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p53 pp 142–159Cite as

p53’s Dilemma in Transcription: Analysis by Microarrays

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Part of the book series: Molecular Biology Intelligence Unit ((MBIU,volume 1))

Abstract

Protection against cancer by p53 is due mainly to its activity as a transcription factor. The function of p53 in transactivation of target genes is analyzed here with emphasis on the dilemma between cell growth arrest and apoptosis pathways. The question as to which of these p53 functions is required for tumor suppression in vivo is revisited in light of new studies that renew the focus on senescence and growth arrest mechanisms in the protection against cancer. Global gene expression analysis by microarrays, employing either transcription or conformation switches for p53 activation were utilized to distinguish primary (direct) p53 targets from secondary (indirect) ones, and to probe pathways of inhibition of p53-induced apoptosis. The profile of gene expression indicates that p53 is a central node in the cellular network of growth control modulation and its activation results in altered expression of more than a thousand genes. Some of these are co-activators of p53 and may be involved in the decision making of the choice between p53 functions. The major conclusion is that the response to p53 activation is heterogeneous and is mainly dependent on the cellular context, which is evident from the pattern of p53-induced genes in different cell types and in various organs in response to irradiation. The analysis of gene expression profiles following activation or suppression of apoptosis by either chemotherapy or cytokines, respectively, may facilitate the identification of ways to bypass the loss of p53 activity and to design new modalities for cancer treatment.

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References

  1. Zakut-Houri R, Oren M, Bienz B SL et al. A single gene and a pseudogene for the cellular tumor antigen p53. Nature 1983; 306:594–597.

    Article  PubMed  CAS  Google Scholar 

  2. Bienz B, Zakut-Houri R, Givol D SL et al. Analysis of the gene coding for the murine cellular tumor antigen p53. EMBO J 3:2179–2183.

    Google Scholar 

  3. Eliyahu D, Raz A, Gruss P SL et al. Participation of p53 cellular tumor antigen in transformation of normal embryonic cells. Nature 1984; 312:646–649.

    Article  PubMed  CAS  Google Scholar 

  4. Eliyahu D, Michalovitz D, Eliyahu S SL et al. Wild-type p53 can inhibit oncogene-mediated focus formation. Proc Natl Acad Sci 1989; 86:8763–8767.

    Article  PubMed  CAS  Google Scholar 

  5. Michalovitz D, Halevy O, Oren M. Conditional inhibition of transformation and of cell proliferation by a temperature-sensitive mutant of p53. Cell 1990; 62:671–680.

    Article  PubMed  CAS  Google Scholar 

  6. McBride OW, Merry DE, Oren M et al. Human p53 cellular antigen is on chromosome 17p13. Cytogenet. and Cell Genet 1985; 40:694.

    Google Scholar 

  7. Zakut-Houri R, Bienz-Tadmor B SL et al. Human p53 cellular tumor antigen: cDNA sequence and expression in COS cells. EMBO J 1985; 4:1251–1255.

    PubMed  CAS  Google Scholar 

  8. McBride OW, Merry D, Givol D. The gene for human p53 cellular tumor antigen is located on chromosome 17 short arm (17p13). Proc Natl Acad Sci 1986; 83:130–134.

    Article  PubMed  CAS  Google Scholar 

  9. Vogelstein B, Fearon ER, Hamilton SR SL et al. Genetic alterations during colorectal-tumor development. New Engl J Med 1988; 319:525–532.

    Article  PubMed  CAS  Google Scholar 

  10. Baker SJ, Fearon ER, Nigro JM et al., Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science, 1989; 244:217–221.

    Article  PubMed  CAS  Google Scholar 

  11. Knudson AG Jr. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci 1971; 68:820–823.

    Article  PubMed  Google Scholar 

  12. Knudson AG. Two genetic hits (more or less) to cancer. Nat Rev Cancer 2001; 1:157–162.

    Article  PubMed  CAS  Google Scholar 

  13. Takahashi T, Nau MM, Chiba I SL et al. p53: a frequent target for genetic abnormalities in lung cancer. Science 1989; 246:491–494.

    Article  PubMed  CAS  Google Scholar 

  14. Finlay CA, Hinds PW, Levine AJ. The p53 proto-oncogene can act as a suppressor of transformation. Cell 1989; 57:1083–1093.

    Article  PubMed  CAS  Google Scholar 

  15. El-Deiry WS, Kern SE, Pietenpol JA SL et al. Definition of a consensus binding site for p53. Nat Genet 1992; 1:45–49.

    Article  PubMed  CAS  Google Scholar 

  16. Cho Y, Gorina S, Jeffrey SL et al. Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations. Science 1994; 265:346–355.

    Article  PubMed  CAS  Google Scholar 

  17. Hoh J, Jin S, Parrado T SL et al. the p53MH algorithm and its application in detecting p53-responsive genes. Proc Natl Acad Sci 2002; 99:8467–8472.

    Article  PubMed  CAS  Google Scholar 

  18. Cawley S, Bekiranov S, Ng HH SL et al. Unbiased mapping of transcription factor binding sites along human chromosomes 21 and 22 points to widespread regulation of noncoding RNAs. Cell 2004; 116:499–509.

    Article  PubMed  CAS  Google Scholar 

  19. Mercer WE, Shields MT, Amin M SL et al. Negative growth regulation in a glioblastoma tumor cell line that conditionally expresses human wild-type p53. Proc Natl Acad Sci 1990; 87:6166–6170.

    Article  PubMed  CAS  Google Scholar 

  20. El-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW and Vogelstein B. WAF1, a potential mediator of p53 tumor suppression. Cell, 1993; 75:817–825.

    Article  PubMed  CAS  Google Scholar 

  21. Noda A, Ning Y, Venable SF SL et al. Cloning of senescent cell derived inhibitors of DNA synthesis using an expression screen. Exp Cell Res 1994; 211:90–98.

    Article  PubMed  CAS  Google Scholar 

  22. Harper JW, Adami GR, Wei N SL et al. The p21 cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin dependent kinases. Cell 1993; 75:805–816.

    Article  PubMed  CAS  Google Scholar 

  23. Xiong Y, Hannon GJ, Zhang H SL et al. p21 is a universal inhibitor of cyclin kinases. Nature 1983; 366:634–635.

    Google Scholar 

  24. Yonish-Rouach E, Resnitzky D, Lotem J SL et al. Wild-type p53 induces apoptosis of myeloid leukaemic cells that is inhibited by interleukin-6. Nature 1991; 352:345–347.

    Article  PubMed  CAS  Google Scholar 

  25. Miyashita T, Reed JC. Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell 1995; 80:293–299.

    Article  PubMed  CAS  Google Scholar 

  26. Owen-Schaub LB, Zhang W, Cusack JC et al., Wild-type human p53 and a temperature-sensitive mutant induce Fas/APO-1 expression. Mol Cell Biol 1995; 15:3032–3040.

    PubMed  CAS  Google Scholar 

  27. Kannan K, Amariglio N, Rechavi G SL et al. Profile of gene expression regulated by induced p53: connection to the TGF-B family. FEBS Lett., 2000; 470:77–82.

    Article  PubMed  CAS  Google Scholar 

  28. Kannan K, Amariglio N, Rechavi G SL et al. DNA microarrays identification of primary and secondary target genes regulated by p53. Oncogene 2001; 20:2225–2234.

    Article  PubMed  CAS  Google Scholar 

  29. Kannan K, Kaminski N, Rechavi G SL et al. DNA microarray analysis of genes involved in p53 mediated apoptosis activation of apaf-1. Oncogene 2001; 20:3449–3455.

    Article  PubMed  CAS  Google Scholar 

  30. Tan M, Wang Y, Guan K SL et al. PTGF-B, a type B transforming growth factor (TGF-B) super-family member, is a p53 target gene that inhibits tumor cell growth via TGF-B signaling pathway. Proc Natl Acad Sci 2000; 97:109–114.

    Article  PubMed  CAS  Google Scholar 

  31. Li C, Shridhar K, Liu J. Molecular characterization of oncostatin M-induced growth arrest of MCF-7 cells expressing a temperature sensitive mutant of p53. Breast Caner Res And Treatment 2003; 80:23–37.

    Article  CAS  Google Scholar 

  32. Yu J, Zhang L, Hwang PM, Rago C, Kinzler KW and Vogelstein B. Identification and classification of p53-regulated genes. Proc Natl Acad Sci 1999; 96:14517–14522.

    Article  PubMed  CAS  Google Scholar 

  33. Kimura T, Gotoh M, Nakamura Y SL et al. hCDC4b, a regulator of cyclin E, as a direct transcriptional target of p53. Cancer Sci 2003; 94:431–436.

    Article  PubMed  CAS  Google Scholar 

  34. Ueda K, Arakawa H, Nakamura Y. Dual-specificity phosphatase 5 (DUSP5) as a direct transcriptional target of tumor suppressor p53. Oncogene 2003; 22:5586–5591.

    Article  PubMed  CAS  Google Scholar 

  35. Ongusaha PP, Ouchi T, Kim K SL et al. BRCA1 shifts p53-mediated cellular outcomes towards irreversible growth arrest. Oncogene 20032; 22:3749–3758.

    Google Scholar 

  36. Zhao R, Gish K, Murphy M SL et al. Analysis of p53-regulated gene expression patterns using oligonucleotide arrays. Genes and Dev 2000; 14:981–993.

    Article  PubMed  CAS  Google Scholar 

  37. Lotem J, Gal H, Kama R SL et al. Inhibition of p53-induced apoptosis without affecting expression of p53 regulated genes. Proc Natl Acad Sci 2003; 100:6718–6723.

    Article  PubMed  CAS  Google Scholar 

  38. Maxwell SA, Davis GE. Differential gene expression in p53-mediated apoptosis-resistant vs. apoptosis-sensitive tumor cell lines. Proc Natl Acad Sci 2000; 97:13009–13014.

    Article  PubMed  CAS  Google Scholar 

  39. Maxwell SA, Davis GE. Biological and molecular characterization of an ECV-304-derived cell line resistant to p53 mediated apoptosis. Apoptosis 2000; 5:277–290.

    Article  PubMed  CAS  Google Scholar 

  40. Stankovic T, Hubank M, Cronin D SL et al. Microarray analysis reveals that TP53-and ATM-mutant B-CLLs share a defect in activating proapoptotic responses after DNA damage but are distinguished by major differences in activating prosurvival responses. Blood 2004; 103:291–300.

    Article  PubMed  CAS  Google Scholar 

  41. Mirza A, Wu Q, Wang L SL et al. Global transcriptional program of p53 target genes during the process of apoptosis and cell cycle progression. Oncogene 2003; 22:3645–3654.

    Article  PubMed  CAS  Google Scholar 

  42. Sax JK, El-Deiry WS. Identification and characterization of the cytoplasmic protein TRAF4 as a p53-regulated proapoptotic gene. J Biol Chem 2003; 278:36435–36444.

    Article  PubMed  CAS  Google Scholar 

  43. Fortin A, Cregan SP. MacLaurin JG SL et al. APAF1 is a key transcriptional target for p53 in the regulation of neuronal cell death. J Cell Biol 2001; 155:207–216.

    Article  PubMed  CAS  Google Scholar 

  44. Robles AI, Bemmels NA. Foraker AB SL et al. APAF-1 is a transcriptional target of p53 in DNA damage-induced apoptosis. Cancer Res., 2001; 61:6660–6664.

    PubMed  CAS  Google Scholar 

  45. Wang Y, Rea T, Bian J SL et al. Identification of the genes responsive to etoposide-induced apoptosis:application of DNA chip technology. FEBS Lett 1999; 445:269–273.

    Article  PubMed  CAS  Google Scholar 

  46. Wu Q, Kirschmeier P, Hockenberry T SL et al. Transcriptional regulation during p21waf1/cip1 induced apoptosis in human ovarian cancer cells. J Biol Chem 2002; 277:36329–36337.

    Article  PubMed  CAS  Google Scholar 

  47. Fei P, Bernhard EJ, El-Deiry WS. Tissue-specific induction of p53 targets in vivo. Cancer Res 2002;62:7316–7327.

    PubMed  CAS  Google Scholar 

  48. Soengas MS, Alarcon RM, Yoshida H SL et al. Apaf-1 and caspase-9 in p53-dependent apoptosis and tumor inhibition. Science, 1999; 284:156–159.

    Article  PubMed  CAS  Google Scholar 

  49. Moroni MC, Hickman ES, Denchi EL SL et al. Apaf-1 is a transcriptional target for E2f and p53. Nat Cell Biol 2001; 3:552–558.

    Article  PubMed  CAS  Google Scholar 

  50. Rozenfeld-Granot G, Krishnamurthy J SL et al. A positive feedback mechanism in the transcriptional activation of Apaf-1 by p53 and the coactivator Zac-1. Oncogene 2002; 21:1469–1476.

    Article  PubMed  CAS  Google Scholar 

  51. Iyer NG, Chin S, Ozdag H, Daigo Y, Hu D, Cariati M, Brindle K, Aparicio S and Caldas C. p300 regulates p53 dependent apoptosis after DNA damage in colorectal cancer cells by modulation of PUMA/p21 levels. Proc Natl Acad Sci 2004; 101:7386–7391.

    Article  PubMed  CAS  Google Scholar 

  52. Yu J, Wang Z, Kinzler KW SL et al. PUMA mediates the apoptotic response to p53 in colorectal cancer cells. Proc Natl Acad Sci 2003; 100:1931–1936.

    Article  PubMed  CAS  Google Scholar 

  53. Nakano K, Vousden KH. PUMA, a novel proapoptotic gene, is induced by p53. Mol Cell 2001; 7:683–694.

    Article  PubMed  CAS  Google Scholar 

  54. Polyak K, Xia Y, Zweier JL SL et al. A model for p53 induced apoptosis. Nature 1997; 389:300–305.

    Article  PubMed  CAS  Google Scholar 

  55. Lotem J, Sachs L. Different mechanisms for suppression of apoptosis by cytokines and calcium mobilizing compounds. Proc Natl Acad Sci 1998; 95:4601–4606.

    Article  PubMed  CAS  Google Scholar 

  56. Kho PS, Wang Z, Zhuang L SL et al. p53-regulated transcriptional program associated with genotoxic stress-induced apoptosis. J Biol Chem 279:21183–21192.

    Google Scholar 

  57. Komarova EA, Diatchenko L, Rokhlin OW SL et al. Stress-induced secretion of growth inhibitors: a novel tumor suppressor function of p53. Oncogene 1998; 17:1089–1096.

    Article  PubMed  CAS  Google Scholar 

  58. Dameron KM, Volpert OV, Tainsky MA SL et al. Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1. Science 1994; 265:1582–1584.

    Article  PubMed  CAS  Google Scholar 

  59. Maxwell SA, Rivera A. Proline oxidase induces apoptosis in tumor cells, and its expression is frequently absent or reduced in renal carcinomas. J Biol Chem 2003; 278:9784–9789.

    Article  PubMed  CAS  Google Scholar 

  60. Fang L, Li G, Liu G SL et al. P53 induction of heparin-binding EGF-like growth factor counteracts p53 growth suppression through activation of MAPK and PI3K/Akt signaling cascades. EMBO J 2001; 20:1931–1939.

    Article  PubMed  CAS  Google Scholar 

  61. Rowan S, Ludwig RL, Haupt Y SL et al. Specific loss of apoptotic but not cell cycle arrest function in a human tumor derived p53 mutant. EMBO J 1996; 15:827–838.

    PubMed  CAS  Google Scholar 

  62. Liu G, Parant JM, Lang G SL et al. Chromosome stability, in the absence of apoptosis, is critical for suppression of tumorigenesis in Trp53 mutant mice. Nat Genet 2003; 36:63–68.

    Article  PubMed  Google Scholar 

  63. Attardi LD, de Vries A, Jacks T. Activation of the p53 dependent G1 checkpoint response in mouse embryo fibroblasts depends on the specific DNA damage inducer. Oncogene 2004; 23:973–980.

    Article  PubMed  CAS  Google Scholar 

  64. Wang Y, Blandino G, Oren M SL et al. Induced p53 expression in lung cancer cell line promotes cell senescence and differentially modifies the cytotoxicity of anti-cancer drugs. Oncogene 1998; 17:1923–1930.

    Article  PubMed  CAS  Google Scholar 

  65. Wang Y, Blandino G, Givol D. Induced p21waf expression in H1299 cell line promotes cell senescence and protects against cytotoxic effect of radiation and doxorubicin. Oncogene 1999; 18:2643–2649.

    Article  PubMed  CAS  Google Scholar 

  66. Sugrue MM, Shin DY, Lee SW SL et al. Wild-type p53 triggers a rapid senescence program in human tumor cells lacking functional p53. Proc Natl Acad Sci 1997; 94:9648–9653.

    Article  PubMed  CAS  Google Scholar 

  67. Fazeli A, Steen RG, Dickinson SL et al. Effects of p53 mutations on apoptosis in mouse intestinal and human colonic adenomas. Proc Natl Acad Sci 1997; 94:10199–10204.

    Article  PubMed  CAS  Google Scholar 

  68. Campisi J. Cellular senescence as a tumor suppressor mechanism. Trends in Cell Biol 2001; 11:S27–S31.

    CAS  Google Scholar 

  69. Vogelstein B, Lane D, Levine AJ. Surfing the p53 network. Nature 2000; 408:307–310.

    Article  PubMed  CAS  Google Scholar 

  70. Berns K, Hijmans EM, Mullenders J et al. A large scale RNAi screen in human cells identifies new components of the p53 pathway. Nature 2004; 428:431–437.

    Article  PubMed  CAS  Google Scholar 

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  1. Cancer Pharmacology, Millennium Pharmaceuticals Inc., 40 Landsdowne Street, Cambridge, MA, 02139, USA

    Karuppiah Kannan

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  1. Karuppiah Kannan
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  2. Gideon Rechavi
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  3. David Givol
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Kannan, K., Rechavi, G., Givol, D. (2010). p53’s Dilemma in Transcription: Analysis by Microarrays. In: p53. Molecular Biology Intelligence Unit, vol 1. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-8231-5_10

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