Advertisement

p53

  • Wen-Wei Tsai
  • Michelle Craig BartonEmail author
Chapter

Abstract

The p53 tumor suppressor is well known as the major target of mutation in human cancers and plays a primary role in protecting cells in the face of genotoxic stresses and challenges to genomic stability. The principal responsibilities of p53 include regulation of genes that promote either arrest of cell cycle or apoptosis, both of which inhibit cellular propagation of DNA damage and tumor development [1–3]. The gene encoding human p53 (TP53) is mutated in more than 50% of all types of human cancers; however, studies of tumor progression in the liver show that mutation of TP53, in the absence of environmental influences discussed below, is a relatively late event in development of hepatocellular carcinoma (HCC) and other cancers of this tissue [4]. In this chapter, we will discuss multiple ways in which dysfunction in p53-signaling occurs, even when TP53 itself is not mutated, in relationship with the biology of p53, its protein domains and specific functions, the influ­ences of p53-family members, and cross-talk with other signaling pathways.

Keywords

Cell Cycle Arrest Ionize Radiation Extrinsic Apoptosis Pathway Intrinsic Mitochondrial Pathway Mediate Cell Cycle Arrest 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Vousden KH, Lane DP (2007) p53 in health and disease. Nat Rev Mol Cell Biol 8(4):275–283PubMedCrossRefGoogle Scholar
  2. 2.
    Laptenko O, Prives C (2006) Transcriptional regulation by p53: one protein, many possibilities. Cell Death Differ 13(6): 951–961PubMedCrossRefGoogle Scholar
  3. 3.
    Riley T et al (2008) Transcriptional control of human p53-regulated genes. Nat Rev Mol Cell Biol 9(5):402–412PubMedCrossRefGoogle Scholar
  4. 4.
    Laurent-Puig P, Zucman-Rossi J (2006) Genetics of hepatocellular tumors. Oncogene 25(27):3778–3786PubMedCrossRefGoogle Scholar
  5. 5.
    Hu W et al (2008) p53: a new player in reproduction. Cell Cycle 7(7):848–852PubMedCrossRefGoogle Scholar
  6. 6.
    Stiewe T (2007) The p53 family in differentiation and tumorigenesis. Nat Rev Cancer 7(3):165–168PubMedCrossRefGoogle Scholar
  7. 7.
    Feng Z et al (2008) The tumor suppressor p53: cancer and aging. Cell Cycle 7(7):842–847PubMedCrossRefGoogle Scholar
  8. 8.
    Donehower LA et al (1992) Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356(6366):215–221PubMedCrossRefGoogle Scholar
  9. 9.
    Donehower LA, Bradley A (1993) The tumor suppressor p53 (review). Biochem Biophys Acta 1155(2):181–205PubMedGoogle Scholar
  10. 10.
    Sah VP et al (1995) A subset of p53-deficient embryos exhibit exencephaly. Nat Genet 10:175–180PubMedCrossRefGoogle Scholar
  11. 11.
    Melino G et al (2003) Functional regulation of p73 and p63: development and cancer. Trends Biochem Sci 28(12):663–670PubMedCrossRefGoogle Scholar
  12. 12.
    Moll UM, Slade N (2004) p63 and p73: roles in development and tumor formation. Mol Cancer Res 2(7):371–386PubMedGoogle Scholar
  13. 13.
    Courtois S, de Fromentel CC, Hainaut P (2004) p53 protein variants: structural and functional similarities with p63 and p73 isoforms. Oncogene 23(3):631–638PubMedCrossRefGoogle Scholar
  14. 14.
    Yang A et al (1998) p63, a p53 homolog at 3q27–29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities. Mol Cell 2(3):305–316PubMedCrossRefGoogle Scholar
  15. 15.
    Yang A et al (1999) p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Nature 398(6729):714–718PubMedCrossRefGoogle Scholar
  16. 16.
    Yang A et al (2000) p73-deficient mice have neurological, pheromonal and inflammatory defects but lack spontaneous tumours. Nature 404(6773):99–103PubMedCrossRefGoogle Scholar
  17. 17.
    Kaghad M et al (1997) Monoallelically expressed gene related to p53 at 1p36, a region frequently deleted in neuroblastoma and other human cancers. Cell 90(4):809–819PubMedCrossRefGoogle Scholar
  18. 18.
    Benard J, Douc-Rasy S, Ahomadegbe JC (2003) TP53 family members and human cancers. Hum Mutat 21(3):182–191PubMedCrossRefGoogle Scholar
  19. 19.
    De Laurenzi V, Melino G (2000) Evolution of functions within the p53/p63/p73 family. Ann N Y Acad Sci 926:90–100PubMedCrossRefGoogle Scholar
  20. 20.
    Flores ER et al (2005) Tumor predisposition in mice mutant for p63 and p73: evidence for broader tumor suppressor functions for the p53 family. Cancer Cell 7(4):363–373PubMedCrossRefGoogle Scholar
  21. 21.
    Lee KC, Crowe AJ, Barton MC (1999) p53-mediated repression of alpha-fetoprotein gene expression by specific DNA binding. Mol Cell Biol 19:1279–1288PubMedGoogle Scholar
  22. 22.
    St Clair S et al (2004) DNA damage-induced downregulation of Cdc25C is mediated by p53 via two independent mechanisms: one involves direct binding to the cdc25C promoter. Mol Cell 16(5):725–736PubMedCrossRefGoogle Scholar
  23. 23.
    Ho JS et al (2005) p53-Dependent transcriptional repression of c-myc is required for G1 cell cycle arrest. Mol Cell Biol 25(17):7423–7431PubMedCrossRefGoogle Scholar
  24. 24.
    Hoffman WH et al (2002) Transcriptional repression of the anti-apoptotic survivin gene by wild type p53. J Biol Chem 277:3247–3257PubMedCrossRefGoogle Scholar
  25. 25.
    Koumenis C et al (2001) Regulation of p53 by hypoxia: dissociation of transcriptional repression and apoptosis from p53-dependent transactivation. Feb;(4). Mol Cell Biol 21: 1297–1310PubMedCrossRefGoogle Scholar
  26. 26.
    Ho J, Benchimol S (2003) Transcriptional repression mediated by the p53 tumour suppressor. Cell Death Differ 10(4): 404–408PubMedCrossRefGoogle Scholar
  27. 27.
    Bode AM, Dong Z (2004) Post-translational modification of p53 in tumorigenesis. Nat Rev Cancer 4(10):793–805PubMedCrossRefGoogle Scholar
  28. 28.
    Choi J, Donehower LA (1999) p53 in embryonic development: maintaining a fine balance. Cell Mol Life Sci 55(1): 38–47PubMedCrossRefGoogle Scholar
  29. 29.
    Chen X et al (1996) p53 levels, functional domains, and DNA damage determine the extent of the apoptotic response of tumor cells. Genes Dev 10(19):2438–2451PubMedCrossRefGoogle Scholar
  30. 30.
    Soussi T, May P (1996) Structural aspects of the p53 protein in relation to gene evolution: a second look. J Mol Biol 260(5):623–637PubMedCrossRefGoogle Scholar
  31. 31.
    Scoumanne A, Harms KL, Chen X (2005) Structural basis for gene activation by p53 family members. Cancer Biol Ther 4(11):1178–1185PubMedGoogle Scholar
  32. 32.
    Toledo F, Wahl GM (2006) Regulating the p53 pathway: in vitro hypotheses, in vivo veritas. Nat Rev Cancer 6(12): 909–923PubMedCrossRefGoogle Scholar
  33. 33.
    Pietenpol JA et al (1994) Sequence-specific transcriptional activation is essential for growth suppression by p53. Proc Natl Acad Sci U S A 91(6):1998–2002PubMedCrossRefGoogle Scholar
  34. 34.
    Lin J et al (1994) Several hydrophobic amino acids in the p53 amino-terminal domain are required for transcriptional activation, binding to mdm-2 and the adenovirus 5 E1B 55-kD protein. Genes Dev 8(10):1235–1246PubMedCrossRefGoogle Scholar
  35. 35.
    Johnson TM et al (2005) The p53QS transactivation-deficient mutant shows stress-specific apoptotic activity and induces embryonic lethality. Nat Genet 37(2):145–152PubMedCrossRefGoogle Scholar
  36. 36.
    Chao C et al (2000) p53 transcriptional activity is essential for p53-dependent apoptosis following DNA damage. EMBO J 19(18):4967–4975PubMedCrossRefGoogle Scholar
  37. 37.
    Zhu J et al (1998) Identification of a novel p53 functional domain that is necessary for mediating apoptosis. J Biol Chem 273(21):13030–13036PubMedCrossRefGoogle Scholar
  38. 38.
    Candau R et al (1997) Two tandem and independent sub-activation domains in the amino terminus of p53 require the adaptor complex for activity. Oncogene 15(7):807–816PubMedCrossRefGoogle Scholar
  39. 39.
    Zhu J et al (1999) Differential regulation of cellular target genes by p53 devoid of the PXXP motifs with impaired apoptotic activity. Oncogene 18(12):2149–2155PubMedCrossRefGoogle Scholar
  40. 40.
    Walker KK, Levine AJ (1996) Identification of a novel p53 functional domain that is necessary for efficient growth suppression. Proc Natl Acad Sci U S A 93(26):15335–15340PubMedCrossRefGoogle Scholar
  41. 41.
    Thoresen SO (1992) Li-Fraumeni syndrome and the p53 gene. Tidsskr Nor Laegeforen 112(7):887–889PubMedGoogle Scholar
  42. 42.
    Murphy M et al (1999) Transcriptional repression by wild-type p53 utilizes histone deacetylases, mediated by interaction with mSin3a. Genes Dev 13(19):2490–2501PubMedCrossRefGoogle Scholar
  43. 43.
    Tsai WW et al (2008) p53-targeted LSD1 functions in repression of chromatin structure and transcription in vivo. Mol Cell Biol 28(17):5139–5146PubMedCrossRefGoogle Scholar
  44. 44.
    el-Deiry WS et al (1992) Definition of a consensus binding site for p53. Nat Genet 1(1):45–49PubMedCrossRefGoogle Scholar
  45. 45.
    Joerger AC, Fersht AR (2007) Structure-function-rescue: the diverse nature of common p53 cancer mutants. Oncogene 26(15):2226–2242PubMedCrossRefGoogle Scholar
  46. 46.
    Guimaraes DP, Hainaut P (2002) TP53: a key gene in human cancer. Biochimie 84(1):83–93PubMedCrossRefGoogle Scholar
  47. 47.
    Ross RK et al (1992) Urinary aflatoxin biomarkers and risk of hepatocellular carcinoma. Lancet 339:943–946PubMedCrossRefGoogle Scholar
  48. 48.
    Groopman JD, Johnson D, Kensler TW (2005) Aflatoxin and hepatitis B virus biomarkers: a paradigm for complex environmental exposures and cancer risk. Cancer Biomark 1(1):5–14PubMedGoogle Scholar
  49. 49.
    Hsu IC et al (1991) Mutational hotspot in the p53 gene in human hepatocellular carcinomas [see comments]. Nature 350(6317):427–428PubMedCrossRefGoogle Scholar
  50. 50.
    Bressac B et al (1991) Selective G to T mutations of p53 gene in hepatocellular carcinoma from southern Africa [see comments]. Nature 350(6317):429–431PubMedCrossRefGoogle Scholar
  51. 51.
    Tan TH, Wallis J, Levine AJ (1986) Identification of the p53 protein domain involved in formation of the simian virus 40 large T-antigen-p53 protein complex. J Virol 59(3): 574–583PubMedGoogle Scholar
  52. 52.
    Jenkins JR et al (1988) Two distinct regions of the murine p53 primary amino acid sequence are implicated in stable complex formation with simian virus 40 T antigen. J Virol 62(10):3903–3906PubMedGoogle Scholar
  53. 53.
    Adams MM, Carpenter PB (2006) Tying the loose ends together in DNA double strand break repair with 53BP1. Cell Div 1:19PubMedCrossRefGoogle Scholar
  54. 54.
    Patel S et al (2008) Molecular interactions of ASPP1 and ASPP2 with the p53 protein family and the apoptotic promoters PUMA and Bax. Nucleic Acids Res 36(16):5139–5151PubMedCrossRefGoogle Scholar
  55. 55.
    Derbyshire DJ et al (2002) Crystal structure of human 53BP1 BRCT domains bound to p53 tumour suppressor. EMBO J 21(14):3863–3872PubMedCrossRefGoogle Scholar
  56. 56.
    Bergamaschi D et al (2004) ASPP1 and ASPP2: common activators of p53 family members. Mol Cell Biol 24(3):1341–1350PubMedCrossRefGoogle Scholar
  57. 57.
    Sakaguchi K et al (1998) DNA damage activates p53 through a phosphorylation-acetylation cascade. Genes Dev 12(18): 2831–2841PubMedCrossRefGoogle Scholar
  58. 58.
    Jeffrey PD, Gorina S, Pavletich NP (267) Crystal structure of the tetramerization domain of the p53 tumor suppressor at 1.7 angstroms. Science 267(5203):1498–1502CrossRefGoogle Scholar
  59. 59.
    Nicholls CD et al (2002) Biogenesis of p53 involves cotranslational dimerization of monomers and posttranslational dimerization of dimers. Implications on the dominant negative effect. J Biol Chem 277(15):12937–12945PubMedCrossRefGoogle Scholar
  60. 60.
    Willis A et al (2004) Mutant p53 exerts a dominant negative effect by preventing wild-type p53 from binding to the promoter of its target genes. Oncogene 23(13):2330–2338PubMedCrossRefGoogle Scholar
  61. 61.
    Bourdon JC et al (2005) p53 isoforms can regulate p53 transcriptional activity. Genes Dev 19(18):2122–2137PubMedCrossRefGoogle Scholar
  62. 62.
    O’Keefe K, Li H, Zhang Y (2003) Nucleocytoplasmic shuttling of p53 is essential for MDM2-mediated cytoplasmic degradation but not ubiquitination. Mol Cell Biol 23(18): 6396–6405PubMedCrossRefGoogle Scholar
  63. 63.
    Kruse JP, Gu W (2008) SnapShot: p53 posttranslational modifications. Cell 133(5):930-30 e1CrossRefGoogle Scholar
  64. 64.
    Tang Y et al (2008) Acetylation is indispensable for p53 activation. Cell 133(4):612–626PubMedCrossRefGoogle Scholar
  65. 65.
    Scoumanne A, Chen X (2008) Protein methylation: a new mechanism of p53 tumor suppressor regulation. Histol Histopathol 23(9):1143–1149PubMedGoogle Scholar
  66. 66.
    Hupp TR et al (1992) Regulation of the specific DNA binding function of p53. Cell 71:875–886PubMedCrossRefGoogle Scholar
  67. 67.
    Tyner SD et al (2002) p53 mutant mice that display early ageing-associated phenotypes. Nature 415(6867):45–53PubMedCrossRefGoogle Scholar
  68. 68.
    Garcia-Cao I et al (2002) “Super p53” mice exhibit enhanced DNA damage response, are tumor resistant and age normally. EMBO J 21(22):6225–6235PubMedCrossRefGoogle Scholar
  69. 69.
    Kress M et al (1979) Simian virus 40-transformed cells express new species of proteins precipitable by anti-simian virus 40 tumor serum. J Virol 31(2):472–483PubMedGoogle Scholar
  70. 70.
    Lane DP, Crawford LV (1979) T antigen is bound to a host protein in SV40-transformed cells. Nature 278(5701): 261–263PubMedCrossRefGoogle Scholar
  71. 71.
    Linzer DI, Levine AJ (1979) Characterization of a 54K dalton cellular SV40 tumor antigen present in SV40-transformed cells and uninfected embryonal carcinoma cells. Cell 17(1): 43–52PubMedCrossRefGoogle Scholar
  72. 72.
    DeLeo AB et al (1979) Detection of a transformation-related antigen in chemically induced sarcomas and other transformed cells of the mouse. Proc Natl Acad Sci U S A 76(5): 2420–2424PubMedCrossRefGoogle Scholar
  73. 73.
    Chumakov PM, Iotsova VS, Georgiev GP (1982) Isolation of a plasmid clone containing the mRNA sequence for mouse nonviral T-antigen. Dokl Akad Nauk SSSR 267(5): 1272–1275PubMedGoogle Scholar
  74. 74.
    Baker SJ et al (1989) Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science 244(4901):217–221PubMedCrossRefGoogle Scholar
  75. 75.
    Levine AJ, Momand J, Finlay CA (1991) The p53 tumour suppressor gene. Nature 351(6326):453–456PubMedCrossRefGoogle Scholar
  76. 76.
    Kastan MB et al (1991) Participation of p53 protein in the cellular response to DNA damage. Cancer Res 51(23 Pt 1): 6304–6311PubMedGoogle Scholar
  77. 77.
    Prives C, Hall PA (1999) The p53 pathway. J Pathol 187(1): 112–126PubMedCrossRefGoogle Scholar
  78. 78.
    Harris SL, Levine AJ (2005) The p53 pathway: positive and negative feedback loops. Oncogene 24(17)):2899–2908PubMedCrossRefGoogle Scholar
  79. 79.
    Brooks CL, Gu W (2006) p53 ubiquitination: Mdm2 and beyond. Mol Cell 21(3):307–315PubMedCrossRefGoogle Scholar
  80. 80.
    de Oca Luna RM, Wagner DS, Lozano G (1995) Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53. Nature 378:206–208CrossRefGoogle Scholar
  81. 81.
    Wu X et al (1993) The p53-mdm-2 autoregulatory feedback loop. Genes Dev 7(7A):1126–1132PubMedCrossRefGoogle Scholar
  82. 82.
    de Rozieres S et al (2000) The loss of mdm2 induces p53-mediated apoptosis. Oncogene 19(13):1691–1697PubMedCrossRefGoogle Scholar
  83. 83.
    Chen J, Lin J, Levine AJ (1995) Regulation of transcription functions of the p53 tumor suppressor by the mdm-2 oncogene. Mol Med 1(2):142–152PubMedGoogle Scholar
  84. 84.
    Honda R, Tanaka H, Yasuda H (1997) Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. FEBS Lett 420(1):25–27PubMedCrossRefGoogle Scholar
  85. 85.
    Seto E et al (1992) Wild-type p53 binds to the TATA-binding protein and represses transcription. Proc Natl Acad Sci U S A 89(24):12028–12032PubMedCrossRefGoogle Scholar
  86. 86.
    Truant R et al (1993) Direct interaction between the transcriptional activation domain of human p53 and the TATA box-binding protein. J Biol Chem 268(4):2284–2287PubMedGoogle Scholar
  87. 87.
    Thut CJ et al (1995) p53 transcriptional activation mediated by coactivators TAFII40 and TAFII60. Science 267(5194):100–104PubMedCrossRefGoogle Scholar
  88. 88.
    Avantaggiati ML et al (1997) Recruitment of p300/CBP in p53-dependent signal pathways. Cell 89(7):1175–1184PubMedCrossRefGoogle Scholar
  89. 89.
    Wadgaonkar R, Collins T (1999) Murine double minute (MDM2) blocks p53-coactivator interaction, a new mechanism for inhibition of p53-dependent gene expression. J Biol Chem 274(20):13760–13767PubMedCrossRefGoogle Scholar
  90. 90.
    Itahana K et al (2007) Targeted inactivation of Mdm2 RING finger E3 ubiquitin ligase activity in the mouse reveals mechanistic insights into p53 regulation. Cancer Cell 12(4): 355–366PubMedCrossRefGoogle Scholar
  91. 91.
    Vassilev LT et al (2004) In Vivo Activation of the p53 Pathway by Small-Molecule Antagonists of MDM2. Science 303(5659):844–848PubMedCrossRefGoogle Scholar
  92. 92.
    Minsky N, Oren M (2004) The RING domain of Mdm2 mediates histone ubiquitylation and transcriptional repression. Mol Cell 16(4):631–639PubMedCrossRefGoogle Scholar
  93. 93.
    Li M et al (2003) Mono- versus polyubiquitination: differential control of p53 fate by Mdm2. Science 302(5652): 1972–1975PubMedCrossRefGoogle Scholar
  94. 94.
    Gottifredi V, Prives C (2001) Molecular biology. Getting p53 out of the nucleus. Science 292(5523):1851–1852PubMedCrossRefGoogle Scholar
  95. 95.
    Shirota Y et al (2002) Hepatitis C virus (HCV) NS5A binds RNA-dependent RNA polymerase (RdRP) NS5B and modulates RNA-dependent RNA polymerase activity. J Biol Chem 277(13):11149–11155PubMedCrossRefGoogle Scholar
  96. 96.
    Murakami S (2001) Hepatitis B virus X protein: a ­multifunctional viral regulator. J Gastroenterol 36(10):651–660PubMedCrossRefGoogle Scholar
  97. 97.
    Hussain SP et al (2007) TP53 mutations and hepatocellular carcinoma: insights into the etiology and pathogenesis of liver cancer. Oncogene 26(15):2166–2176PubMedCrossRefGoogle Scholar
  98. 98.
    Elmore LW et al (1997) Hepatitis B virus X protein and p53 tumor suppressor interactions in the modulation of apoptosis. Proc Natl Acad Sci U S A 94:14707–14712PubMedCrossRefGoogle Scholar
  99. 99.
    Cheng Z et al (1997) Inhibition of hepatocellular carcinoma development in hepatitis B virus transfected mice by low dietary casein. Hepatology 26:1351–1354PubMedGoogle Scholar
  100. 100.
    Ogden SK, Lee KC, Barton MC (2000) Hepatitis B viral transactivator HBx alleviates p53-mediated repression of a-fetoprotein gene expression. J Biol Chem 275: 27806–27814PubMedGoogle Scholar
  101. 101.
    Murakami S (1999) Hepatitis B virus X protien: structure, function and biology. Intervirology 42:81–99PubMedCrossRefGoogle Scholar
  102. 102.
    Murray-Zmijewski F, Slee EA, Lu X (2008) A complex ­barcode underlies the heterogeneous response of p53 to stress. Nat Rev Mol Cell Biol 9(9):702–712PubMedCrossRefGoogle Scholar
  103. 103.
    Liebermann DA, Hoffman B, Vesely D (2007) p53 induced growth arrest versus apoptosis and its modulation by survival cytokines. Cell Cycle 6(2):166–170PubMedGoogle Scholar
  104. 104.
    Schwartz D, Rotter V (1998) p53-dependent cell cycle control: response to genotoxic stress. Semin Cancer Biol 8(5):325–336PubMedCrossRefGoogle Scholar
  105. 105.
    Di Leonardo A et al (1994) DNA damage triggers a prolonged p53-dependent G1 arrest and long-term induction of Cip1 in normal human fibroblasts. Genes Dev 8(21): 2540–2551PubMedCrossRefGoogle Scholar
  106. 106.
    Genovese C et al (2006) Cell cycle control and beyond: emerging roles for the retinoblastoma gene family. Oncogene 25(38):5201–5209PubMedCrossRefGoogle Scholar
  107. 107.
    Sherr CJ (1998) Tumor surveillance via the ARF-p53 pathway. Genes Dev 12(19):2984–2991PubMedCrossRefGoogle Scholar
  108. 108.
    Giaccia AJ, Kastan MB (1998) The complexity of p53 modulation: emerging patterns from divergent signals. Genes Dev 12(19):2973–2983PubMedCrossRefGoogle Scholar
  109. 109.
    Kastan MB et al (1992) A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia. Cell 71(4):587–597PubMedCrossRefGoogle Scholar
  110. 110.
    Zhan Q et al (1994) The p53-dependent gamma-ray response of GADD45. Cancer Res 54(10):2755–2760PubMedGoogle Scholar
  111. 111.
    Kuerbitz SJ et al (1992) Wild-type p53 is a cell cycle checkpoint determinant following irradiation. Proc Natl Acad Sci U S A 89(16):7491–7495PubMedCrossRefGoogle Scholar
  112. 112.
    Kessis TD et al (1993) Human papillomavirus 16 E6 expression disrupts the p53-mediated cellular response to DNA damage. Proc Natl Acad Sci U S A 90(9): 3988–3992PubMedCrossRefGoogle Scholar
  113. 113.
    Taylor WR, Stark GR (2001) Regulation of the G2/M transition by p53. Oncogene 20(15):1803–1815PubMedCrossRefGoogle Scholar
  114. 114.
    Nurse P (1990) Universal control mechanism regulating onset of M-phase. Nature 344(6266):503–508PubMedCrossRefGoogle Scholar
  115. 115.
    Pines J (1995) Cyclins and cyclin-dependent kinases: a biochemical view. Biochem J 308(Pt 3):697–711PubMedGoogle Scholar
  116. 116.
    Taylor WR et al (1999) Mechanisms of G2 arrest in response to overexpression of p53. Mol Biol Cell 10(11): 3607–3622PubMedGoogle Scholar
  117. 117.
    Agarwal ML et al (1995) 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 92(18):8493–8497PubMedCrossRefGoogle Scholar
  118. 118.
    Bunz F et al (1998) Requirement for p53 and p21 to sustain G2 arrest after DNA damage. Science 282(5393): 1497–1501PubMedCrossRefGoogle Scholar
  119. 119.
    Boulaire J, Fotedar A, Fotedar R (2000) The functions of the cdk-cyclin kinase inhibitor p21WAF1. Pathol Biol (Paris) 48(3):190–202Google Scholar
  120. 120.
    Vairapandi M et al (2002) GADD45b and GADD45g are cdc2/cyclinB1 kinase inhibitors with a role in S and G2/M cell cycle checkpoints induced by genotoxic stress. J Cell Physiol 192(3):327–338PubMedCrossRefGoogle Scholar
  121. 121.
    Wang XW et al (1999) GADD45 induction of a G2/M cell cycle checkpoint. Proc Natl Acad Sci U S A 96(7): 3706–3711PubMedCrossRefGoogle Scholar
  122. 122.
    Zhan Q et al (1999) Association with Cdc2 and inhibition of Cdc2/Cyclin B1 kinase activity by the p53-regulated protein Gadd45. Oncogene 18(18):2892–2900PubMedCrossRefGoogle Scholar
  123. 123.
    Hermeking H et al (1997) 14–3-3 sigma is a p53-regulated inhibitor of G2/M progression. Mol Cell 1(1):3–11PubMedCrossRefGoogle Scholar
  124. 124.
    Chan TA et al (1999) 14–3-3Sigma is required to prevent mitotic catastrophe after DNA damage. Nature 401(6753):616–620PubMedCrossRefGoogle Scholar
  125. 125.
    Passalaris TM et al (1999) The G(2) checkpoint is maintained by redundant pathways. Mol Cell Biol 19(9): 5872–5881PubMedGoogle Scholar
  126. 126.
    Innocente SA et al (1999) p53 regulates a G2 checkpoint through cyclin B1. Proc Natl Acad Sci U S A 96(5): 2147–2152PubMedCrossRefGoogle Scholar
  127. 127.
    Zhou J et al (2001) A role for p53 in base excision repair. EMBO J 20(4):914–923PubMedCrossRefGoogle Scholar
  128. 128.
    Tanaka H et al (2000) A ribonucleotide reductase gene involved in a p53-dependent cell-cycle checkpoint for DNA damage. Nature 404(6773):42–49PubMedCrossRefGoogle Scholar
  129. 129.
    Nakano K et al (2000) A ribonucleotide reductase gene is a transcriptional target of p53 and p73. Oncogene 19(37): 4283–4289PubMedCrossRefGoogle Scholar
  130. 130.
    Bargonetti J, Manfredi JJ (2002) Multiple roles of the tumor suppressor p53. Curr Opin Oncol 14(1):86–91PubMedCrossRefGoogle Scholar
  131. 131.
    Palacios G et al (2008) Mitochondrially targeted wild-type p53 induces apoptosis in a solid human tumor xenograft model. Cell Cycle 7(16):2584–2590PubMedGoogle Scholar
  132. 132.
    Murphy ME, Leu JI, George DL (2004) p53 moves to mitochondria: a turn on the path to apoptosis. Cell Cycle 3(7):836–839PubMedGoogle Scholar
  133. 133.
    Selvakumaran M et al (1994) Immediate early up-regulation of bax expression by p53 but not TGF beta 1: a paradigm for distinct apoptotic pathways. Oncogene 9(6): 1791–1798PubMedGoogle Scholar
  134. 134.
    Nakano K, Vousden KH (2001) PUMA, a novel proapoptotic gene, is induced by p53. Mol Cell 7(3):683–694PubMedCrossRefGoogle Scholar
  135. 135.
    Yu J et al (2001) PUMA induces the rapid apoptosis of colorectal cancer cells. Mol Cell 7(3):673–682PubMedCrossRefGoogle Scholar
  136. 136.
    Oda E et al (2000) Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. Science 288(5468):1053–1058PubMedCrossRefGoogle Scholar
  137. 137.
    Miyashita T et al (1994) Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo. Oncogene 9(6):1799–1805PubMedGoogle Scholar
  138. 138.
    Moroni MC et al (2001) Apaf-1 is a transcriptional target for E2F and p53. Nat Cell Biol 3(6):552–558PubMedCrossRefGoogle Scholar
  139. 139.
    Lindsten T et al (2000) The combined functions of proapoptotic Bcl-2 family members bak and bax are essential for normal development of multiple tissues. Mol Cell 6(6):1389–1399PubMedCrossRefGoogle Scholar
  140. 140.
    Knudson CM et al (1995) Bax-deficient mice with lymphoid hyperplasia and male germ cell death. Science 270(5233):96–99PubMedCrossRefGoogle Scholar
  141. 141.
    Michalak E et al (2005) Death squads enlisted by the tumour suppressor p53. Biochem Biophys Res Commun 331(3):786–798PubMedCrossRefGoogle Scholar
  142. 142.
    Owen-Schaub LB et al (1995) Wild-type human p53 and a temperature-sensitive mutant induce Fas/APO-1 expression. Mol Cell Biol 15(6):3032–3040PubMedGoogle Scholar
  143. 143.
    Bennett M et al (1998) Cell surface trafficking of Fas: a rapid mechanism of p53-mediated apoptosis. Science 282(5387):290–293PubMedCrossRefGoogle Scholar
  144. 144.
    Vesely DL, Hoffman B, Liebermann DA (2007) Phosphatidylinositol 3-kinase/Akt signaling mediates interleukin-6 protection against p53-induced apoptosis in M1 myeloid leukemic cells. Oncogene 26(21): 3041–3050PubMedCrossRefGoogle Scholar
  145. 145.
    Qian H et al (2002) Groups of p53 target genes involved in specific p53 downstream effects cluster into different classes of DNA binding sites. Oncogene 21(51):7901–7911PubMedCrossRefGoogle Scholar
  146. 146.
    Contente A et al (2002) A polymorphic microsatellite that mediates induction of PIG3 by p53. Nat Genet 30(3): 315–320PubMedCrossRefGoogle Scholar
  147. 147.
    Midgley CA et al (1995) Coupling between gamma irradiation, p53 induction and the apoptotic response depends upon cell type in vivo. J Cell Sci 108(Pt 5):1843–1848PubMedGoogle Scholar
  148. 148.
    Terzian T et al (2008) The inherent instability of mutant p53 is alleviated by Mdm2 or p16INK4a loss. Genes Dev 22(10):1337–1344PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  1. 1.Department of Biochemistry and Molecular BiologyUniversity of Texas M.D. Anderson Cancer CenterHoustonUSA

Personalised recommendations