Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Suppression of the p53- or pRB-mediated G1 checkpoint is required for E2F-induced S-phase entry

Nature Genetics volume 31, pages 190–194 (2002)Cite this article

Abstract

Deregulation of the retinoblastoma protein (pRB) pathway is a hallmark of cancer1. In the absence of other genetic alterations, this deregulation results in lack of differentiation, hyperproliferation and apoptosis2. The pRB protein acts as a transcriptional repressor by targeting the E2F transcription factors, whose functions are required for entry into S phase3,4. Increased E2F activity can induce S phase in quiescent cells—this is a central element of most models for the development of cancer1,3,4. We show that although E2F1 alone is not sufficient to induce S phase in diploid mouse and human fibroblasts, increased E2F1 activity can result in S-phase entry in diploid fibroblasts in which the p53-mediated G1 checkpoint is suppressed. In addition, we show that E2F1 can induce S phase in primary mouse fibroblasts lacking pRB. These results indicate that, in addition to acting as an E2F-dependent transcriptional repressor, pRB is also required for the cells to retain the G1 checkpoint in response to unprogrammed proliferative signals.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: E2F1 is not sufficient to induce S phase in diploid fibroblasts.
Figure 2: Activation of E2F1 results in increased expression of p14ARF, p53 and p21.
Figure 3: Loss of function in the ARF-MDM2-p53 pathway allows E2F1-induced S phase.
Figure 4: Loss of p21 or pRB is required for E2F1-induced S phase.
Figure 5: Model for the regulation of cell proliferation by the pRB pathway.

Similar content being viewed by others

References

  1. Hanahan, D. & Weinberg, R.A. The hallmarks of cancer. Cell 100, 57–70 (2000).

    Article  CAS  Google Scholar 

  2. Lipinski, M.M. & Jacks, T. The retinoblastoma gene family in differentiation and development. Oncogene 18, 7873–7882 (1999).

    Article  CAS  Google Scholar 

  3. Dyson, N. The regulation of E2F by pRB-family proteins. Genes Dev. 12, 2245–2262 (1998).

    Article  CAS  Google Scholar 

  4. Harbour, J.W. & Dean, D.C. The Rb/E2F pathway: expanding roles and emerging paradigms. Genes Dev. 14, 2393–2409 (2000).

    Article  CAS  Google Scholar 

  5. Johnson, D.G., Schwarz, J.K., Cress, W.D. & Nevins, J.R. Expression of transcription factor E2F1 induces quiescent cells to enter S phase. Nature 365, 349–352 (1993).

    Article  CAS  Google Scholar 

  6. Qin, X.-Q., Livingston, D.M., Kaelin, W.G. & Adams, P. Deregulated E2F1 expression leads to S-phase entry and p53-mediated apoptosis. Proc. Natl Acad. Sci. USA 91, 10918–10922 (1994).

    Article  CAS  Google Scholar 

  7. Shan, B. & Lee, W.-H. Deregulated expression of E2F-1 induces S-phase entry and leads to apoptosis. Mol. Cell. Biol. 14, 8166–8173 (1994).

    Article  CAS  Google Scholar 

  8. Dimri, G.P., Hara, E. & Campisi, J. Regulation of two E2F-related genes in presenescent and senescent human fibroblasts. J. Biol. Chem. 296, 16180–16186 (1994).

    Google Scholar 

  9. Lukas, J., Petersen, B.O., Holm, K., Bartek, J. & Helin, K. Deregulated expression of E2F family members induces S-phase entry and overcomes p16INK4A-mediated growth suppression. Mol. Cell. Biol. 16, 1047–1057 (1996).

    Article  CAS  Google Scholar 

  10. Quinlan, M.P., Sullivan, N. & Grodzicker, T. Growth factor(s) produced during infection with an adenovirus variant stimulates proliferation of nonestablished epithelial cells. Proc. Natl Acad. Sci. USA 84, 3283–3287 (1987).

    Article  CAS  Google Scholar 

  11. Zerler, B., Roberts, R.J., Mathews, M.B. & Moran, E. Different functional domains of the adenovirus E1A gene are involved in regulation of host cell cycle products. Mol. Cell. Biol. 7, 821–829 (1987).

    Article  CAS  Google Scholar 

  12. Vigo, E. et al. CDC25A phosphatase is a target of E2F and is required for efficient E2F-1 induced S phase. Mol. Cell. Biol. 19, 6379–6395 (1999).

    Article  CAS  Google Scholar 

  13. Moroni, M.C. et al. APAF-1 is a transcriptional target for E2F and p53. Nature Cell Biol. 3, 552–558 (2001).

    Article  CAS  Google Scholar 

  14. Müller, H. et al. E2Fs regulate the expression of genes involved in differentiation, development, proliferation and apoptosis. Genes Dev. 15, 267–285 (2001).

    Article  Google Scholar 

  15. Sherr, C.J. Tumor surveillance via the ARF-p53 pathway. Genes Dev. 12, 2984–2991 (1998).

    Article  CAS  Google Scholar 

  16. Jacobs, J.J.L., Kieboom, K., Marino, S., DePinho, R.A. & van Lohuizen, M. The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature 397, 164–168 (1999).

    Article  CAS  Google Scholar 

  17. Vogelstein, B., Lane, D. & Levine, A.J. Surfing the p53 network. Nature 408, 307–310 (2000).

    Article  CAS  Google Scholar 

  18. Mann, D.J. & Jones, N.C. E2F-1 but not E2F-4 can overcome a p16-induced G1 cell-cycle arrest. Curr. Biol. 6, 474–483 (1996).

    Article  CAS  Google Scholar 

  19. Macleod, K.F., Hu, Y. & Jacks, T. Loss of Rb activates both p53-dependent and independent cell death pathways in the developing mouse nervous system. EMBO J. 15, 6178–6188 (1996).

    Article  CAS  Google Scholar 

  20. Harrington, E.A., Bruce, J.L., Harlow, E. & Dyson, N. pRB plays an essential role in cell cycle arrest induced by DNA damage. Proc. Natl Acad. Sci. USA 95, 11945–11950 (1998).

    Article  CAS  Google Scholar 

  21. Brugaloras, J. et al. Inhibition of cyclin-dependent kinase 2 by p21 is necessary for retinoblastoma protein-mediated G1 arrest after γ-irradiation. Proc. Natl Acad. Sci. USA 96, 1002–1007 (1999).

    Article  Google Scholar 

  22. Lasorella, A., Noseda, M., Beyna, M., Yokota, Y. & Iavarone, A. Id2 is a retinoblastoma protein target and mediates signalling by Myc oncoproteins. Nature 407, 592–598 (2000).

    Article  CAS  Google Scholar 

  23. Helin, K., Harlow, E. & Fattaey, A.R. Inhibition of E2F-1 transactivation by direct binding of the retinoblastoma protein. Mol. Cell. Biol. 13, 6501–6508 (1993).

    Article  CAS  Google Scholar 

  24. Helin, K. & Harlow, E. Heterodimerization of the transcription factors E2F-1 and DP-1 is required for binding to the adenovirus E4 (ORF6/7) protein. J. Virol. 68, 5027–5035 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Fattaey, A.R., Harlow, E. & Helin, K. Independent regions of adenovirus E1A are required for binding to and dissociation of E2F-protein complexes. Mol. Cell. Biol. 13, 7267–7277 (1993).

    Article  CAS  Google Scholar 

  26. Kamijo, T. et al. Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF. Cell 91, 649–659 (1997).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  28. Jacks, T. et al. Tumor spectrum analysis in p53-mutant mice. Curr. Biol. 4, 1–7 (1994).

    Article  CAS  Google Scholar 

  29. Brugarolas, J. et al. Radiation-induced cell cycle arrest compromised by p21 deficiency. Nature 377, 552–557 (1995).

    Article  CAS  Google Scholar 

  30. Helin, K. et al. Heterodimerization of the transcription factors E2F-1 and DP-1 leads to cooperative transactivation. Genes Dev. 7, 1850–1861 (1993).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank A. Fattaey, P.G. Pelicci, G. Peters, N. Dyson and members of the Helin laboratory for discussions, and C. Attwooll, A. Fattaey and N.H. Heintz for comments on the manuscript. M.R.J. was supported by a Marie Curie fellowship from the European Union. This work was supported by grants from the Associazione Italiana per la Ricerca sul Cancro, the Fondazione Italiana per la Ricerca sul Cancro, The Italian Health Ministry and the Human Frontiers Science Program.

Author information

Authors and Affiliations

  1. Department of Experimental Oncology, European Institute of Oncology, Via Ripamonti 435, Milan, 20141, Italy

    Marina Lomazzi, M. Cristina Moroni, Michael R. Jensen, Emanuela Frittoli & Kristian Helin

  2. The FIRC Institute for Molecular Oncology, Milan, Italy

    Michael R. Jensen & Kristian Helin

Authors
  1. Marina Lomazzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. Cristina Moroni
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael R. Jensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Emanuela Frittoli
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kristian Helin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kristian Helin.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lomazzi, M., Moroni, M., Jensen, M. et al. Suppression of the p53- or pRB-mediated G1 checkpoint is required for E2F-induced S-phase entry. Nat Genet 31, 190–194 (2002). https://doi.org/10.1038/ng891

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng891

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing