Abstract
D-TYPE cyclins, in association with the cyclin-dependent kinases Cdk4 or Cdk6, promote progression through the Gl phase of the cell cycle1–6 by phosphorylating the retinoblastoma protein (RB)7,8. The activities of Cdk4 and Cdk6 are constrained by inhibitors9–12 such as pi6, the product of the CDKN2 gene on human chromosome 9p21 (refs 12–14). The frequent deletion or mutation of CDKN2 in tumour cells suggests that pi6 acts as a tumour suppressor. We show that wild-type pi6 arrests normal diploid cells in late Gl, whereas a tumour-associated mutant of pi6 does not. Significantly, the ability of pi6 to induce cell-cycle arrest is lost in cells lacking functional RB, including primary fibroblasts from Rb-/- mouse embryos. Thus, loss of pi6, overexpression of D-cyclins and loss of RB have similar effects on Gl progression, and may represent a common pathway to tumorigenesis.
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References
Baldin, V., Lukas, J., Marcotte, M. J., Pagano, M. & Draetta, G. Genes Dev. 7, 812–821 (1993).
Jiang, W. et al. Oncogene 8, 3447–3457 (1993).
Quelle, D. E. et al. Genes Dev. 7, 1559–1571 (1993).
Lukas, J., Pagano, M., Staskova, Z., Draetta, G. & Bartek, J. Oncogene 9, 707–718 (1994).
Musgrove, E. A., Lee, C. S. L., Buckley, M. F. & Sutherland, R. L. Proc. natn. Acad. Sci. U.S.A. 91, 8022–8026 (1994).
Resnitzky, D., Gossen, M., Bujard, H. & Reed, S. I. Molec. cell. Biol. 14, 1669–1679 (1994).
Hunter, T. & Pines, J. Cell 79, 573–582 (1994).
Sherr, C. J. Cell 79, 551–555 (1994).
Guan, K.-L. et al. Genes Dev. 8, 2939–2952 (1994).
Hannon, G. J. & Beach, D. Nature 371, 257–261 (1994).
Jen, J. et al. Cancer Res. 54, 6353–6358 (1994).
Serrano, M., Hannon, G. J. & Beach, D. Nature 366, 704–707 (1993).
Kamb, A. et al. Science 264, 436–440 (1994).
Nobori, T. et al. Nature 368, 753–756 (1994).
Okamoto, A. et al. Proc. natn. Acad. Sci. U.S.A. 91, 11045–11049 (1994).
Li, Y., Nichols, M. A., Shay, J. W. & Xiong, Y. Cancer Res. 54, 6078–6082 (1994).
Otterson, G. A., Kratzke, R. A., Coxon, A., Kim, Y. W. & Kaye, F. J. Oncogene 9, 3375–3378 (1994).
Tam, S. W. Shay, J. W. & Pagano, M. Cancer Res. 54, 5816–5820 (1994).
Parry, D., Bates, S., Mann, D. J. & Peters, G. EMBO J. 14, 503–511 (1995).
Ohta, M. et al. Cancer Res. 54, 5269–5272 (1994).
Kato, J., Matsushime, H., Hiebert, S. W., Ewen, M. E. & Sherr, C. J. Genes Dev. 7, 331–342 (1993).
Lukas, J. et al. J. Cell Biol. 125, 625–638 (1994).
Serrano, M., Gómez-Lahoz, E., DePinho, R. A., Beach, D. & Bar-Sagi, D. Science 267, 249–252 (1995).
Lukas, J. et al. Oncogene (in the press).
van den Heuvel, S. & Harlow, E. Science 262, 2050–2054 (1993).
Clarke, A. R. et al. Nature 359, 328–330 (1992).
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Lukas, J., Parry, D., Aagaard, L. et al. Retinoblastoma-protein-dependent cell-cycle inhibition by the tumour suppressor p16. Nature 375, 503–506 (1995). https://doi.org/10.1038/375503a0
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DOI: https://doi.org/10.1038/375503a0
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