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Myc and Ras collaborate in inducing accumulation of active cyclin E/Cdk2 and E2F

An Erratum to this article was published on 26 June 1997

Abstract

Considerable evidence points to a role for Gl cyclin-dependent kinase (CDK) in allowing the accumulation of E2F transcription factor activity and induction of the S phase of the cell cycle1,2. Numerous experiments have also demonstrated a critical role for both Myc and Ras activities in allowing cell-cycle progression3. Here we show that inhibition of Ras activity blocks the normal growth-dependent activation of G1 CDK, prevents activation of the target genes of E2F, and results in cell-cycle arrest in G1. We also show that Ras is essential for entry into the S phase in Rb+/+fibroblasts but not in Rb-/- fibroblasts, establishing a link between Ras and the G1 CDK/Rb/E2F pathway. However, although expression of Ras alone will not induce G1 CDK activity or S phase, coexpression of Ras with Myc allows the generation of cyclin E-dependent kinase activity and the induction of S phase, coincident with the loss of the p27 cyclin-dependent kinase inhibitor (CKI). These results suggest that Ras, along with the activation of additional pathways, is required for the generation of G1 CDK activity, and that activation of cyclin E-dependent kinase in particular depends on the cooperative action of Ras and Myc.

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References

  1. Weinberg, R. A. The retinoblastoma protein and cell cycle control. Cell 81, 323–330 (1995).

    Article  CAS  Google Scholar 

  2. Sherr, C. J. & Roberts, J. M. Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev. 9, 1149–1163 (1995).

    Article  CAS  Google Scholar 

  3. Eisenman, R. N. & Cooper, J. A. Signal transduction: Beating a path to Myc. Nature 378, 438–439 (1995).

    Article  ADS  CAS  Google Scholar 

  4. Mulcahy, L. S., Smith, M. R. & Stacey, D. W. Requirement for ras proto-oncogene function during serum-stimulated growth of NIH 3T3 cells. Nature 313, 241–243 (1985).

    Article  ADS  CAS  Google Scholar 

  5. Lowry, D. R. & Willumsen, B. M. Function and regulation of ras. Annu. Rev. Biochem. 62, 851–891 (1993).

    Article  Google Scholar 

  6. Feig, L. A. & Cooper, G. M. Inhibition of NIH 3T3 cell proliferation by a mutant ras protein with preferential affinity for GDP. Mol. Cell. Biol. 8, 3235–3243 (1988).

    Article  CAS  Google Scholar 

  7. Land, H., Parada, L. F. & Weinberg, R. A. Tumorigenic conversion of primary embryo fibroblasts requires at least two cooperating oncogenes. Nature 304, 596–602 (1982).

    Article  ADS  Google Scholar 

  8. Kohl, N. E. & Ruley, H. E. Role of c-myc in the transformation of REF52 cells by viral and cellular oncogenes. Oncogene 2, 41–48 (1987).

    CAS  PubMed  Google Scholar 

  9. Leone, G., DeGregori, J., Jakoi, L. & Nevins, J. R. Collaboration of E2F and cyclin E/cdk2 in the induction of S phase. Proc. Natl Acad. Sci. USA (submitted).

  10. Hatekeyama, M., Brill, J. A., Fink, G. R. & Weinberg, R. A. Collaboration of G1 cyclins in the functional inactivation of the retinoblastoma protein. Genes Dev. 8, 1759–1771 (1994).

    Article  Google Scholar 

  11. Resnitzky, D. & Reed, S. I. Different roles for cyclins D1 and E in regulation of the G1-to-S transition. Mol. Cell. Biol. 15, 3463–3469 (1995).

    Article  CAS  Google Scholar 

  12. Galaktionov, K., Chen, X. & Beach, D. Cdc25 cell-cycle phosphatase as a target of c-myc. Nature 382, 511–517 (1996).

    Article  ADS  CAS  Google Scholar 

  13. Duronio, R. J., O'Farrell, P. H., Xie, J.-E., Brook, A. & Dyson, N. The transcription factor E2F is required for S phase during Drosophila embryogenesis. Genes Dev. 9, 1445–1455 (1995).

    Article  CAS  Google Scholar 

  14. Duronio, R. J., Brook, A., Dyson, N. & O'Farrell, P. H. E2F-induced S phase requires cyclin E. Genes Dev. 10, 2505–2513 (1996).

    Article  CAS  Google Scholar 

  15. Steiner, P. et al. Identification of a Myc-dependent step during the formation of active G1 cyclin-cdk complexes. EMBO J. 14, 4814–4826 (1995).

    Article  CAS  Google Scholar 

  16. Coats, S., Flanagan, W. M., Nourse, J. & Roberts, J. M. Requirement of p27Kipl for restriction point control of the fibroblast cell cycle. Science 272, 877–880 (1996).

    Article  ADS  CAS  Google Scholar 

  17. Nourse, J. et al. Interleukin-2-mediated elimination of the p27Kipl cyclin-dependent kinase inhibitor prevented by rapamycin. Nature 372, 570–573 (1994).

    Article  ADS  CAS  Google Scholar 

  18. Galaktionov, K., Jessus, C. & Beach, D. Rafl interaction with Cdc25 phosphatase ties mitogenic signal transduction to cell cycle activation. Genes Dev. 9, 1046–1058 (1995).

    Article  CAS  Google Scholar 

  19. Nevins, J. R., DeGregori, J., Jakoi, L. & Leone, G. Functional analysis of E2F. Methods Enzymol. (in the press).

  20. DeGregori, J., Kowalik, T. & Nevins, J. R. Cellular targets for activation by the E2F1 transcription factor include DNA synthesis and G1/S regulatory cells. Mol. Cell. Biol. 15, 4215–4224 (1995).

    Article  CAS  Google Scholar 

  21. Schwarz, J. K. et al. Expression of the E2F1 transcription factor overcomes type β transforming growth factor-mediated growth suppression. Proc. Natl Acad. Sci. USA 92, 483–487 (1995).

    Article  ADS  CAS  Google Scholar 

  22. Farnsworth, C. L. & Reig, L. A. Dominant inhibitory mutations in the Mg2+-binding site of RasH prevent its activation by GTP. Mol. Cell. Biol. 11, 4822–4829 (1991).

    Article  CAS  Google Scholar 

  23. Khosravi-Far, R., Solski, P. A., Clark, G. J., Kinch, M. S. & Der, C. J. Activation of Racl, RhoA, and mitogen-activated protein kinases is required for Ras transformation. Mol. Cell. Biol. 15, 6443–6453 (1995).

    Article  CAS  Google Scholar 

  24. Ikeda, M.-A., Jakoi, L. & Nevins, J. R. A unique role for the Rb protein in controlling E2F accumulation during cell growth and differentiation. Proc. Natl Acad. Sci. USA 93, 3215–3220 (1996).

    Article  ADS  CAS  Google Scholar 

  25. Jacks, T. et al. Effects of an Rb mutation in the mousse. Nature 359, 295–300 (1992).

    Article  ADS  CAS  Google Scholar 

  26. Smith, E. J., Leone, G., DeGregori, J., Jakoi, L. & Nevins, J. R. The accumulation of an E2F-p130 transcriptional represser distinguishes a GO from a Gl cell state. Mol. Cell. Biol. 16, 6965–6976 (1996).

    Article  CAS  Google Scholar 

  27. DeGregori, J., Leone, G., Ohtani, K., Miron, A. & Nevins, J. R. E2F1 accumulation bypasses a G1 arrest resulting from the inhibition of G1 cyclin-dependent kinase activity. Genes Dev. 9, 2873–2887 (1995).

    Article  CAS  Google Scholar 

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Leone, G., DeGregori, J., Sears, R. et al. Myc and Ras collaborate in inducing accumulation of active cyclin E/Cdk2 and E2F. Nature 387, 422–426 (1997). https://doi.org/10.1038/387422a0

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