing J. R., Ashmun R. A., Grosveld G., Sherr C. J. Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF. Cell. 1997 Nov 28;91(5):649–659. doi: 10.1016/s0092-8674(00)80452-3. [DOI] [PubMed] [Google Scholar]
  89. Kapoor M., Lozano G. Functional activation of p53 via phosphorylation following DNA damage by UV but not gamma radiation. Proc Natl Acad Sci U S A. 1998 Mar 17;95(6):2834–2837. doi: 10.1073/pnas.95.6.2834. [DOI] [PMC free article] [PubMed] [Google Scholar]
  90. Kastan M. B., Zhan Q., el-Deiry W. S., Carrier F., Jacks T., Walsh W. V., Plunkett B. S., Vogelstein B., Fornace A. J., Jr A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia. Cell. 1992 Nov 13;71(4):587–597. doi: 10.1016/0092-8674(92)90593-2. [DOI] [PubMed] [Google Scholar]
  91. Khosravi R., Maya R., Gottlieb T., Oren M., Shiloh Y., Shkedy D. Rapid ATM-dependent phosphorylation of MDM2 precedes p53 accumulation in response to DNA damage. Proc Natl Acad Sci U S A. 1999 Dec 21;96(26):14973–14977. doi: 10.1073/pnas.96.26.14973. [DOI] [PMC free article] [PubMed] [Google Scholar]
  92. Kirch H. C., Flaswinkel S., Rumpf H., Brockmann D., Esche H. Expression of human p53 requires synergistic activation of transcription from the p53 promoter by AP-1, NF-kappaB and Myc/Max. Oncogene. 1999 Apr 29;18(17):2728–2738. doi: 10.1038/sj.onc.1202626. [DOI] [PubMed] [Google Scholar]
  93. Kobet E., Zeng X., Zhu Y., Keller D., Lu H. MDM2 inhibits p300-mediated p53 acetylation and activation by forming a ternary complex with the two proteins. Proc Natl Acad Sci U S A. 2000 Nov 7;97(23):12547–12552. doi: 10.1073/pnas.97.23.12547. [DOI] [PMC free article] [PubMed] [Google Scholar]
  94. Komarov P. G., Komarova E. A., Kondratov R. V., Christov-Tselkov K., Coon J. S., Chernov M. V., Gudkov A. V. A chemical inhibitor of p53 that protects mice from the side effects of cancer therapy. Science. 1999 Sep 10;285(5434):1733–1737. doi: 10.1126/science.285.5434.1733. [DOI] [PubMed] [Google Scholar]
  95. Koumenis C., Alarcon R., Hammond E., Sutphin P., Hoffman W., Murphy M., Derr J., Taya Y., Lowe S. W., Kastan M. Regulation of p53 by hypoxia: dissociation of transcriptional repression and apoptosis from p53-dependent transactivation. Mol Cell Biol. 2001 Feb;21(4):1297–1310. doi: 10.1128/MCB.21.4.1297-1310.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  96. Kubbutat M. H., Jones S. N., Vousden K. H. Regulation of p53 stability by Mdm2. Nature. 1997 May 15;387(6630):299–303. doi: 10.1038/387299a0. [DOI] [PubMed] [Google Scholar]
  97. Kubbutat M. H., Ludwig R. L., Levine A. J., Vousden K. H. Analysis of the degradation function of Mdm2. Cell Growth Differ. 1999 Feb;10(2):87–92. [PubMed] [Google Scholar]
  98. Kubbutat M. H., Vousden K. H. Proteolytic cleavage of human p53 by calpain: a potential regulator of protein stability. Mol Cell Biol. 1997 Jan;17(1):460–468. doi: 10.1128/mcb.17.1.460. [DOI] [PMC free article] [PubMed] [Google Scholar]
  99. Lakin N. D., Jackson S. P. Regulation of p53 in response to DNA damage. Oncogene. 1999 Dec 13;18(53):7644–7655. doi: 10.1038/sj.onc.1203015. [DOI] [PubMed] [Google Scholar]
  100. Laín S., Midgley C., Sparks A., Lane E. B., Lane D. P. An inhibitor of nuclear export activates the p53 response and induces the localization of HDM2 and p53 to U1A-positive nuclear bodies associated with the PODs. Exp Cell Res. 1999 May 1;248(2):457–472. doi: 10.1006/excr.1999.4433. [DOI] [PubMed] [Google Scholar]
  101. Li P. F., Dietz R., von Harsdorf R. p53 regulates mitochondrial membrane potential through reactive oxygen species and induces cytochrome c-independent apoptosis blocked by Bcl-2. EMBO J. 1999 Nov 1;18(21):6027–6036. doi: 10.1093/emboj/18.21.6027. [DOI] [PMC free article] [PubMed] [Google Scholar]
  102. Lin Y., Benchimol S. Cytokines inhibit p53-mediated apoptosis but not p53-mediated G1 arrest. Mol Cell Biol. 1995 Nov;15(11):6045–6054. doi: 10.1128/mcb.15.11.6045. [DOI] [PMC free article] [PubMed] [Google Scholar]
  103. Lin Y., Ma W., Benchimol S. Pidd, a new death-domain-containing protein, is induced by p53 and promotes apoptosis. Nat Genet. 2000 Sep;26(1):122–127. doi: 10.1038/79102. [DOI] [PubMed] [Google Scholar]
  104. Liu L., Scolnick D. M., Trievel R. C., Zhang H. B., Marmorstein R., Halazonetis T. D., Berger S. L. p53 sites acetylated in vitro by PCAF and p300 are acetylated in vivo in response to DNA damage. Mol Cell Biol. 1999 Feb;19(2):1202–1209. doi: 10.1128/mcb.19.2.1202. [DOI] [PMC free article] [PubMed] [Google Scholar]
  105. Ljungman M. Dial 9-1-1 for p53: mechanisms of p53 activation by cellular stress. Neoplasia. 2000 May-Jun;2(3):208–225. doi: 10.1038/sj.neo.7900073. [DOI] [PMC free article] [PubMed] [Google Scholar]
  106. Lohrum M. A., Ashcroft M., Kubbutat M. H., Vousden K. H. Identification of a cryptic nucleolar-localization signal in MDM2. Nat Cell Biol. 2000 Mar;2(3):179–181. doi: 10.1038/35004057. [DOI] [PubMed] [Google Scholar]
  107. Lohrum M., Scheidtmann K. H. Differential effects of phosphorylation of rat p53 on transactivation of promoters derived from different p53 responsive genes. Oncogene. 1996 Dec 19;13(12):2527–2539. [PubMed] [Google Scholar]
  108. Loughran O., La Thangue N. B. Apoptotic and growth-promoting activity of E2F modulated by MDM2. Mol Cell Biol. 2000 Mar;20(6):2186–2197. doi: 10.1128/mcb.20.6.2186-2197.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  109. Lu W., Pochampally R., Chen L., Traidej M., Wang Y., Chen J. Nuclear exclusion of p53 in a subset of tumors requires MDM2 function. Oncogene. 2000 Jan 13;19(2):232–240. doi: 10.1038/sj.onc.1203262. [DOI] [PubMed] [Google Scholar]
  110. Lundberg A. S., Hahn W. C., Gupta P., Weinberg R. A. Genes involved in senescence and immortalization. Curr Opin Cell Biol. 2000 Dec;12(6):705–709. doi: 10.1016/s0955-0674(00)00155-1. [DOI] [PubMed] [Google Scholar]
  111. Lundgren K., Montes de Oca Luna R., McNeill Y. B., Emerick E. P., Spencer B., Barfield C. R., Lozano G., Rosenberg M. P., Finlay C. A. Targeted expression of MDM2 uncouples S phase from mitosis and inhibits mammary gland development independent of p53. Genes Dev. 1997 Mar 15;11(6):714–725. doi: 10.1101/gad.11.6.714. [DOI] [PubMed] [Google Scholar]
  112. Luo J., Su F., Chen D., Shiloh A., Gu W. Deacetylation of p53 modulates its effect on cell growth and apoptosis. Nature. 2000 Nov 16;408(6810):377–381. doi: 10.1038/35042612. [DOI] [PubMed] [Google Scholar]
  113. Ma Y., Yuan R., Meng Q., Goldberg I. D., Rosen E. M., Fan S. P53-independent down-regulation of Mdm2 in human cancer cells treated with adriamycin. Mol Cell Biol Res Commun. 2000 Feb;3(2):122–128. doi: 10.1006/mcbr.2000.0201. [DOI] [PubMed] [Google Scholar]
  114. Maestro R., Dei Tos A. P., Hamamori Y., Krasnokutsky S., Sartorelli V., Kedes L., Doglioni C., Beach D. H., Hannon G. J. Twist is a potential oncogene that inhibits apoptosis. Genes Dev. 1999 Sep 1;13(17):2207–2217. doi: 10.1101/gad.13.17.2207. [DOI] [PMC free article] [PubMed] [Google Scholar]
  115. Maheswaran S., Englert C., Bennett P., Heinrich G., Haber D. A. The WT1 gene product stabilizes p53 and inhibits p53-mediated apoptosis. Genes Dev. 1995 Sep 1;9(17):2143–2156. doi: 10.1101/gad.9.17.2143. [DOI] [PubMed] [Google Scholar]
  116. Malkin D., Li F. P., Strong L. C., Fraumeni J. F., Jr, Nelson C. E., Kim D. H., Kassel J., Gryka M. A., Bischoff F. Z., Tainsky M. A. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science. 1990 Nov 30;250(4985):1233–1238. doi: 10.1126/science.1978757. [DOI] [PubMed] [Google Scholar]
  117. Marchenko N. D., Zaika A., Moll U. M. Death signal-induced localization of p53 protein to mitochondria. A potential role in apoptotic signaling. J Biol Chem. 2000 May 26;275(21):16202–16212. doi: 10.1074/jbc.275.21.16202. [DOI] [PubMed] [Google Scholar]
  118. Marechal V., Elenbaas B., Piette J., Nicolas J. C., Levine A. J. The ribosomal L5 protein is associated with mdm-2 and mdm-2-p53 complexes. Mol Cell Biol. 1994 Nov;14(11):7414–7420. doi: 10.1128/mcb.14.11.7414. [DOI] [PMC free article] [PubMed] [Google Scholar]
  119. Marin M. C., Jost C. A., Irwin M. S., DeCaprio J. A., Caput D., Kaelin W. G., Jr Viral oncoproteins discriminate between p53 and the p53 homolog p73. Mol Cell Biol. 1998 Nov;18(11):6316–6324. doi: 10.1128/mcb.18.11.6316. [DOI] [PMC free article] [PubMed] [Google Scholar]
  120. Maya R., Oren M. Unmasking of phosphorylation-sensitive epitopes on p53 and Mdm2 by a simple Western-phosphatase procedure. Oncogene. 2000 Jun 29;19(28):3213–3215. doi: 10.1038/sj.onc.1203658. [DOI] [PubMed] [Google Scholar]
  121. Mayo L. D., Turchi J. J., Berberich S. J. Mdm-2 phosphorylation by DNA-dependent protein kinase prevents interaction with p53. Cancer Res. 1997 Nov 15;57(22):5013–5016. [PubMed] [Google Scholar]
  122. McCormick F. Interactions between adenovirus proteins and the p53 pathway: the development of ONYX-015. Semin Cancer Biol. 2000 Dec;10(6):453–459. doi: 10.1006/scbi.2000.0336. [DOI] [PubMed] [Google Scholar]
  123. McKay B. C., Ljungman M., Rainbow A. J. Potential roles for p53 in nucleotide excision repair. Carcinogenesis. 1999 Aug;20(8):1389–1396. doi: 10.1093/carcin/20.8.1389. [DOI] [PubMed] [Google Scholar]
  124. Meek D. W. Mechanisms of switching on p53: a role for covalent modification? Oncogene. 1999 Dec 13;18(53):7666–7675. doi: 10.1038/sj.onc.1202951. [DOI] [PubMed] [Google Scholar]
  125. Meyn M. S. Ataxia-telangiectasia, cancer and the pathobiology of the ATM gene. Clin Genet. 1999 May;55(5):289–304. doi: 10.1034/j.1399-0004.1999.550501.x. [DOI] [PubMed] [Google Scholar]
  126. Midgley C. A., Desterro J. M., Saville M. K., Howard S., Sparks A., Hay R. T., Lane D. P. An N-terminal p14ARF peptide blocks Mdm2-dependent ubiquitination in vitro and can activate p53 in vivo. Oncogene. 2000 May 4;19(19):2312–2323. doi: 10.1038/sj.onc.1203593. [DOI] [PubMed] [Google Scholar]
  127. Miyashita T., Reed J. C. Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell. 1995 Jan 27;80(2):293–299. doi: 10.1016/0092-8674(95)90412-3. [DOI] [PubMed] [Google Scholar]
  128. Momand J., Zambetti G. P., Olson D. C., George D., Levine A. J. The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell. 1992 Jun 26;69(7):1237–1245. doi: 10.1016/0092-8674(92)90644-r. [DOI] [PubMed] [Google Scholar]
  129. Montes de Oca Luna R., Wagner D. S., Lozano G. Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53. Nature. 1995 Nov 9;378(6553):203–206. doi: 10.1038/378203a0. [DOI] [PubMed] [Google Scholar]
  130. Muller S., Berger M., Lehembre F., Seeler J. S., Haupt Y., Dejean A. c-Jun and p53 activity is modulated by SUMO-1 modification. J Biol Chem. 2000 May 5;275(18):13321–13329. doi: 10.1074/jbc.275.18.13321. [DOI] [PubMed] [Google Scholar]
  131. Muslin A. J., Xing H. 14-3-3 proteins: regulation of subcellular localization by molecular interference. Cell Signal. 2000 Dec;12(11-12):703–709. doi: 10.1016/s0898-6568(00)00131-5. [DOI] [PubMed] [Google Scholar]
  132. Nakano K., Bálint E., Ashcroft M., Vousden K. H. A ribonucleotide reductase gene is a transcriptional target of p53 and p73. Oncogene. 2000 Aug 31;19(37):4283–4289. doi: 10.1038/sj.onc.1203774. [DOI] [PubMed] [Google Scholar]
  133. Nakano K., Vousden K. H. PUMA, a novel proapoptotic gene, is induced by p53. Mol Cell. 2001 Mar;7(3):683–694. doi: 10.1016/s1097-2765(01)00214-3. [DOI] [PubMed] [Google Scholar]
  134. Nishimori H., Shiratsuchi T., Urano T., Kimura Y., Kiyono K., Tatsumi K., Yoshida S., Ono M., Kuwano M., Nakamura Y. A novel brain-specific p53-target gene, BAI1, containing thrombospondin type 1 repeats inhibits experimental angiogenesis. Oncogene. 1997 Oct;15(18):2145–2150. doi: 10.1038/sj.onc.1201542. [DOI] [PubMed] [Google Scholar]
  135. O'Connor D. J., Lu X. Stress signals induce transcriptionally inactive E2F-1 independently of p53 and Rb. Oncogene. 2000 May 11;19(20):2369–2376. doi: 10.1038/sj.onc.1203540. [DOI] [PubMed] [Google Scholar]
  136. Oda E., Ohki R., Murasawa H., Nemoto J., Shibue T., Yamashita T., Tokino T., Taniguchi T., Tanaka N. Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. Science. 2000 May 12;288(5468):1053–1058. doi: 10.1126/science.288.5468.1053. [DOI] [PubMed] [Google Scholar]
  137. Oda K., Arakawa H., Tanaka T., Matsuda K., Tanikawa C., Mori T., Nishimori H., Tamai K., Tokino T., Nakamura Y. p53AIP1, a potential mediator of p53-dependent apoptosis, and its regulation by Ser-46-phosphorylated p53. Cell. 2000 Sep 15;102(6):849–862. doi: 10.1016/s0092-8674(00)00073-8. [DOI] [PubMed] [Google Scholar]
  138. Offer H., Zurer I., Banfalvi G., Reha'k M., Falcovitz A., Milyavsky M., Goldfinger N., Rotter V. p53 modulates base excision repair activity in a cell cycle-specific manner after genotoxic stress. Cancer Res. 2001 Jan 1;61(1):88–96. [PubMed] [Google Scholar]
  139. Ohki R., Nemoto J., Murasawa H., Oda E., Inazawa J., Tanaka N., Taniguchi T. Reprimo, a new candidate mediator of the p53-mediated cell cycle arrest at the G2 phase. J Biol Chem. 2000 Jul 28;275(30):22627–22630. doi: 10.1074/jbc.C000235200. [DOI] [PubMed] [Google Scholar]
  140. Oliner J. D., Kinzler K. W., Meltzer P. S., George D. L., Vogelstein B. Amplification of a gene encoding a p53-associated protein in human sarcomas. Nature. 1992 Jul 2;358(6381):80–83. doi: 10.1038/358080a0. [DOI] [PubMed] [Google Scholar]
  141. Ongkeko W. M., Wang X. Q., Siu W. Y., Lau A. W., Yamashita K., Harris A. L., Cox L. S., Poon R. Y. MDM2 and MDMX bind and stabilize the p53-related protein p73. 1999 Jul 29-Aug 12Curr Biol. 9(15):829–832. doi: 10.1016/s0960-9822(99)80367-4. [DOI] [PubMed] [Google Scholar]
  142. Owen-Schaub L. B., Zhang W., Cusack J. C., Angelo L. S., Santee S. M., Fujiwara T., Roth J. A., Deisseroth A. B., Zhang W. W., Kruzel E. Wild-type human p53 and a temperature-sensitive mutant induce Fas/APO-1 expression. Mol Cell Biol. 1995 Jun;15(6):3032–3040. doi: 10.1128/mcb.15.6.3032. [DOI] [PMC free article] [PubMed] [Google Scholar]
  143. Pariat M., Carillo S., Molinari M., Salvat C., Debüssche L., Bracco L., Milner J., Piechaczyk M. Proteolysis by calpains: a possible contribution to degradation of p53. Mol Cell Biol. 1997 May;17(5):2806–2815. doi: 10.1128/mcb.17.5.2806. [DOI] [PMC free article] [PubMed] [Google Scholar]
  144. Pearson M., Carbone R., Sebastiani C., Cioce M., Fagioli M., Saito S., Higashimoto Y., Appella E., Minucci S., Pandolfi P. P. PML regulates p53 acetylation and premature senescence induced by oncogenic Ras. Nature. 2000 Jul 13;406(6792):207–210. doi: 10.1038/35018127. [DOI] [PubMed] [Google Scholar]
  145. Perry M. E., Mendrysa S. M., Saucedo L. J., Tannous P., Holubar M. p76(MDM2) inhibits the ability of p90(MDM2) to destabilize p53. J Biol Chem. 2000 Feb 25;275(8):5733–5738. doi: 10.1074/jbc.275.8.5733. [DOI] [PubMed] [Google Scholar]
  146. Phillips A. C., Ernst M. K., Bates S., Rice N. R., Vousden K. H. E2F-1 potentiates cell death by blocking antiapoptotic signaling pathways. Mol Cell. 1999 Nov;4(5):771–781. doi: 10.1016/s1097-2765(00)80387-1. [DOI] [PubMed] [Google Scholar]
  147. Pietenpol J. A., Tokino T., Thiagalingam S., el-Deiry W. S., Kinzler K. W., Vogelstein B. Sequence-specific transcriptional activation is essential for growth suppression by p53. Proc Natl Acad Sci U S A. 1994 Mar 15;91(6):1998–2002. doi: 10.1073/pnas.91.6.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  148. Polyak K., Xia Y., Zweier J. L., Kinzler K. W., Vogelstein B. A model for p53-induced apoptosis. Nature. 1997 Sep 18;389(6648):300–305. doi: 10.1038/38525. [DOI] [PubMed] [Google Scholar]
  149. Pomerantz J., Schreiber-Agus N., Liégeois N. J., Silverman A., Alland L., Chin L., Potes J., Chen K., Orlow I., Lee H. W. The Ink4a tumor suppressor gene product, p19Arf, interacts with MDM2 and neutralizes MDM2's inhibition of p53. Cell. 1998 Mar 20;92(6):713–723. doi: 10.1016/s0092-8674(00)81400-2. [DOI] [PubMed] [Google Scholar]
  150. Prisco M., Hongo A., Rizzo M. G., Sacchi A., Baserga R. The insulin-like growth factor I receptor as a physiologically relevant target of p53 in apoptosis caused by interleukin-3 withdrawal. Mol Cell Biol. 1997 Mar;17(3):1084–1092. doi: 10.1128/mcb.17.3.1084. [DOI] [PMC free article] [PubMed] [Google Scholar]
  151. Radfar A., Unnikrishnan I., Lee H. W., DePinho R. A., Rosenberg N. p19(Arf) induces p53-dependent apoptosis during abelson virus-mediated pre-B cell transformation. Proc Natl Acad Sci U S A. 1998 Oct 27;95(22):13194–13199. doi: 10.1073/pnas.95.22.13194. [DOI] [PMC free article] [PubMed] [Google Scholar]
  152. Rampino N., Yamamoto H., Ionov Y., Li Y., Sawai H., Reed J. C., Perucho M. Somatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype. Science. 1997 Feb 14;275(5302):967–969. doi: 10.1126/science.275.5302.967. [DOI] [PubMed] [Google Scholar]
  153. Riemenschneider M. J., Büschges R., Wolter M., Reifenberger J., Boström J., Kraus J. A., Schlegel U., Reifenberger G. Amplification and overexpression of the MDM4 (MDMX) gene from 1q32 in a subset of malignant gliomas without TP53 mutation or MDM2 amplification. Cancer Res. 1999 Dec 15;59(24):6091–6096. [PubMed] [Google Scholar]
  154. Rodriguez M. S., Desterro J. M., Lain S., Midgley C. A., Lane D. P., Hay R. T. SUMO-1 modification activates the transcriptional response of p53. EMBO J. 1999 Nov 15;18(22):6455–6461. doi: 10.1093/emboj/18.22.6455. [DOI] [PMC free article] [PubMed] [Google Scholar]
  155. Roth J. A., Swisher S. G., Meyn R. E. p53 tumor suppressor gene therapy for cancer. Oncology (Williston Park) 1999 Oct;13(10 Suppl 5):148–154. [PubMed] [Google Scholar]
  156. Ryan K. M., Ernst M. K., Rice N. R., Vousden K. H. Role of NF-kappaB in p53-mediated programmed cell death. Nature. 2000 Apr 20;404(6780):892–897. doi: 10.1038/35009130. [DOI] [PubMed] [Google Scholar]
  157. Ryan K. M., Vousden K. H. Characterization of structural p53 mutants which show selective defects in apoptosis but not cell cycle arrest. Mol Cell Biol. 1998 Jul;18(7):3692–3698. doi: 10.1128/mcb.18.7.3692. [DOI] [PMC free article] [PubMed] [Google Scholar]
  158. Sakaguchi K., Herrera J. E., Saito S., Miki T., Bustin M., Vassilev A., Anderson C. W., Appella E. DNA damage activates p53 through a phosphorylation-acetylation cascade. Genes Dev. 1998 Sep 15;12(18):2831–2841. doi: 10.1101/gad.12.18.2831. [DOI] [PMC free article] [PubMed] [Google Scholar]
  159. Sakaguchi K., Saito S., Higashimoto Y., Roy S., Anderson C. W., Appella E. Damage-mediated phosphorylation of human p53 threonine 18 through a cascade mediated by a casein 1-like kinase. Effect on Mdm2 binding. J Biol Chem. 2000 Mar 31;275(13):9278–9283. doi: 10.1074/jbc.275.13.9278. [DOI] [PubMed] [Google Scholar]
  160. Sakaguchi K., Sakamoto H., Lewis M. S., Anderson C. W., Erickson J. W., Appella E., Xie D. Phosphorylation of serine 392 stabilizes the tetramer formation of tumor suppressor protein p53. Biochemistry. 1997 Aug 19;36(33):10117–10124. doi: 10.1021/bi970759w. [DOI] [PubMed] [Google Scholar]
  161. Scheffner M., Huibregtse J. M., Vierstra R. D., Howley P. M. The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53. Cell. 1993 Nov 5;75(3):495–505. doi: 10.1016/0092-8674(93)90384-3. [DOI] [PubMed] [Google Scholar]
  162. Selivanova G., Iotsova V., Okan I., Fritsche M., Ström M., Groner B., Grafström R. C., Wiman K. G. Restoration of the growth suppression function of mutant p53 by a synthetic peptide derived from the p53 C-terminal domain. Nat Med. 1997 Jun;3(6):632–638. doi: 10.1038/nm0697-632. [DOI] [PubMed] [Google Scholar]
  163. Sengupta S., Vonesch J. L., Waltzinger C., Zheng H., Wasylyk B. Negative cross-talk between p53 and the glucocorticoid receptor and its role in neuroblastoma cells. EMBO J. 2000 Nov 15;19(22):6051–6064. doi: 10.1093/emboj/19.22.6051. [DOI] [PMC free article] [PubMed] [Google Scholar]
  164. Sharp D. A., Kratowicz S. A., Sank M. J., George D. L. Stabilization of the MDM2 oncoprotein by interaction with the structurally related MDMX protein. J Biol Chem. 1999 Dec 31;274(53):38189–38196. doi: 10.1074/jbc.274.53.38189. [DOI] [PubMed] [Google Scholar]
  165. Shaw P., Freeman J., Bovey R., Iggo R. Regulation of specific DNA binding by p53: evidence for a role for O-glycosylation and charged residues at the carboxy-terminus. Oncogene. 1996 Feb 15;12(4):921–930. [PubMed] [Google Scholar]
  166. Sherr C. J., Weber J. D. The ARF/p53 pathway. Curr Opin Genet Dev. 2000 Feb;10(1):94–99. doi: 10.1016/s0959-437x(99)00038-6. [DOI] [PubMed] [Google Scholar]
  167. Shieh S. Y., Ahn J., Tamai K., Taya Y., Prives C. The human homologs of checkpoint kinases Chk1 and Cds1 (Chk2) phosphorylate p53 at multiple DNA damage-inducible sites. Genes Dev. 2000 Feb 1;14(3):289–300. [PMC free article] [PubMed] [Google Scholar]
  168. Shieh S. Y., Ikeda M., Taya Y., Prives C. DNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2. Cell. 1997 Oct 31;91(3):325–334. doi: 10.1016/s0092-8674(00)80416-x. [DOI] [PubMed] [Google Scholar]
  169. Shvarts A., Steegenga W. T., Riteco N., van Laar T., Dekker P., Bazuine M., van Ham R. C., van der Houven van Oordt W., Hateboer G., van der Eb A. J. MDMX: a novel p53-binding protein with some functional properties of MDM2. EMBO J. 1996 Oct 1;15(19):5349–5357. [PMC free article] [PubMed] [Google Scholar]
  170. Sigalas I., Calvert A. H., Anderson J. J., Neal D. E., Lunec J. Alternatively spliced mdm2 transcripts with loss of p53 binding domain sequences: transforming ability and frequent detection in human cancer. Nat Med. 1996 Aug;2(8):912–917. doi: 10.1038/nm0896-912. [DOI] [PubMed] [Google Scholar]
  171. Sionov R. V., Moallem E., Berger M., Kazaz A., Gerlitz O., Ben-Neriah Y., Oren M., Haupt Y. c-Abl neutralizes the inhibitory effect of Mdm2 on p53. J Biol Chem. 1999 Mar 26;274(13):8371–8374. doi: 10.1074/jbc.274.13.8371. [DOI] [PubMed] [Google Scholar]
  172. Smith M. L., Chen I. T., Zhan Q., Bae I., Chen C. Y., Gilmer T. M., Kastan M. B., O'Connor P. M., Fornace A. J., Jr Interaction of the p53-regulated protein Gadd45 with proliferating cell nuclear antigen. Science. 1994 Nov 25;266(5189):1376–1380. doi: 10.1126/science.7973727. [DOI] [PubMed] [Google Scholar]
  173. Smith M. L., Ford J. M., Hollander M. C., Bortnick R. A., Amundson S. A., Seo Y. R., Deng C. X., Hanawalt P. C., Fornace A. J., Jr p53-mediated DNA repair responses to UV radiation: studies of mouse cells lacking p53, p21, and/or gadd45 genes. Mol Cell Biol. 2000 May;20(10):3705–3714. doi: 10.1128/mcb.20.10.3705-3714.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  174. Soengas M. S., Alarcón R. M., Yoshida H., Giaccia A. J., Hakem R., Mak T. W., Lowe S. W. Apaf-1 and caspase-9 in p53-dependent apoptosis and tumor inhibition. Science. 1999 Apr 2;284(5411):156–159. doi: 10.1126/science.284.5411.156. [DOI] [PubMed] [Google Scholar]
  175. Soengas M. S., Capodieci P., Polsky D., Mora J., Esteller M., Opitz-Araya X., McCombie R., Herman J. G., Gerald W. L., Lazebnik Y. A. Inactivation of the apoptosis effector Apaf-1 in malignant melanoma. Nature. 2001 Jan 11;409(6817):207–211. doi: 10.1038/35051606. [DOI] [PubMed] [Google Scholar]
  176. Srivastava S., Zou Z. Q., Pirollo K., Blattner W., Chang E. H. Germ-line transmission of a mutated p53 gene in a cancer-prone family with Li-Fraumeni syndrome. Nature. 1990 Dec 20;348(6303):747–749. doi: 10.1038/348747a0. [DOI] [PubMed] [Google Scholar]
  177. Stommel J. M., Marchenko N. D., Jimenez G. S., Moll U. M., Hope T. J., Wahl G. M. A leucine-rich nuclear export signal in the p53 tetramerization domain: regulation of subcellular localization and p53 activity by NES masking. EMBO J. 1999 Mar 15;18(6):1660–1672. doi: 10.1093/emboj/18.6.1660. [DOI] [PMC free article] [PubMed] [Google Scholar]
  178. Stott F. J., Bates S., James M. C., McConnell B. B., Starborg M., Brookes S., Palmero I., Ryan K., Hara E., Vousden K. H. The alternative product from the human CDKN2A locus, p14(ARF), participates in a regulatory feedback loop with p53 and MDM2. EMBO J. 1998 Sep 1;17(17):5001–5014. doi: 10.1093/emboj/17.17.5001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  179. Takekawa M., Adachi M., Nakahata A., Nakayama I., Itoh F., Tsukuda H., Taya Y., Imai K. p53-inducible wip1 phosphatase mediates a negative feedback regulation of p38 MAPK-p53 signaling in response to UV radiation. EMBO J. 2000 Dec 1;19(23):6517–6526. doi: 10.1093/emboj/19.23.6517. [DOI] [PMC free article] [PubMed] [Google Scholar]
  180. Takimoto R., El-Deiry W. S. Wild-type p53 transactivates the KILLER/DR5 gene through an intronic sequence-specific DNA-binding site. Oncogene. 2000 Mar 30;19(14):1735–1743. doi: 10.1038/sj.onc.1203489. [DOI] [PubMed] [Google Scholar]
  181. Tanaka H., Arakawa H., Yamaguchi T., Shiraishi K., Fukuda S., Matsui K., Takei Y., Nakamura Y. A ribonucleotide reductase gene involved in a p53-dependent cell-cycle checkpoint for DNA damage. Nature. 2000 Mar 2;404(6773):42–49. doi: 10.1038/35003506. [DOI] [PubMed] [Google Scholar]
  182. Tanimura S., Ohtsuka S., Mitsui K., Shirouzu K., Yoshimura A., Ohtsubo M. MDM2 interacts with MDMX through their RING finger domains. FEBS Lett. 1999 Mar 19;447(1):5–9. doi: 10.1016/s0014-5793(99)00254-9. [DOI] [PubMed] [Google Scholar]
  183. Tao W., Levine A. J. Nucleocytoplasmic shuttling of oncoprotein Hdm2 is required for Hdm2-mediated degradation of p53. Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):3077–3080. doi: 10.1073/pnas.96.6.3077. [DOI] [PMC free article] [PubMed] [Google Scholar]
  184. Thornborrow E. C., Manfredi J. J. One mechanism for cell type-specific regulation of the bax promoter by the tumor suppressor p53 is dictated by the p53 response element. J Biol Chem. 1999 Nov 19;274(47):33747–33756. doi: 10.1074/jbc.274.47.33747. [DOI] [PubMed] [Google Scholar]
  185. Unger T., Juven-Gershon T., Moallem E., Berger M., Vogt Sionov R., Lozano G., Oren M., Haupt Y. Critical role for Ser20 of human p53 in the negative regulation of p53 by Mdm2. EMBO J. 1999 Apr 1;18(7):1805–1814. doi: 10.1093/emboj/18.7.1805. [DOI] [PMC free article] [PubMed] [Google Scholar]
  186. Van Antwerp D. J., Martin S. J., Kafri T., Green D. R., Verma I. M. Suppression of TNF-alpha-induced apoptosis by NF-kappaB. Science. 1996 Nov 1;274(5288):787–789. doi: 10.1126/science.274.5288.787. [DOI] [PubMed] [Google Scholar]
  187. Vaziri H., West M. D., Allsopp R. C., Davison T. S., Wu Y. S., Arrowsmith C. H., Poirier G. G., Benchimol S. ATM-dependent telomere loss in aging human diploid fibroblasts and DNA damage lead to the post-translational activation of p53 protein involving poly(ADP-ribose) polymerase. EMBO J. 1997 Oct 1;16(19):6018–6033. doi: 10.1093/emboj/16.19.6018. [DOI] [PMC free article] [PubMed] [Google Scholar]
  188. Vogelstein B., Lane D., Levine A. J. Surfing the p53 network. Nature. 2000 Nov 16;408(6810):307–310. doi: 10.1038/35042675. [DOI] [PubMed] [Google Scholar]
  189. Vousden K. H. p53: death star. Cell. 2000 Nov 22;103(5):691–694. doi: 10.1016/s0092-8674(00)00171-9. [DOI] [PubMed] [Google Scholar]
  190. Wadgaonkar R., Collins T. Murine double minute (MDM2) blocks p53-coactivator interaction, a new mechanism for inhibition of p53-dependent gene expression. J Biol Chem. 1999 May 14;274(20):13760–13767. doi: 10.1074/jbc.274.20.13760. [DOI] [PubMed] [Google Scholar]
  191. Waldman T., Kinzler K. W., Vogelstein B. p21 is necessary for the p53-mediated G1 arrest in human cancer cells. Cancer Res. 1995 Nov 15;55(22):5187–5190. [PubMed] [Google Scholar]
  192. Waldman T., Lengauer C., Kinzler K. W., Vogelstein B. Uncoupling of S phase and mitosis induced by anticancer agents in cells lacking p21. Nature. 1996 Jun 20;381(6584):713–716. doi: 10.1038/381713a0. [DOI] [PubMed] [Google Scholar]
  193. Wang X. W., Zhan Q., Coursen J. D., Khan M. A., Kontny H. U., Yu L., Hollander M. C., O'Connor P. M., Fornace A. J., Jr, Harris C. C. GADD45 induction of a G2/M cell cycle checkpoint. Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3706–3711. doi: 10.1073/pnas.96.7.3706. [DOI] [PMC free article] [PubMed] [Google Scholar]
  194. Wang X., Ohnishi K., Takahashi A., Ohnishi T. Poly(ADP-ribosyl)ation is required for p53-dependent signal transduction induced by radiation. Oncogene. 1998 Dec 3;17(22):2819–2825. doi: 10.1038/sj.onc.1202216. [DOI] [PubMed] [Google Scholar]
  195. Wani M. A., Zhu Q. Z., El-Mahdy M., Wani A. A. Influence of p53 tumor suppressor protein on bias of DNA repair and apoptotic response in human cells. Carcinogenesis. 1999 May;20(5):765–772. doi: 10.1093/carcin/20.5.765. [DOI] [PubMed] [Google Scholar]
  196. Waterman M. J., Stavridi E. S., Waterman J. L., Halazonetis T. D. ATM-dependent activation of p53 involves dephosphorylation and association with 14-3-3 proteins. Nat Genet. 1998 Jun;19(2):175–178. doi: 10.1038/542. [DOI] [PubMed] [Google Scholar]
  197. Weber J. D., Kuo M. L., Bothner B., DiGiammarino E. L., Kriwacki R. W., Roussel M. F., Sherr C. J. Cooperative signals governing ARF-mdm2 interaction and nucleolar localization of the complex. Mol Cell Biol. 2000 Apr;20(7):2517–2528. doi: 10.1128/mcb.20.7.2517-2528.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  198. Weber J. D., Taylor L. J., Roussel M. F., Sherr C. J., Bar-Sagi D. Nucleolar Arf sequesters Mdm2 and activates p53. Nat Cell Biol. 1999 May;1(1):20–26. doi: 10.1038/8991. [DOI] [PubMed] [Google Scholar]
  199. Wu G. S., Burns T. F., McDonald E. R., 3rd, Jiang W., Meng R., Krantz I. D., Kao G., Gan D. D., Zhou J. Y., Muschel R. KILLER/DR5 is a DNA damage-inducible p53-regulated death receptor gene. Nat Genet. 1997 Oct;17(2):141–143. doi: 10.1038/ng1097-141. [DOI] [PubMed] [Google Scholar]
  200. Wu H., Lozano G. NF-kappa B activation of p53. A potential mechanism for suppressing cell growth in response to stress. J Biol Chem. 1994 Aug 5;269(31):20067–20074. [PubMed] [Google Scholar]
  201. Wu L., Levine A. J. Differential regulation of the p21/WAF-1 and mdm2 genes after high-dose UV irradiation: p53-dependent and p53-independent regulation of the mdm2 gene. Mol Med. 1997 Jul;3(7):441–451. [PMC free article] [PubMed] [Google Scholar]
  202. Wu X., Bayle J. H., Olson D., Levine A. J. The p53-mdm-2 autoregulatory feedback loop. Genes Dev. 1993 Jul;7(7A):1126–1132. doi: 10.1101/gad.7.7a.1126. [DOI] [PubMed] [Google Scholar]
  203. Yam C. H., Siu W. Y., Arooz T., Chiu C. H., Lau A., Wang X. Q., Poon R. Y. MDM2 and MDMX inhibit the transcriptional activity of ectopically expressed SMAD proteins. Cancer Res. 1999 Oct 15;59(20):5075–5078. [PubMed] [Google Scholar]
  204. Yu Z. K., Geyer R. K., Maki C. G. MDM2-dependent ubiquitination of nuclear and cytoplasmic P53. Oncogene. 2000 Nov 30;19(51):5892–5897. doi: 10.1038/sj.onc.1203980. [DOI] [PubMed] [Google Scholar]
  205. Zaika A., Marchenko N., Moll U. M. Cytoplasmically "sequestered" wild type p53 protein is resistant to Mdm2-mediated degradation. J Biol Chem. 1999 Sep 24;274(39):27474–27480. doi: 10.1074/jbc.274.39.27474. [DOI] [PubMed] [Google Scholar]
  206. Zeimet A. G., Riha K., Berger J., Widschwendter M., Hermann M., Daxenbichler G., Marth C. New insights into p53 regulation and gene therapy for cancer. Biochem Pharmacol. 2000 Oct 15;60(8):1153–1163. doi: 10.1016/s0006-2952(00)00442-1. [DOI] [PubMed] [Google Scholar]
  207. Zeng X., Chen L., Jost C. A., Maya R., Keller D., Wang X., Kaelin W. G., Jr, Oren M., Chen J., Lu H. MDM2 suppresses p73 function without promoting p73 degradation. Mol Cell Biol. 1999 May;19(5):3257–3266. doi: 10.1128/mcb.19.5.3257. [DOI] [PMC free article] [PubMed] [Google Scholar]
  208. Zeng X., Keller D., Wu L., Lu H. UV but not gamma irradiation accelerates p53-induced apoptosis of teratocarcinoma cells by repressing MDM2 transcription. Cancer Res. 2000 Nov 1;60(21):6184–6188. [PubMed] [Google Scholar]
  209. Zhang W., Lu Q., Xie Z. J., Mellgren R. L. Inhibition of the growth of WI-38 fibroblasts by benzyloxycarbonyl-Leu-Leu-Tyr diazomethyl ketone: evidence that cleavage of p53 by a calpain-like protease is necessary for G1 to S-phase transition. Oncogene. 1997 Jan 23;14(3):255–263. doi: 10.1038/sj.onc.1200841. [DOI] [PubMed] [Google Scholar]
  210. Zhang Y., Xiong Y., Yarbrough W. G. ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell. 1998 Mar 20;92(6):725–734. doi: 10.1016/s0092-8674(00)81401-4. [DOI] [PubMed] [Google Scholar]
  211. Zhou J., Ahn J., Wilson S. H., Prives C. A role for p53 in base excision repair. EMBO J. 2001 Feb 15;20(4):914–923. doi: 10.1093/emboj/20.4.914. [DOI] [PMC free article] [PubMed] [Google Scholar]
  212. el-Deiry W. S., Tokino T., Velculescu V. E., Levy D. B., Parsons R., Trent J. M., Lin D., Mercer W. E., Kinzler K. W., Vogelstein B. WAF1, a potential mediator of p53 tumor suppression. Cell. 1993 Nov 19;75(4):817–825. doi: 10.1016/0092-8674(93)90500-p. [DOI] [PubMed] [Google Scholar]