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PTEN tumour suppressor is linked to the cell cycle control through the retinoblastoma protein

Oncogene volume 18, pages 7462–7468 (1999)Cite this article

Abstract

The tumour suppressor PTEN, also named MMAC1 or TEP1, is associated with a number of malignancies in human populations. This protein has a dual protein phosphatase activity, being also capable to dephosphorylate phosphatidylinositol 3,4,5 triphosphate. We have studied the mechanism of growth suppression attributable to PTEN. We observed that PTEN overexpression inhibits cell growth in a variety of normal and transformed, human and murine cells. Bromodeoxyuridine (BrdU) incorporation and TUNEL labelling experiments in transiently transfected cells demonstrate that this inhibition is due to a cell cycle arrest rather than induction of apoptosis. Given that PTEN is unable to cause cell growth arrest in retinoblastoma (Rb)-deficient cell lines, we have explored the possible requirement for pRb in the PTEN-induced inhibition of cell proliferation. We found that the co-expression of SV40 antigen, but not a mutant form (which binds exclusively to p53), and cyclin D1/cdk4 are able to overcome the PTEN-mediated growth suppression. In addition, the reintroduction of a functional pRb, but not its relatives p107 or p130, in Rb-deficient cells restores the sensitivity to PTEN-induced arrest. Finally, the hyperphosphorylation of transfected pRb is inhibited by PTEN co-expression and restored by PI-3K co-expression. Accordingly, PTEN gene is mostly expressed, in parallel to Akt, in mid-late G1 phase during cell cycle progression prior to pRb hyperphosphorylation. Finally, we have studied the signal transduction pathways modulated by PTEN expression. We found that PTEN-induced growth arrest can be rescued by the co-expression of active PI-3K and downstream effectors such as Akt or PDK1, and also certain small GTPases such as Rac1 and Cdc42, but not by active Ha-ras, raf or RhoA. Collectively, our data link the tumour suppressor activities of PTEN to the machinery controlling cell cycle through the modulation of signalling molecules whose final target is the functional inactivation of the retinoblastoma gene product.

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References

  • Alessi DR, Kozlowski MT, Weng Q-P, Morrice N and Avruch J . (1997). Curr. Biol. 8: 69–81.

  • Berra E, Diaz-Meco MT, Lozano J, Frutos S, Municio MM, Sanchez P, Sanz L and Moscat J. . 1995 EMBO J. 14: 6157–6163.

  • Burgering BM and Coffer PJ. . 1995 Nature 376: 599–602.

  • Cai H, Smola U, Wixler V, EisenmannTappe I, Diaz-Meco MT, Moscat J, Rapp U and Cooper GM. . 1997 Mol. Cell Biol. 17: 732–741.

  • Chou MM and Blenis J. . 1996 Cell 85: 573–583.

  • Di Cristofano A, Pesce B, Cordon-Cardo C and Pandolfi PP. . 1998 Nat. Genet. 19: 348–355.

  • Fahraeus R, Paramio JM, Ball KL, Lain S and Lane DP. . 1996 Curr. Biol. 6: 84–91.

  • Furnari FB, Huang H-JS and Cavenee WK. . 1998 Cancer Res. 58: 5002–5008.

  • Furnari FB, Lin H, Huang HS and Cavenee WK. . 1997 Proc. Natl. Acad. Sci. USA 94: 12479–12484.

  • Geng Y and Weinberg RA. . 1993 Proc. Natl. Acad. Sci. USA 90: 10315–10319.

  • Gu J, Tamura M and Yamada KM. . 1998 J. Cell. Biol. 143: 1375–1383.

  • Haas-Kogan D, Shalev N, Wong M, Mills G, Young G and Stokoe D. . 1998 Curr. Biol. 8: 1195–1198.

  • Hashemolhosseini S, Nagamine Y, Morley SJ, Desrivieres S, Mercep L and Ferrari S. . 1998 J. Biol. Chem. 273: 14424–14429.

  • Hinds PW, Mittnacht S, Dulic S, Arnold A, Reed SI and Weinberg RA. . 1992 Cell 70: 993–1006.

  • Keely PJ, Westwick JK, Whitehead IP, Der CJ and Parise LV. . 1997 Nature 390: 632–636.

  • Klippel A, Escobedo MA, Wachowicz MS, Apell G, Brown TW, Giedlin MA, Kavanaugh WM and Williams LT. . 1998 Mol. Cell. Biol. 18: 5699–5711.

  • Klippel A, Reinhard C, Kavanaugh WM, Apell G, Escobedo MA and Williams LT. . 1996 Mol. Cell Biol. 16: 4117–4127.

  • Li D-M and Sun H. . 1998 Proc. Natl. Acad. Sci. USA 95: 15406–15411.

  • Li J, Simpson L, Takahashi M, Miliaresis C, Myers MP, Tonks N and Parsons R. . 1998 Cancer Res. 58: 5667–5672.

  • Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Giovanella BC, Ittman M, Tycko B, Hibshoosh H, Wigler MH and Parsons R. . 1997 Science 275: 1943–1947.

  • Lukas J, Müller H, Bartkova J, Spitovsky D, Kjerulff AA, Jansen-Dürr P, Strauss M and Bartek J. . 1994 J. Cell. Biol. 125: 625–638.

  • Maehama T and Dixon JE. . 1998 J. Biol. Chem. 273: 13375–13378.

  • Myers MP, Stolarov JP, Eng C, Li J, Wang SI, Wigler MH, Parsons R and Tonks NK. . 1997 Proc. Natl. Acad. Sci. USA 94: 9052–9057.

  • Olson MF, Ashworth A and Hall A. . 1995 Science 269: 1270–1272.

  • Olson MF, Paterson HF and Marshall CJ. . 1998 Nature 394: 295–299.

  • Paramio JM, Casanova MLI, Segrelles C, Mittnacht S, Lane EB and Jorcano JL. . 1999 Mol. Cell Biol. 19: 3086–3094.

  • Paramio JM, Laín S, Segrelles C, Lane EB and Jorcano JL. . 1998 Oncogene 17: 949–958.

  • Pearson RB and Thomas G. . 1995 Prog. Cell Cycle Res. 1: 21–32.

  • Picksley SM and Lane DP. . 1994 Curr. Opin. Cell. Biol. 6: 853–858.

  • Prennan P, Babbage JW, Burgering BMT, Groner B, Reif K and Cantrell DA. . 1997 Immunity 7: 679–689.

  • Roche S, Koegl M and Courtneidge SA. . 1994 Proc. Natl. Acad. Sci. USA 91: 9185–9189.

  • Rodriguez-Viciana P, Warne PH, Vanhasebroeck B, Waterfield MD and Downward J. . 1996 EMBO J. 15: 2442–2451.

  • Scheffner M, Münger K, Byrne JC and Howley PM. . (1991) Proc. Natl. Acad. Sci. USA 88: 5523–5527.

  • Stambolic V, Suzuki A, de la Pompa JL, Brothers GM, Mirtsos C, Sasaki T, Ruland J, Penninger J, Siderovski DP and Mak TW. . 1998 Cell 95: 29–39.

  • Steck PA, Pershouse MA, Jasser SA, Yung WK, Lin H, Ligon AH, Langford LA, Baumgard ML, Hattier T and Davis T, Frye C, Hu R, Swedlund B, Teng DH and Tavtigian SV. . 1997 Nat. Genet. 15: 356–362.

  • Suzuki A, de la Pompa JL, Stambolic V, Elia AJ, Sasaki T, del Barco Barrantes I, Ho A, Wakeman A, Itie A, Khoo W, Fukumoto M and Mak TW. . 1998 Curr. Biol. 8: 1169–1178.

  • Takuwa N, Fukui Y and Takuwa Y. . 1999 Mol. Cell Biol. 19: 1346–1358.

  • Tamura M, Gu J, Matsumoto K, Aota S-I, Parsons R and Yamada KM. . 1998 Science 280: 1614–1617.

  • Tolias KF, Cantley LC and Carpenter CL. . 1995 J. Biol. Chem. 270: 17656–17659.

  • Weinberg RA. . 1995 Cell 81: 323–330.

  • Wu X, Senechal K, Neshat MS, Whang YE and Sawyers CL. . 1998 Proc. Natl. Acad. Sci. USA 95: 15587–15591.

  • Zheng Y, Bagrodia S and Cerione RA. . 1994 J. Biol. Chem. 269: 18727–18730.

  • Zhu L, Enders G, Lees JA, Beijersbergen RL, Bernards R and Harlow E. . 1995 EMBO J. 14: 1904–1913.

  • Zhu L, van der Heuvel S, Helin K, Fattay A, Ewen M, Livingston D, Dyson N and Harlow E. . 1993 Genes Dev. 7: 1111–1125.

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Acknowledgements

We want to express our acknowledgement to JC Lacal, J Downward, K Anderson, DP Lane and J Moscat for their generous gift of materials used in these studies. Technical support by P Hernández is also acknowledged. This work was supported by grants SAF98-0047 from CICYT (Spain) and PB94-1230 from CICYT (Spain).

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  1. Cell and Molecular Biology Department, CIEMAT, Avenue Complutense 22, Madrid, E-28040, Spain

    Jesús M Paramio, Manuel Navarro, Carmen Segrelles, Elena Gómez-Casero & José L Jorcano

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  1. Jesús M Paramio
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Paramio, J., Navarro, M., Segrelles, C. et al. PTEN tumour suppressor is linked to the cell cycle control through the retinoblastoma protein. Oncogene 18, 7462–7468 (1999). https://doi.org/10.1038/sj.onc.1203151

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