Advertisement

p21/p53, Cellular Growth Control and Genomic Integrity

  • W. S. El-Deiry
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 227)

Abstract

In the short time since its discovery in 1993, the prototype cyclin-dependent kinase (CDK) inhibitor p21 (CIP1, Harper et al. 1993; WAF1, El-Deiry et al. 1993; p21, Xiong et al. 1993a; CAP20, Gu et al. 1993; SDI1, Noda et al. 1994; MDA6, Jiang et al. 1995) has become an intensely studied molecule. Much has been learned about its molecular structure, biochemical interactions, and physiological role. p21 is a focal point that integrates many types of signals that impact on processes of cell division and cell death. Since 1995 to date there have been over 600 references in Current Contents dealing with WAF1 or CIP1 and they are increasing at a rate of up to 25 per week. The p53 field which dates back to 1979 has had some 6000 references on Medline since 1993. This chapter will highlight some of the recent discoveries emphasizing the role of p21 and p53 in growth control and the maintenance of genomic integrity.

Keywords

Human Papilloma Virus Nucleotide Excision Repair Genomic Integrity Increase Mutation Frequency Cellular Growth Control 
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.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Aprelikova O. Xiong Y, Liu ET (1995) Both p16 and p21 families of cyclin-dependent kinase ( CDK) inhibitors block the phosphorylation of cyclin-dependent kinases by the CDK-activating kinase. J Biol Chem 270: 18195–18197PubMedGoogle Scholar
  2. Bae I, Smith ML, Fornace AJ Jr (1995) Induction of p53-, MDM2- and WAFT/CIPI-like molecules in insect cells by DNA-damaging agents. Exp Cell Res 217: 541–545PubMedGoogle Scholar
  3. Balbin M, Hannon GJ, Pendas AM, Ferrando AA, Vizoso F, Fueyo A, Lopez-Otin C (1996) Functional analysis of a p21 WAFI/CIPI /SDI I mutant (arg94-trp) identified in a human breast carcinoma. J Biol Chem 271: 15782–15786PubMedGoogle Scholar
  4. Ball KL, Lane DP (1996) Human and plant proliferating-cell nuclear antigen have a highly conserved binding site for the p53-inducible gene product p21WAFl. Eur J Biochem 237: 854–861PubMedGoogle Scholar
  5. Barlow C, Hirotsune S, Paylor R, Liyanage M, Eckhaus M, Collins F, Shiloh Y, Crawley JN, Ried T, Tagle D, Wynshaw-Boris A (1996) Atm-Deficient mice: a paradigm of Ataxia Telangiectasia. Cell 86: 159–171PubMedGoogle Scholar
  6. Blagosklonny MV, Wu GS, Omura S, El-Deiry WS (1996) Proteasome-dependent regulation of p2IWAFI/CIPI expression. Biochem Biophys Res Commun 227: 564–569PubMedGoogle Scholar
  7. Bogue MA, Zhu C, Aguilar-Cordova E, Donehower LA, Roth DB (1996) p53 is required for both radiation-induced differentiation and rescue of V(D)J rearrangement in seid mouse thymocytes. Genes Dev 10: 553–565PubMedGoogle Scholar
  8. Bohmer R-M, Scharf E, Assoian RK (1996) Cytoskeletal integrity is required throughout the mitogen stimulation phase of the cell cycle and mediates the anchorage-dependent expression of cyclin DI. Mol Biol Cell 7: 101–111PubMedGoogle Scholar
  9. Brugarolas J, Chandrasekaran C, Gordon JI, Beach D, Jacks T, Hannon G.1 (1995) Radiation-induced cell cycle arrest compromised by p21 deficiency. Nature 377: 552–557Google Scholar
  10. Buettner VL, Hill KA, Nishino H, Schaid DJ, Frisk CS, Sommer SS (1996) Increased mutation frequency and altered spectrum in one of four thymic lymphomas derived from tumor prone p53/Big Blue double transgenic mice. Oncogene 13: 2407–2413PubMedGoogle Scholar
  11. Chen IT, Smith ML, O’Connor PM, Fornace AJ Jr (1995a) Direct interaction of Gadd45 with PCNA and evidence for competitive interaction of Gadd45 and p21Wafl/Cipl with PCNA. Oncogene 11: 1931–1937PubMedGoogle Scholar
  12. Chen J, Jackson PK, Kirschner MW, Dutta A (1995b) Separate domains of p2 involved in the inhibition of Cdk kinase and PCNA. Nature 374: 386–388PubMedGoogle Scholar
  13. Chen J, Chen S, Saha P, Dutta A (1996) p2lCipl/Wafl disrupts the recruitment of human Fen1 by proliferating-cell nuclear antigen into the DNA replication complex. Proc Natl Acad Sci USA 93: 11597–11602PubMedGoogle Scholar
  14. Chin YE, Kitagawa M, Su W-CS, You Z-H, Iwamoto Y, Fu X-Y (1996) Cell growth arrest and induction of cyclin-dependent kinase inhibitor p21WAF1/CIPI mediate by STATI. Science 272: 719–722PubMedGoogle Scholar
  15. Cox LS, Midgley CA, Lane DP (1994) Xenopus p53 is biochemically similar to the human tumour suppressor protein p53 and is induced upon DNA damage in somatic cells. Oncogene 9: 2951–2959PubMedGoogle Scholar
  16. Cross SM, Sanchez CA, Morgan CA, Schimke MK, Ramel S, Idzerda RL, Raskind WH, Reid BJ (1995) A p53-dependent mouse spindle checkpoint. Science 267: 1353–1356PubMedGoogle Scholar
  17. Datto MB, Yu Y, Wang XF (1995) Functional analysis of the transforming growth factor beta responsive elements in the WAFI/Cipl/p21 promoter. J Biol Chem 270: 28623–28628PubMedGoogle Scholar
  18. de Nooij JC, Letendre MA, Hariharan IK (1996) A cyclin-dependent kinase inhibitor, Dacapo, is nec- essary for timely exit from the cell cycle during Drosophila embryogenesis. Cell 87: 1237–1247Google Scholar
  19. Deng C, Zhang P, Harper JW, Elledge SJ, Leder P (1995) Mice lacking p21CIPl/WAFT undergo normal development, but are defective in GI checkpoint control. Cell 82: 675–684PubMedGoogle Scholar
  20. Donehower LA, Godley LA, Aldaz CM, Pyle R, Shi Yp, Pinkel D, Gray J, Bradley A, Medine D, Varmus HE (1995) Deficiency of p53 accelerates mammary tumorigenesis in Wnt-1 transgenic mice and promotes chromosomal instability. Genes Dev 9: 882–895PubMedGoogle Scholar
  21. Dulic V, Kaufmann WK, Wilson SJ, Tlsty TD, Lees E, Harper JW, Elledge SJ, Reed SI (1994) p53-dependent inhibition of cyclin-dependent kinase activities in human fibroblasts during radiation-induced GI arrest. Cell 76: 1013–1024PubMedGoogle Scholar
  22. EI-Deiry WS (1996) p53, p21 WAFT/CIPI and the control of cell proliferation. In: Thomas NSB (ed) Cell cycle control and apoptosis in malignant disease. Bios Scientific, Oxford, UK, pp 55–75Google Scholar
  23. EI-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW, Vogelstein B (1993) WAF1, a potential mediator of p53 tumor suppression. Cell 75: 817–825Google Scholar
  24. EI-Deiry WS, Harper JW, O’Connor PM, Velculescu VE, Canman CE, Jackman J, Pietenpol JA, Burrell M, Hill DE, Wang Y, Wiman KG, Mercer WE, Kinzler KW, Vogelstein B (1994) WAFT/CIP1 is induced in p53-mediated GI arrest and apoptosis. Cancer Res 54: 1169–1174Google Scholar
  25. El-Deiry WS, Tokino T, Waldman T, Velculescu V, Oliner JD, Burell M, Hill DE, Rees JL, Hamilton SR, Kinzler KW, Vogelstein B (1995) Topological control of p21WAF1/CIPI expression in normal and neoplastic tissues. Cancer Res 55: 2910–2919PubMedGoogle Scholar
  26. Elledge SJ (1996) Cell cycle checkpoints: preventing an identity crisis. Science 274: 1664–1672PubMedGoogle Scholar
  27. Fan S, Chang JK, Smith ML, Duba D, Fornace AJ Jr, O’Connor PM (1997) Cells lacking CIPI/WAFT genes exhibit preferential sensitivity to cisplatin and nitrogen mustard. Oncogene 14: 2127–2136PubMedGoogle Scholar
  28. Ford JM, Hanawalt PC (1995) 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 USA 92: 8876–8880PubMedGoogle Scholar
  29. Fukasawa K, Choi T, Kuriyama R, Rulong S, Vande Woude GF (1996) Abnormal centrosome amplification in the absence of p53. Science 271: 1744–1747PubMedGoogle Scholar
  30. Givol I, Givol D, Rulong S, Resau J, Tsarfaty I, Hughes SH (1995) Overexpression of human p2lwafl/ cipl arrests the growth of chicken embryo firboblasts transformed by individual oncogenes. Oncogene I 1: 2609–2618Google Scholar
  31. Gorospe M, Wang X, Guyton KZ, Holbrook NJ (1996) Protective role of p2lWafl/Cipl against prostaglandin A2-mediated apoptosis of human colorectal carcinoma cells. Mol Cell Biol 16: 6654–6660PubMedGoogle Scholar
  32. Griffiths SD, Clarke AR, Healy LE, Ross G, Ford AM, Hooper ML, Wyllie AH, Greaves M (1997) Absence of p53 permits propagation of mutant cells following genotoxic damage. Oncogene 14: 523–531PubMedGoogle Scholar
  33. Gu Y, Turck CW, Morgan DO (1993) Inhibition of CDK2 activity in vivo by an associated 20K regulatory subunit. Nature 366: 707–710PubMedGoogle Scholar
  34. Gulbis JM, Kelman Z, Hurwitz J, O’Donnell M, Kuriyan J (1996) Structure of the C-terminal region of p2IWAFI/CIPI complexed with human PCNA. Cell 87: 297–306PubMedGoogle Scholar
  35. Hakem R, Luis de la Pompa J, Elia A, Potter J, Mak TW (1997) Partial rescue of BRCA15–6 early embryonic lethality by p53 or p21 null mutation. Nature Gen 16: 298–302Google Scholar
  36. Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ (1993) The p2I cdk-interacting protein Cipl is a potent inhibitor of GI cyclin-dependent kinases. Cell 75: 805–816PubMedGoogle Scholar
  37. Harper JW, Elledge SJ, Keyomarsi K, Dynlacht B, Tsai L-H, Zhang P, Dobrowolski S, Bai C, Connell-Crowley L, Swindell E, Fox MP, Wei N (1995) Inhibition of cyclin-dependent kinases by p21. Mol Biol Cell 6: 387–400PubMedGoogle Scholar
  38. Harvey M, Sands AT, Weiss RS, Hegi ME, Wiseman RW, Pantazis P, Giovanella BC, Tainsky MA, Bradley A, Donehower LA (1993) In vitro growth characteristics of embryo fibroblasts isolated from p53-deficient mice. Oncogene 8: 2457–2467PubMedGoogle Scholar
  39. Haupt Y, Maya R, Kazaz A, Oren M (1997) Mdm2 promotes the rapid degradation of p53. Nature 387: 296–299PubMedGoogle Scholar
  40. Havre PA, Yuan J, Hedrick L, Cho KR, Glazer PM (1995) p53 inactivation by HPV16 E6 results in increased mutagenesis in human cells. Cancer Res 55: 4420–4424PubMedGoogle Scholar
  41. Hundley JE, Koester SK, Troyer DA, Hilsenbeck SG, Subler MA, Windle JJ (1997) Increased tumor proliferation and genomic instability without decreased apoptosis in MMTV-ras mice deficient in p53. Mol Cell Biol 17: 723–731PubMedGoogle Scholar
  42. Huppi K, Siwarski D, Dosik J, Michieli P, Chedid M, Reed S, Mock B, Givol D, Mushinski JF (1994) Molecular cloning, sequencing, chromosomal localization and expression of mouse p21 ( Waft ). Oncogene 9: 3017–3020Google Scholar
  43. Jiang H, Lin J, Su ZZ, Herlyn M, Kerbel RS, Weissman BE, Welch DR, Fisher PB (1995) The melanoma differentiation-associated gene mda-6, which encodes the cyclin-dependent kinase inhibitor p21, is differentially expressed during growth, differentiation and progression in human melanoma cells. Oncogene 10: 1855–1864PubMedGoogle Scholar
  44. Kastan MB, Zhan Q, EI-Deiry WS, Carrier F, Jacks T, Walsh WV, Plunkett BS, Vogelstein B, Fornace AJ Jr (1992) A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia telangiectasia. Cell 71: 587–597PubMedGoogle Scholar
  45. Kubbutat MHG, Jones SN, Vousden KH (1997) Regulation of p53 stability by Mdm2. Nature 387: 299–303PubMedGoogle Scholar
  46. LaBaer J, Garrett MD, Stevenson LF, Slingerland JM, Sandhu C, Chou HS, Fattaey A, Harlow E (1997) New functional activities for the p2I family of CDK inhibitors. Genes Dev 11: 847–862PubMedGoogle Scholar
  47. Lane ME, Sauer K, Wallace K, Jan YN, Lehner CF, Vaessin H (1996) Dacapo, a cyclin-dependent kinase inhibitor, stops cell proliferation during Drosophila development. Cell 87: 1225–1235PubMedGoogle Scholar
  48. Lengauer C, Kinzler KW, Vogelstein B (1997) Genetic instability in colorectal cancers. Nature 386: 623–627PubMedGoogle Scholar
  49. Levine AJ (1997) p53, the cellular gatekeeper for growth and division. Cell 88:323–331PubMedGoogle Scholar
  50. Li K-S, Rishi AK, Shao Z-M, Dawson MI, Jong L, Shroot B, Reichert U, OrdonezJ, Fontana JA (1996) Posttranscriptional regulation of p2I WAF1/CIPI expression in human breast carcinoma cells. Cancer Res 56: 5055–5062Google Scholar
  51. Li R, Waga S, Hannon GJ, Beach D, Stillman B (1994) Differential effects by the p21 cdk inhibitor on PCNA-dependent DNA replication and repair. Nature 371: 534–537PubMedGoogle Scholar
  52. Li W, Fan J, Hochhauser D, Bertino JR (1997) Overexpression of p2lwafl leads to increased inhibition of E2F-I phosphorylation and sensitivity to anticancer drugs in retinoblastoma-negative human sarcoma cells. Cancer Res 57: 2193–2199PubMedGoogle Scholar
  53. Lin J, Reichner C, Wu X, Levine AJ (1996) Analysis of wild-type and mutant p21 WAFT gene activities. Mol Cell Biol 16: 1786–1793PubMedGoogle Scholar
  54. Liu M, Lee MH, Cohen M, Bommakanti M, Freedman LP (1996a) Transciptional activation of the Cdk inhibitor by vitamin D3 leads to the induced differentiation of the myelomonocytic cell line U937. Genes Dev 10: 142–153PubMedGoogle Scholar
  55. Liu M, Iavarone A, Freedman LP (1996b) Transcriptional activation of the human p2I WAFI/CIPI gene by retinoic acid receptor. J Biol Chem 271: 31723–31728PubMedGoogle Scholar
  56. Liu PK, Kraus E, Wu TA, Strong LC, Tainsky MA (1996e) Analysis of genomic instability in LiFraumeni fibroblasts with germline p53 mutations. Oncogene 12: 2267–2278PubMedGoogle Scholar
  57. Liu Y, Martindale JL, Gorospe M, Holbrook NJ (1996d) Regulation of p21WAF1/CIPI expression through mitogen-activated protein kinase signaling pathway. Cancer Res 56: 31–35PubMedGoogle Scholar
  58. Livingstone LR, White A, Sprouse J, Livanos E, Jacks T, Tlsty TD (1992) Altered cell cycle arrest and gene amplification potential accompany loss of wild-type p53. Cell 70: 923–935PubMedGoogle Scholar
  59. Lundgren K, Montes de Oca Luna R, McNeill YB, Emerick EP, Spencer B, Barfield CR, Lozano G, Rosenberg MP, Finlay CA (1997) Targeted expression of MDM2 uncouples S phase from mitosis and inhibits mammary gland development independent of p53. Genes Dev 11: 714–725PubMedGoogle Scholar
  60. Luo Y, Hurwitz J, Massague J (1995) Cell-cycle inhibition by independent CDK and PCNA binding domains in p2lCipl. Nature 375: 159–161PubMedGoogle Scholar
  61. Malkowicz SB, Tomaszewski JE, Linnenbach AJ, Cangiano TA, Maruta Y, McGarvey TW (1996) Novel p21WAFI/CIPI mutations in superficial and invasive transitional cell carcinomas. Oncogene 13: 1831–1837PubMedGoogle Scholar
  62. McDonald ER III, Wu GS, Waldman T, El-Deiry WS (1996) Repair defect in p21WAF1/CIPI —/human cancer cells. Cancer Res 56: 2250–2255PubMedGoogle Scholar
  63. Mekeel KL, Tang W, Kachnic LA, Luo C-M, DeFrank JS, Powell SN (1997) Inactivation of p53 results in high rates of homologous recombination. Oncogene 14: 1847–1857PubMedGoogle Scholar
  64. Mekeel KL, Tang W, Kachnic LA, Luo C-M, DeFrank JS, Powell SN (1997) Inactivation of p53 results in high rates of homologous recombination. Oncogene 14: 1847–1857PubMedGoogle Scholar
  65. Michieli P, Chedid M, Lin D, Pierce JH, Mercer WE, Givol D (1994) Induction of WAFI /CIPI by a p53-independent pathway. Cancer Res 54: 3391–3395PubMedGoogle Scholar
  66. Michieli P, Li W, Lorenzi MV, Miki T, Zakut R, Givol D, Pierce JH (1996) Inhibition of oncogene-mediated transformation by ectopie expression of p21 Wafl in NIH3T3 cells. Oncogene 12: 775–784PubMedGoogle Scholar
  67. Missero C, Di Cunto F, Kiyokawa H, Koff A, Dotto GP (1996) The absence of p2lCipl/WAFI alters keratinocyte growth and differentiation and promotes ras-tumor progression. Genes Dev 10: 3065–3075PubMedGoogle Scholar
  68. Noda A, Nina Y, Venable SF, Pereira-Smith OM, Smith JR (1994) Cloning of senescent cell-derived inhibitors of DNA synthesis using an expression screen. Exp Cell Res 211: 90–98PubMedGoogle Scholar
  69. Noda A, Nina Y, Venable SF, Pereira-Smith OM, Smith JR (1994) Cloning of senescent cell-derived inhibitors of DNA synthesis using an expression screen. Exp Cell Res 211: 90–98PubMedGoogle Scholar
  70. Parker SB, Eichele G, Zhang P, Rawls A, Sands AT, Bradley A, Olson EN, Harper JW, Elledge SJ (1995) p53-independent expression of p2lCipl in muscle and other terminally differentiating cells. Science 267: 1024–1027PubMedGoogle Scholar
  71. Perkins ND, Felzien LK, Betts JC, Leung K, Beach DH, Nabel GJ (1997) Regulation of NF-x13 by cyclin-dependent kinases associated with the p300 coactivator. Science 275: 523–527PubMedGoogle Scholar
  72. Polyak K, Waldman T, He T-C, Kinzler KW, Volgelstein B (1996) Genetic determinants of p53-induced apoptosis and growth arrest. Genes Dev 10: 1945–1952PubMedGoogle Scholar
  73. Prabhu NS, Blagosklonny MV, Zeng Y-X, Wu GS, Waldman T, El-Deiry WS (1996) Suppression of cancer cell growth by adenovirus expressing p2IWAFI/CIPI deficient in PCNA interaction. Clin Cancer Res 2: 1221–1229PubMedGoogle Scholar
  74. Reynisdottir I, Massague J (1997) The subcellular locations of pl5Ink4b and p27Kipl coordinate their inhibitory interactions with cdk4 and cdk2. Genes Dev 11: 492–503PubMedGoogle Scholar
  75. Russo AA, Jeffrey PD, Patten AK, Massague J, Pavletich NP (1996) Crystal structure of the p27Kipl cyclin-dependent-kinase inhibitor bound to the cyclin A-Cdk2 complex. Nature 382: 325–331PubMedGoogle Scholar
  76. Sabbatini P, Han J, Chiou S-K, Nicholson DW, White E (1997) Interleukin l(3 converting enzyme-like proteases are essential for p53-mediated transcriptionally dependent apoptosis. Cell Growth Differ 8: 643–653PubMedGoogle Scholar
  77. Sabbatini P, Han J, Chiou S-K, Nicholson DW, White E (1997) Interleukin l(3 converting enzyme-like proteases are essential for p53-mediated transcriptionally dependent apoptosis. Cell Growth Differ 8: 643–653PubMedGoogle Scholar
  78. Schwartz JL, Jordan R (1997) Selective elimination of human lymphoid cells with unstable chromosome aberrations by p53-dependent apoptosis. Carcinogenesis 18: 201–205PubMedGoogle Scholar
  79. Scully R, Chen J, Plug A, Xiao Y, Weaver D, Feunteun J, Ashley T, Livingston DM (1997) Association of BRCAI with RadSI in mitotic and meiotic cells. Cell 88: 265–275PubMedGoogle Scholar
  80. Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW (1997) Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and pl6INK4A. Cell 88: 59302Google Scholar
  81. Sharan SK, Morimatsu M, Albrecht U, Lim D-S, Regel E, Dinh C, Sands A, Eichele G, Hasty P, Bradley A (1997) Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2. Nature 386: 804–810PubMedGoogle Scholar
  82. Sheikh MS, Rochefort H, Garcia M (1995) Overexpression of p21WAFI/CIPI induces growth arrest, giant cell formation and apoptosis in human breast carcinoma cell lines. Oncogene 11: 1899–1905PubMedGoogle Scholar
  83. Sheikh MS, Chen YQ, Smith ML, Fornace AJ Jr (1997) Role of p21Wafl/Cipl/Sdil in cell death and DNA repair as studied using a tetracycline-inducible system in p53-deficient cells. Oncogene 14: 1875–1882PubMedGoogle Scholar
  84. Shim J, Lee H, Park J, Kim H, Choi EJ (1996) A non-enzymatic p21 protein inhibitor of stress-activated protein kinases. Nature 381: 804–806PubMedGoogle Scholar
  85. Shin KH, Tannyhill RJ, Liu X, Park NH (1996) Oncogenic transformation of HPV-immortalized human oral keratinocytes is associated with the genetic instability of cells. Oncogene 12: 1089–1096PubMedGoogle Scholar
  86. Shiohara M, El-Deiry WS, Wada M, Nakamaki T, Tekeuchi S, Yang R, Chen D-L, Vogelstein B, Koeffler HP (1994) Absence of WAFT mutations in a variety of human malignancies. Blood 84: 3781–3784PubMedGoogle Scholar
  87. Shou W, Dunphy WG (1996) Cell cycle control by Xenopus p28Kixl, a developmentally regulated inhibitor of cyclin-dependent kinases. Mol Biol Cell 7: 457–469PubMedGoogle Scholar
  88. Sigalas I, Calvert AH, Anderson JJ, Neal DE, Lunec J (1996) Alternatively spliced mdm2 transcripts with loss of p53 binding domain sequences: transforming ability and frequent detection in human cancer. Nature Med 2: 912–917PubMedGoogle Scholar
  89. Smith ML, Kontny HU, Zhan Q, Sreenath A, O’Connor PM, Fornace AJ Jr (1996) Antisense GADD45 expression results in decreased DNA repair and sensitizes cells to u.v.-irradiation or cisplatin. Oncogene 13: 2255–2263PubMedGoogle Scholar
  90. Somasundaram K, El-Deiry WS (1997) Inhibition of p53-mediated transactivation and cell cycle arrest by E I A through its p300/CBP-interacting region. Oncogene 14: 1047–1057Google Scholar
  91. Somasundaram K, Zhang H, Zeng Y-X, Houvras Y, Peng Y, Zhang H, Wu GS, Licht JD, Weber BL, ElDeiry WS (1997) Arrest of the cell cycle by the tumour suppressor BRCAI requires the CDK-inhibitor p2lWafl/Cipl. Nature 389: 187–190PubMedGoogle Scholar
  92. Struzbecher H-W, Donzelmann B, Henning W, Knippschild U, Buchhop S (1996) p53 is linked directly to homologous recombination processes via RAD51/RecA protein interaction. EMBO J 15: 1992–2002Google Scholar
  93. Tanaka N, Ishihara M, Lamphier MS, Nozawa H, Matsuyama T, Mak TW, Aizawa S, Tokino T, Oren M, Taniguchi T (1996) Cooperation of the tumor suppressors IRF-1 and p53 in response to DNA damage. Nature 382: 816–818PubMedGoogle Scholar
  94. Timchenko NA, Wilde M, Nakanishi M, Smith JR, Darlington GJ (1996) CCAAT/enhancer-binding protein a (C/EBPa) inhibits cell proliferation through the p21 (WAFI/CIPI/SDI-1) protein. Genes Dev 10: 804–815PubMedGoogle Scholar
  95. Velculescu VE, EI-Deiry WAS (1996) Biological and clinical importance of the p53 tumor suppressor gene. Clin Chem 42: 858–868PubMedGoogle Scholar
  96. Waldman T, Kinzler KW, Vogelstein B (1995) p21 is necessary for the p53-mediated GI arrest in human cancer cells. Cancer Res 55: 5187–5190PubMedGoogle Scholar
  97. Somasundaram K, El-Deiry WS (1997) Inhibition of p53-mediated transactivation and cell cycle arrest by E I A through its p300/CBP-interacting region. Oncogene 14: 1047–1057Google Scholar
  98. Waldman T, Lengauer C, Kinzler KW, Vogelstein B (1996) Uncoupling of S phase and mitosis induced by anticancer agents in cells lacking p21. Nature 381: 713–716PubMedGoogle Scholar
  99. Waldman T, Lengauer C, Kinzler KW, Vogelstein B (1996) Uncoupling of S phase and mitosis induced by anticancer agents in cells lacking p21. Nature 381: 713–716PubMedGoogle Scholar
  100. Wang J, Walsh K (1996) Resistance to apoptosis conferred by cdk inhibitors during myocyte differentiation. Science 273: 359–361PubMedGoogle Scholar
  101. Wang XW, Yeh H, Schaeffer L, Roy R, Moncollin V, Egly J-M, Wang Z, Friedberg EC, Evans MK, Taffe BG, Bohr VA, Weeda G, Hoeijmakers JHJ, Forrester K, Harris CC (1995) p53 modulation of TFIIH-associated nucleotide excision repair activity. Nature Gen 10: 188–195Google Scholar
  102. Wang XW, Vermeulen W, Courser JD, Gibson M, Lupold SE, Forrester K, Xu G, Elmore L, Yeh H, Hoeijmakers JH,I, Harris CC (1996) The XPB and XPD DNA helicases are components of the p53-mediated apoptosis pathway. Genes Dev 10: 1219–1232PubMedGoogle Scholar
  103. White A, Livanos EM, Tlsty TD (1994) Differential disruption of genomic integrity and cell cycle reg-ulation in normal human fibroblasts by the HPV oncoproteins. Genes Dev 8: 666–677PubMedGoogle Scholar
  104. White A, Livanos EM, Tlsty TD (1994) Differential disruption of genomic integrity and cell cycle reg-ulation in normal human fibroblasts by the HPV oncoproteins. Genes Dev 8: 666–677PubMedGoogle Scholar
  105. Wu H, Wade M, Krall L, Grisham J, Xiong Y, Van Dyke T (1996) Targeted in vivo expression of the cyclin-dependent kinase inhibitor p21 halts hepatocyte cell-cycle progression, postnatal liver development, and regeneration. Genes Dev 10: 245–260PubMedGoogle Scholar
  106. Wyllie FS, Haughton MF, Bond JA, Rowson JM, Jones Cl, Wynford-Thomas D (1996) S phase cell-cycle arrest following DNA damage is independent of the p53/p21WAF1 signaling pathway. Oncogene 12: 1077–1082PubMedGoogle Scholar
  107. Xiong Y, Hannon GJ, Zhang H, Casso D, Kobayashi R, Beach D (1993a) p21 is a universal inhibitor of cyclin kinases. Nature 366: 701–704Google Scholar
  108. Xiong Y, Zhang H, Beach D (1993b) Subunit rearrangement of the cyclin-dependent kinases is associated with cellular transformation. Genes Dev 7: 1572–1583PubMedGoogle Scholar
  109. Xiong Y, Kuppuswamy D, Li Y, Livanos EM, Hixon M, White A, Beach D, Tlsty TD (1996) Alteration of cell cycle kinase complexes in human papilloma E6- and E7-expressing fibroblasts precedes neo-plastic transformation. J Virol 70: 999–1008PubMedGoogle Scholar
  110. Xu Y, Baltimore D (1996) Dual roles of ATM in the cellular response to radiation and in cell growth control. Genes Dev 10: 2401–2410PubMedGoogle Scholar
  111. Xu Y, Ashley T, Brainerd EE, Bronson RT, Meyn MS, Baltimore D (1996) Targeted disruption of ATM leads to growth retardation, chromosomal fragmentation during meiosis, immune defects, and thymic lymphoma. Genes Dev 10: 2411–2422PubMedGoogle Scholar
  112. Yin Y, Tainsky MA, Bischoff FZ, Strong LC, Wahl GM (1992) Wild-type p53 restores cell cycle control and inhibits gene amplification in cells with mutant p53 alleles. Cell 70: 937–948PubMedGoogle Scholar
  113. Zakut R, Givol D (1995) The tumor suppression function of p21 Waf is contained in its N-terminal half (“half-WAF”). Oncogene 11: 393–395PubMedGoogle Scholar
  114. Zeng Y-X, El-Deiry WS (1996) Regulation of p21 WAFT/CIPI expression by p53-independent pathways. Oncogene 12: 1557–1564PubMedGoogle Scholar
  115. Zeng Y-X, Somasundaram K, El-Deiry WS (1997) AP2 inhibits cancer cell growth and activates p21WAFl/CIPI expression. Nature Gen 15: 78–82Google Scholar
  116. Zhan Q, EI-Deiry W, Bae I, Alamo I Jr, Kastan MB, Vogelstein B, Fornace AJ Jr (1995) Similarity of the DNA-damage responsiveness and growth suppressive properties of WAFT/CIPI and GADD45. Int J Oncol 6: 937–946PubMedGoogle Scholar
  117. Zhang H, Hannon GJ, Beach D (1994) p21-containing cyclin kinases exist in both active and inactive states. Genes Dev 8: 1750–1758PubMedGoogle Scholar
  118. Zhang W, Grasso L, McLain CD, Gambel AM, Cha Y, Travali S, Deisseroth AB, Mercer WE (1995) p53-independent induction of WAF1/CIP1 in human leukemia cells is correlated with growth arrest accompanying monocyte/macrophage differentiation. Cancer Res 55: 668–674PubMedGoogle Scholar
  119. Zhu L, Harlow E, Dynlacht BD (1995) p107 uses a p21 (CIP1)-related domain to bind cyclin/cdk2 and regulate interactions with E2F. Genes Dev 9: 1740–1752PubMedGoogle Scholar
  120. Zhu X, Ohtsubo M, Bohmer RM, Roberts JM, Assoian RK (1996) Adhesion-dependent cell cycle progression linked to the expression of cyclin D1, activation of cyclin E-cdk2, and phosphorylation of the retinoblastoma protein. J Cell Biol 133: 391–403PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1998

Authors and Affiliations

  • W. S. El-Deiry
    • 1
  1. 1.Laboratory of Molecular Oncology and Cell Cycle Regulation, Howard Hughes Medical Institute, Department of Medicine, Genetics and Cancer CenterUniversity of Pennsylvania School of MedicinePhiladelphiaUSA

Personalised recommendations