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Loss of E2F-1 reduces tumorigenesis and extends the lifespan of Rb1(+/−) mice

Abstract

Mutation of the retinoblastoma tumour-suppressor gene (RB) leads to the deregulation of many proteins and transcription factors that interact with the retinoblastoma gene product (pRB), including members of the E2F transcription factor family1,2. As pRB is known to repress E2F transcriptional activity and overexpression of E2F is sufficient for cell cycle progression, it is thought that pRB suppresses growth in part by repressing E2F-mediated transcription3. Previously, we reported that loss of E2f1 in mice results in tissue-specific tumour induction and tissue atrophy4, demonstrating that E2F-1 normally controls growth both positively and negatively in a tissue-specific fashion4,5. To determine whether E2F-1 deregulation—as a result of loss of pRB—promotes proliferation in vivo, we have tested whether loss of E2f1 interferes with the pituitary and thyroid tumorigenesis that occurs in Rb1(+/−) mice6–9. We have found that loss of E2f1 reduces the frequency of pituitary and thyroid tumours, and greatly lengthens the lifespan of Rb1(+/−); E2f1(−/−) animals, demonstrating that E2F-1 is an important downstream target of pRB during tumorigenesis. Furthermore, loss of E2f1 reduces a previously reported strain-dependent difference in Rb1(+/−) lifespan9,10, suggesting that E2f1 or an E2F-1-regulated gene acts as a genetic modifier between the 129/Sv and C57BL/6 strains.

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References

  1. Riley, D.J., Lee, E.Y. & Lee, W.-H. The retinoblastoma protein: more than a tumor suppressor. Annual Rev. Cell Biol. 10, 1–29 (1994).

    Article  CAS  Google Scholar 

  2. Horowitz, J.M. & Udvadia, A.J. Transcriptional regulation by the Retinoblastoma (Rb) protein. Mol. Cell. Differ. 3, 275–314 (1995).

    CAS  Google Scholar 

  3. Slansky, J.E. & Farnham, P.J. Introduction to the E2F family: protein structure and gene regulation. Curr. Top. Microbiol. Immunol. 208, 1–30 (1996).

    CAS  PubMed  Google Scholar 

  4. Yamasaki, L. et al. Tumor induction and tissue atrophy in mice lacking E2F-1. Cell 85, 537–548 (1996).

    Article  CAS  PubMed  Google Scholar 

  5. Field, S.J. et al. E2F-1 functions in mice to promote apoptosis and suppress proliferation. Cell 85, 549–561 (1996).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  7. Harrison, D.J., Hooper, M.L., Armstrong, J.F. & Clarke, A.R. Effects of heterozygosity for the Rb-1t19neo allele in the mouse. Oncogene 10, 1615–1620 (1995).

    CAS  PubMed  Google Scholar 

  8. Hu, N. et al. Heterozygous Rb-1 delta 20/+mice are predisposed to tumors of the pituitary gland with a nearly complete penetrance. Oncogene 9, 1021–1027 (1994).

    CAS  PubMed  Google Scholar 

  9. Williams, B.O. et al. Cooperative tumorigenic effects of germline mutations in Rb and p53. Nature Genet. 7, 480–484 (1994).

    Article  CAS  PubMed  Google Scholar 

  10. Williams, B.O. et al. Extensive contribution of Rb-deficient cells to adult chimeric mice with limited histopathological consequences. EMBO J. 13, 4251–4259 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Sherr, C.J. Cancer cell cycles. Science 274, 1672–1677 (1996).

    Article  CAS  PubMed  Google Scholar 

  12. 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  PubMed  Google Scholar 

  13. Qin, X.-Q., Livingston, D.M., Kaelin, W.G.J. & Adams, P. Deregulated transcription factor E2F-1 expression leads to S-phase entry and p53-mediated apoptosis. Proc. Natl. Acad. Sci. USA 91, 10918–10922 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. 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  PubMed  PubMed Central  Google Scholar 

  15. Kowalik, T.F., DeGregori, J., Schwarz, J.K. & Nevins, J.R. E2F1 overexpression in quiescent fibroblasts leads to induction of cellular DNA synthesis and apoptosis. J. Virol. 69, 2491–2500 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Johnson, D.G., Cress, W.D., Jakoi, L. & Nevins, J.R. Oncogenic capacity of the E2F1 gene. Proc. Natl. Acad. Sci. USA 91, 12823–12827 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Singh, P., Wong, S.H. & Hong, W. Overexpression of E2F-1 in rat embryo f ibroblasts leads to neoplastic transformation. EMBO J. 13, 3329–3338 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Xu, G., Livingston, D.M. & Krek, W. Multiple members of the E2F transcription factor family are the products of oncogenes. Proc. Natl. Acad. Sci. USA 92, 1357–1361 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wu, X. & Levine, A.J. p53 and E2F-1 cooperate to mediate apoptosis. Proc. Natl. Acad. Sci. USA 91, 3602–3606 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Hsieh, J.-K., Fredersdorf, S., Kouzarides, T., Martin, K. & Lu, X. E2F1-induced apoptosis requires DNA binding but not transactivation and is inhibited by the retinoblastoma protein through direct interaction. Genes Dev. 11, 1840–1852 (1997).

    Article  CAS  PubMed  Google Scholar 

  21. Phillips, A.C., Bates, S., Ryan, K.M., Helin, K. & Vousden, K.H. Induction of DNA synthesis and apoptosis are separable functions of E2F-1. Genes Dev. 11, 1853–1863 (1997).

    Article  CAS  PubMed  Google Scholar 

  22. Nip, J. et al. E2F-1 cooperates with topoisomerase II inhibition and DNA damage to selectively augment p53-independent apoptosis. Mol. Cell. Biol. 17, 1049–1056 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Maandag, E.C.R. et al. Developmental rescue of an embryonic-lethal mutatuion in the retinoblastoma gene in chimeric mice. EMBO J. 13, 4260–4268 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Clarke, A.R. et al. Requirement for a functional Rb-1 gene in murine development. Nature 359, 328–330 (1992).

    Article  CAS  PubMed  Google Scholar 

  25. Lee, E.Y. et al. Mice deficient for Rb are nonviable and show defects in neurogenesis and haematopoiesis. Nature 359, 288–294 (1992).

    Article  CAS  PubMed  Google Scholar 

  26. 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  PubMed  PubMed Central  Google Scholar 

  27. Bronson, R.T. Rate of occurrence of lesions in 20 inbred and hybrid genotypes of rats and mice sacrificed at 6 month intervals during the first years of life. in Genetic Effects on Aging II (ed. Harrison, D.E.) 279–358 (Telford Press, Inc., Caldwell, New Jersey, 1990).

    Google Scholar 

  28. Simpson, E.M. et al. Genetic variation among 129 substrains and its importance for targeted mutagenesis in mice. Nature Genet. 16, 19–27 (1997).

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Lili Yamasaki.

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Yamasaki, L., Bronson, R., Williams, B. et al. Loss of E2F-1 reduces tumorigenesis and extends the lifespan of Rb1(+/−) mice. Nat Genet 18, 360–364 (1998). https://doi.org/10.1038/ng0498-360

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