Inactivating E2f1 reverts apoptosis resistance and cancer sensitivity in Trp53-deficient mice

N. Wikonkál, E. Remenyik, Dejan Knezevic, Wengeng Zhang, Ming Liu, Hongyu Zhao, T. R. Berton, David G. Johnson, Douglas E. Brash

Research output: Contribution to journalArticle

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Abstract

The E2f1 transcription factor, which regulates genes required for S-phase entry1-4, also induces apoptosis by transcriptional and post-translational mechanisms5-8. As E2f1 is inducible by DNA damage9,10 we investigated its importance in vivo in ultraviolet (UV)-induced apoptosis, a protective mechanism that prevents the epidermis from accumulating UV-induced mutations 11,12. Contrary to expectation, E2f1-/- mice demonstrated enhanced keratinocyte apoptosis after UVB exposure, whereas apoptosis was suppressed by epidermis-specific overexpression of human E2F1. Apoptosis induced by γ-radiation was also repressed by E2f1. E2f1-/-; Trp53-/- double knockout mice exhibited the elevated UVB-induced apoptosis of E2f1-/- alone, rather than the profound apoptosis defect seen in Trp53-/- mice, indicating that Trp53 (p53) lies functionally upstream of E2f1. Transfecting E2F1 into E2F1-/- ;Trp53-/- primary fibroblasts suppressed UVB-induced apoptosis and this suppression was relieved by Trp53. The double knockout also reverted the abnormal sex ratio and early-onset tumours of Trp53-/- mice. These results imply that E2f1 functions as a suppressor of an apoptosis pathway that is initiated by DNA photoproducts and perhaps genetic abnormalities; p53 relieves this suppression.

Original languageEnglish
Pages (from-to)655-660
Number of pages6
JournalNature Cell Biology
Volume5
Issue number7
DOIs
Publication statusPublished - Jul 1 2003

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Apoptosis
Neoplasms
Epidermis
E2F1 Transcription Factor
DNA
Sex Ratio
S Phase
Keratinocytes
Knockout Mice
Fibroblasts
Radiation
Mutation
Genes

ASJC Scopus subject areas

  • Cell Biology

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Inactivating E2f1 reverts apoptosis resistance and cancer sensitivity in Trp53-deficient mice. / Wikonkál, N.; Remenyik, E.; Knezevic, Dejan; Zhang, Wengeng; Liu, Ming; Zhao, Hongyu; Berton, T. R.; Johnson, David G.; Brash, Douglas E.

In: Nature Cell Biology, Vol. 5, No. 7, 01.07.2003, p. 655-660.

Research output: Contribution to journalArticle

Wikonkál, N, Remenyik, E, Knezevic, D, Zhang, W, Liu, M, Zhao, H, Berton, TR, Johnson, DG & Brash, DE 2003, 'Inactivating E2f1 reverts apoptosis resistance and cancer sensitivity in Trp53-deficient mice', Nature Cell Biology, vol. 5, no. 7, pp. 655-660. https://doi.org/10.1038/ncb1001
Wikonkál, N. ; Remenyik, E. ; Knezevic, Dejan ; Zhang, Wengeng ; Liu, Ming ; Zhao, Hongyu ; Berton, T. R. ; Johnson, David G. ; Brash, Douglas E. / Inactivating E2f1 reverts apoptosis resistance and cancer sensitivity in Trp53-deficient mice. In: Nature Cell Biology. 2003 ; Vol. 5, No. 7. pp. 655-660.
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