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Transcriptional activation of p21WAF1by PTEN/MMAC1 tumr suppressor

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Abstract

The recently discovered tumor suppressor gene PTEN has been found mutated in many types of advanced tumors. When introduced into tumor cells that lack the wild-type allele of the gene, PTEN was able to suppress the growth of these cells. Here, we have analyzed how PTEN might alter cell cycle-regulatory controls to achieve this growth-inhibitory effect. We found that overexpression of PTEN stimulates the synthesis of three inhibitors of cyclin-dependent kinases, p21WAF1, p27KIP1, and p57,KIP2. This effect is very specific, as the expression of other components of the cell cycle engine, various cyclins and cyclin-dependent kinases, is not affected. For p21WAF1 we show that this induction is due to the p53-independent transcriptional activation of its promoter. In addition, increased expression of PTEN rendered the cells more sensitive to apoptotic cell death. Therefore, our data suggest a two-fold mechanism of growth inhibition by PTEN: one that acts via the increased expression of CKIs such as p21WAF1, and another that augments the cellular propensity for apoptotic cell death.

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References

  1. Steck PA, Pershouse MA, Jasser SA, Alfred YWK, Lin H, Ligon AH, Langford LA, Baumgard ML, Hattier T, Davis T, Frye C, Hu R, Swedlund B, Teng DHF, Tavtigian SV: Identification of a candidate tumour suppressor gene, MMAC1, at chromosone 10q23.3 that is mutated in multiple advanced cancers. Nat Genet 15: 356-362, 1997

    Google Scholar 

  2. Myers MP, Tonks NK: PTEN: Sometimes taking it off can be better than putting it on. Am J Hum Genet 61: 1234-1238, 1997

    Google Scholar 

  3. Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Giovanella BC, Michael I, Tycko B, Hibshoosh H, Wigler M H, Parsons R: PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast and prostate cancer. Science 275: 1943-1947, 1997

    Google Scholar 

  4. Li D-M Sun H: TEP1, encoded by the candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor β. Cancer Res 57: 2124-2129, 1997

    Google Scholar 

  5. Myers MP, Stolarov JP, Eng C, Li J, Wang SI, Wigler MH, Parsons R, Tonks NK:P-TEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity phosphatase. Proc Natl Acad Sci USA 94: 9052-9057, 1997

    Google Scholar 

  6. Tamura M, Gu J, Matsumoto K, Aota S, Parsons R, Yamada KM: Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN. Science 280: 1614-1617, 1998

    Google Scholar 

  7. Tamura M, Gu J, Takino T, Yamada KM: Tumor suppressor PTEN inhibition of cell invasion, migration, and growth: Differential involvement of focal adhesion kinase and p130Cas. Cancer Res 59: 442-449, 1999

    Google Scholar 

  8. Myers MP, Pass I, Batty IH, Van der Kaay J, Stolarov JP, Hemmings BA, Wigler MH, Downes CP, Tonks NK: The lipid phosphatase activity of PTEN is critical for its tumor supressor function. Proc Natl Acad Sci U S A 95: 13513-13518, 1998

    Google Scholar 

  9. Maehama T Dixon JE: The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem 273: 13375-13378, 1998

    Google Scholar 

  10. Ramaswamy S, Nakamura N, Vazquez F, Batt DB, Perera S, Roberts TM, Sellers WR: Regulation of G1 progression by the PTEN tumor suppressor protein is linked to inhibition of the phosphatidylinositol 3-kinase/Akt pathway [In Process Citation]. Proc Natl Acad Sci USA 96: 2110-2115, 1999

    Google Scholar 

  11. Li J, Simpson L, Takahashi M, Miliaresis C, Myers M P, Tonks N, Parsons R: The PTEN/MMAC1 tumor suppressor induces cell death that is rescued by the AKT/protein kinase B oncogene [In Process Citation]. Cancer Res 58: 5667-5672, 1998

    Google Scholar 

  12. Robertson GP, Furnari FB, Miele ME, Glendening MJ, Welch DR, Fountain JW, Lugo TG, Huang HJ, Cavenee WK: In vitro loss of heterozygosity targets the PTEN/MMAC1 gene in melanoma. Proc Natl Acad Sci USA 95: 9418-9423, 1998

    Google Scholar 

  13. Cheney IW, Johnson DE, Vaillancourt M-T, Avanzini J, Morimoto A, Demers GW, Wills KN, Shabram PW, Bolen JB, Tavtigian SV, Bookstein R: Suppression of tumorgenicity of glioblastoma cells by adenovirus-mediated MMAC1/PTEN gene transfer. Cancer Res 58: 2331-2334, 1998

    Google Scholar 

  14. Furnari FB, Lin H, Huang H-JS, Cavenee WK: Growth suppression of glioma cells by PTEN requires a functional phosphatase catalytic domain. Proc Natl Acad Sci USA 94: 12479-12484, 1997

    Google Scholar 

  15. Li, D.-M. and Sun H: PTEN/MMAC/TEP1 suppresses the tumorigenicity and induces G1 cell cycle arrest in human glioblastoma cells. Proc Natl Acad Sci USA 95: 15406-16411, 1998

    Google Scholar 

  16. Morimoto AM, Berson AE, Fujii GH, Teng DH, Tavtigian SV, Bookstein R, Steck PA Bolen JB: Phenotypic analysis of human glioma cells expressing the MMAC1 tumor suppressor phosphatase. Oncogene 18: 1261-1266, 1999

    Google Scholar 

  17. Stambolic V, Suzuki A, de la Pompa JL, Brothers GM, Mirtsos C, Sasaki T, Ruland J, Penninger JM, Siderovski DP, Mak TW: Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell 95: 29-39, 1998

    Google Scholar 

  18. Di Cristofano A, Pesce B, Cordon-Cardo C, Pandolfi PP: Pten is essential for embryonic development and tumour suppression. Nat Genet 19: 348-355, 1998

    Google Scholar 

  19. Morgan DO: Principles of CDK regulation. Nature 374: 131-134, 1997

    Google Scholar 

  20. Graña X, Reddy EP: Cell cycle control in mammalian cells: Role of cyclins, cyclin dependent kinases (CDK's), growth suppressor genes and cylin-dependent kinase inhibitors (CKI's). Oncogene 11: 211-219, 1995

    Google Scholar 

  21. Hunter T, Pines J: Cyclins and cancer II: Cyclin D and CDK inhibitors come of age. Cell 79: 573-582, 1994

    Google Scholar 

  22. Harper JW, Elledge SJ: Cdk inhibitors in development and cancer. Curr Opin Genetics Devel 6: 56-64, 1996

    Google Scholar 

  23. Sherr CJ, Roberts JM: Inhibitors of mammalian G1 cyclindependent kinases. Genes Devel 9: 1149-1163, 1995

    Google Scholar 

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

    Google Scholar 

  25. El-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, Kastan MB, Kohn KW, Elledge SJ, Kinzler KW, Vogelstein B: WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. Cancer Res 54: 1169-1174, 1994

    Google Scholar 

  26. Sheikh MS, Li X, Chen J, Shao Z, Ordonez JV, Foutana JA: Mechanisms of regulation of WAF1/CIP1 gene expression in human breast carcinoma: Role of p53-dependent and independent signal transduction pathways. Oncogene 9: 3407-3415, 1994

    Google Scholar 

  27. Owen GI, Richer JK, Tung L, Takimoto G, Horwitz KB: Progesterone regulates transcription of the p21(WAF1) cyclindependent kinase inhibitor gene through Sp1 and CBP/p300. J Biol Chem 273: 10696-10701, 1998

    Google Scholar 

  28. Alpan RS, Pardee AB: p21WAF1/CIP1/SDI1 is elevated through a p53-independent pathway by mimosine. Cell Growth Diff 7: 893-901, 1996

    Google Scholar 

  29. Liu Y, Martindale JL, Gorospe M, Holbrook NJ: Regulation of p21WAF1/CIP1 expression through mitogen-activated protein kinase signaling pathway. Cancer Res 56: 31-35, 1996

    Google Scholar 

  30. Parker SB, Eichele G, Zhang P, Rawls A, Sands AT, Bradley A, Olson EN, Harper JW, Elledge S J: p53-independent expression of p21Cip1 in muscle and other terminally differentiating cells. Science 267: 1024-1027, 1995

    Google Scholar 

  31. Prowse DM, Bolgan L, Molnár Á, Dotto GP: Involvement of the SP3 transcription factor in induction of p21Cip1/WAF1 in keratinocyte differentiation. J Biol Chem 272: 1308-1314, 1997

    Google Scholar 

  32. Wahl AF, Donaldson KL, Fairchild C, Lee FY, Foster SA, Demers GW, Galloway DA: Loss of normal p53 function confers sensitization to Taxol by increasing G2/M arrest and apoptosis. Nat Med 2: 72-79, 1996

    Google Scholar 

  33. Waldman T, Lengauer C, Kinzler KW, Vogelstein B: Uncoupling of S phase and mitosis induced by anticancer agents in cells lacking p21. Nature 381: 713-716, 1996

    Google Scholar 

  34. Lowe SW, Ruley HE, Jacks T, Housman DE: p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell 74: 957-967, 1993

    Google Scholar 

  35. Banerjee D, Lenz H-J, Schnieders B, Manno DJ, Ju JF, Spears CP, Hochhauser D, Danenberg K, Danenberg P, Bertino JR: Transfection of wild-type but not mutant p53 induces early monocytic differentiation in HL60 cells and increases their sensitivity to stress. Cell Growth Diff 6: 1405-1413, 1995

    Google Scholar 

  36. Fan S, El-Deiry WS, Bae I, Freeman J, Jondle D, Bhatia K, Fornace AJ, Magrath I, Kohn KW, O'Connor PM: p53 mutations are associated with decreased sensitivity of human lymphoma cells to DNA-damaging agents. Cancer Res 54: 5824-5830, 1994

    Google Scholar 

  37. Wu GS, El-Deiry WS: p53 and chemosensitivity. Nat Med 2: 255-256, 1996

    Google Scholar 

  38. Cote RJ, Esrig D, Groshen S, Jones PA, Skinner DG: p53 and treatment of bladder cancer. Nature 385: 123-124, 1997

    Google Scholar 

  39. O'Connor PM, Jackman J, Bae I, Myers TG, Fan S, Mutoh M, Scudiero DA, Monks A, Sausville EA, Weinstein JN, Friend S, Fornace Jr, AJ, Kohn KW: Characterization of the p53 tumor suppressor pathway in cell lines of the National Cancer Institute Anticancer Drug Screen and correlations with the growthinhibitory potency of 123 anticancer drugs. Cancer Res 57: 4285-4300, 1997

    Google Scholar 

  40. Van Meir EG, Kikuchi T, Tada M, Li H, Diserens AC, Wojcik BE, Huang HJ, Friedmann T, de Tribolet N, Cavenee WK: Analysis of the p53 gene and its expression in human glioblastoma cells. Cancer Res 54: 649-652, 1994

    Google Scholar 

  41. No D, Yao T-P, Evans RM: Ecdysone-inducible gene expression in mammalian cells and transgenic mice. Proc Natl Acad Sci USA 93: 3346-3351, 1996

    Google Scholar 

  42. El-Deiry WS, Tokino T, Waldman T, Oliner JD, Velculescu VE, Burrell M, Hill DE, Healy E, Rees JL, Hamilton SR, Kinzler KW, Vogelstein B: Topological control of p21WAF1/CIP1 expression in normal and neoplastic tissues. Cancer Res 55: 2910-2919, 1995

    Google Scholar 

  43. Baharians Z, Schönthal AH: Autoregulation of protein phosphatase type 2A expression. J Biol Chem 273: 19019-19024, 1998

    Google Scholar 

  44. Ausubel FM, Brent R, Kingston RE, Moore DD, Seidman JG, Smith JA, Struhl K: Current Protocols in Molecular Biology. In: V. B. Chanda (ed). John Wiley & Sons, Inc., 1994

  45. Harlow E, Lane D: Antibodies: A Laboratory Manual. Cold Spring Harbor. NY: Cold Spring Harbor Laboratory, 1988

    Google Scholar 

  46. Lassar AB, Davis RL, Wright WE, Kadesch T, Murre C, Voronova A, Baltimore D, Weintraub H: Functional activity of myogenic HLH proteins requires hetero-oligomerization with E12/E47-like proteins in vivo. Cell 66: 305-315, 1991

    Google Scholar 

  47. Wu R-C, Schönthal AH: Activation of p53-p21waf1 pathway in response to disruption of cell-matrix interactions. J Biol Chem 272: 29091-29098, 1997

    Google Scholar 

  48. Schönthal AH, Feramisco JR: Inhibition of histone H1 kinase expression, retinoblastoma protein phosphorylation, and cell proliferation by the phosphatase inhibitor okadaic acid. Oncogene 8: 433-441, 1993

    Google Scholar 

  49. Zhang Z, Zheng J, Zhao Y, Li G, Batres Y, Luo MP, Wan M, Ying SY: Overexpression of activin A inhibits growth, induces apoptosis, and supresses tumorgenicity in an androgen-sensitive human prostate cancer cell line LNCaP. Int J Oncol 11: 727-736, 1997

    Google Scholar 

  50. Graham FL, Smiley J, Russell WC, Nairn R: Characteristics of a human cell line transformed by DNA from human adenovirus type 5. J Gen Virol 36: 59-74, 1977

    Google Scholar 

  51. Moran E: Interaction of adenoviral proteins with pRB and p53. FASEB J 7: 880-885, 1993

    Google Scholar 

  52. Pagano M, Tam SW, Theodoras AM, Beer-Romero P, Del Sal G, Chau V, Yew PR, Draetta GF, Rolfe M: Role of the ubiquitin-proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27. Science 269: 682-685, 1995

    Google Scholar 

  53. Esposito F, Cuccovillo F, Vanoni M, Cimino F, Anderson CW, Appella E, Russo T: Redox-mediated regulation of p21(waf1/ cip1) expression involves a post-transcriptional mechanism and activation of the mitogen-activated protein kinase pathway. Eur J Biochem 245: 730-737, 1997

    Google Scholar 

  54. Zeng Y-X, El-Deiry WS: Regulation of p21WAF1/CIP1 expression by p53-independent pathways. Oncogene 12: 1557-1564, 1996

    Google Scholar 

  55. Forman HJ, Cadenas E: Oxidative Stress and Signal Transduction. Chapman & Hall, New York, 1997

    Google Scholar 

  56. Wu R-C, Hohenstein A, Park JM, Qiu X, Mueller S, Cadenas E, Schönthal AH: Role of p53 in aziridinylbenzoquinone-induced p21waf1 expression. Oncogene 17: 357-365, 1998

    Google Scholar 

  57. Qiu X, Forman HJ, Schönthal AH, Cadenas E: Induction of p21 mediated by reactive oxygen species formed during the metabolism of aziridinylbenzoquinones by HCT116 cells. J Biol Chem 271: 31915-31921, 1996

    Google Scholar 

  58. de Murcia JM, Niedergang C, Trucco C, Ricoul M, Dutrillaux B, Mark M, Oliver FJ, Masson M, Dierich A, LeMeur M, Walztinger C, Chambon P, de Murcia G: Requirement of poly(ADP-ribose) polymerase in recovery from DNA damage in mice and in cells. Proc Natl Acad Sci USA 94: 7303-7307, 1997

    Google Scholar 

  59. Duriez PJ, Shah GM: Cleavage of poly(ADP-ribose) polymerase: A sensitive parameter to study cell death. Biochem Cell Biol 75: 337-349, 1997

    Google Scholar 

  60. Hinds PW, Weinberg RA: Tumor suppressor genes. Curr Opin Genetics Devel 4: 135-141, 1994

    Google Scholar 

  61. Levine A J: p53, the cellular gatekeeper for growth and division. Cell 88: 323-331, 1997

    Google Scholar 

  62. Nelen MR, van Staveren WC, Peeters EA, Hassel MB, Gorlin RJ, Hamm H, Lindboe CF, Fryns JP, Sijmons RH, Woods DG, Mariman EC, Padberg GW, Kremer H: Germline mutations in the PTEN/ MMAC1 gene in patients with Cowden disease. Hum Mol Genet 6: 1383-1387, 1997

    Google Scholar 

  63. Toker A, Cantley LC: Signalling through the lipid products of phosphoinositide-3-OH kinase. Nature 387: 673-676, 1997

    Google Scholar 

  64. Harris CC: p53 Tumor suppressor gene: From the basic research laboratory to the clinic — an abridged historical perspective. Carcinogenesis 17: 1187-1198, 1996

    Google Scholar 

  65. Wu X, Senechal K, Neshat MS, Whang YE, Sawyers CL: The PTEN/MMAC1 tumor suppressor phosphatase functions as a negative regulator of the phosphoinositide 3-kinase/Akt pathway [In Process Citation]. Proc Natl Acad Sci USA 95: 15587-15591, 1998

    Google Scholar 

  66. Hawkins DS, Demers GW, Galloway DA: Inactivation of p53 enhances sensitivity to multiple chemotherapeutic agents. Cancer Res 56: 892-898, 1996.

    Google Scholar 

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Wu, RC., Li, X. & Schönthal, A. Transcriptional activation of p21WAF1by PTEN/MMAC1 tumr suppressor. Mol Cell Biochem 203, 59–71 (2000). https://doi.org/10.1023/A:1007024624967

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