Inactivating E2f1 reverts apoptosis resistance and cancer sensitivity in Trp53-deficient mice.
The E2f1 transcription factor, which regulates genes required for S-phase entry, also induces apoptosis by transcriptional and post-translational mechanisms. As E2f1 is inducible by DNA damage we investigated its importance in vivo in ultraviolet (UV)-induced apoptosis, a protective mechanism that prevents the epidermis from accumulating UV-induced mutations. 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 -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.
Wikonkal
Norbert M
NM
Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520 USA.
Remenyik
Eva
E
Knezevic
Dejan
D
Zhang
Wengeng
W
Liu
Ming
M
Zhao
Hongyu
H
Berton
T R
TR
Johnson
David G
DG
Brash
Douglas E
DE
D000818:Animals; D017209:Apoptosis / Q000235:genetics* / Q000528:radiation effects; D018797:Cell Cycle Proteins; D002470:Cell Survival / Q000235:genetics* / Q000528:radiation effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D004249:DNA Damage / Q000235:genetics / Q000528:radiation effects; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D016153:Genes, Suppressor / Q000502:physiology*; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics / Q000528:radiation effects; D012744:Sex Ratio; D012878:Skin Neoplasms / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics; D014466:Ultraviolet Rays / Q000009:adverse effects
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53