Letter | Published:

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

Nature Genetics volume 18, pages 360364 (1998) | Download Citation

Subjects

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    , & The retinoblastoma protein: more than a tumor suppressor. Annual Rev. Cell Biol. 10, 1–29 (1994).

  2. 2.

    & Transcriptional regulation by the Retinoblastoma (Rb) protein. Mol. Cell. Differ. 3, 275–314 (1995).

  3. 3.

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

  4. 4.

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

  5. 5.

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

  6. 6.

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

  7. 7.

    , , & Effects of heterozygosity for the Rb-1t19neo allele in the mouse. Oncogene 10, 1615–1620 (1995).

  8. 8.

    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).

  9. 9.

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

  10. 10.

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

  11. 11.

    Cancer cell cycles. Science 274, 1672–1677 (1996).

  12. 12.

    , , & Expression of transcription factor E2F1 induces quiescent cells to enter S phase. Nature 365, 349–352 (1993).

  13. 13.

    , , & Deregulated transcription factor E2F-1 expression leads to S-phase entry and p53-mediated apoptosis. Proc. Natl. Acad. Sci. USA 91, 10918–10922 (1994).

  14. 14.

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

  15. 15.

    , , & E2F1 overexpression in quiescent fibroblasts leads to induction of cellular DNA synthesis and apoptosis. J. Virol. 69, 2491–2500 (1995).

  16. 16.

    , , & Oncogenic capacity of the E2F1 gene. Proc. Natl. Acad. Sci. USA 91, 12823–12827 (1994).

  17. 17.

    , & Overexpression of E2F-1 in rat embryo f ibroblasts leads to neoplastic transformation. EMBO J. 13, 3329–3338 (1994).

  18. 18.

    , & Multiple members of the E2F transcription factor family are the products of oncogenes. Proc. Natl. Acad. Sci. USA 92, 1357–1361 (1995).

  19. 19.

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

  20. 20.

    , , , & 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).

  21. 21.

    , , , & Induction of DNA synthesis and apoptosis are separable functions of E2F-1. Genes Dev. 11, 1853–1863 (1997).

  22. 22.

    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).

  23. 23.

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

  24. 24.

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

  25. 25.

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

  26. 26.

    , & Loss of RB activates both p53-dependent and independent cell death pathways in the developing mouse nervous system. EMBO J. 15, 6178–6188 (1996).

  27. 27.

    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).

  28. 28.

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

Download references

Author information

Affiliations

  1. Massachusetts General Hospital Cancer Center, Bldg 149, 13th Street, Charlestown, Massachusetts 02129, USA.

    • Lili Yamasaki
    • , Nicholas J. Dyson
    •  & Ed Harlow
  2. USDA Human Nutrition Research Center on Aging, Department of Pathology, School of Veterinary Medicine, Tufts University, Boston, Massachusetts 02111, USA.

    • Roderick Bronson
  3. Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Center for Cancer Research, Cambridge, Massachusetts 02139, USA.

    • Bart O. Williams
    •  & Tyler Jacks
  4. Present address: Department of Biological Sciences, Columbia University, 1102 Fairchild Bldg, 1212 Amsterdam Avenue, New York, New York 10027, USA.

    • Lili Yamasaki

Authors

  1. Search for Lili Yamasaki in:

  2. Search for Roderick Bronson in:

  3. Search for Bart O. Williams in:

  4. Search for Nicholas J. Dyson in:

  5. Search for Ed Harlow in:

  6. Search for Tyler Jacks in:

Corresponding author

Correspondence to Lili Yamasaki.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ng0498-360

Further reading