A transcriptionally active pRb-E2F1-P/CAF signaling pathway is central to TGFβ-mediated apoptosis.
Transforming growth factor-β (TGFβ) modulates the expression of multiple apoptotic target genes; however, a common and central signaling pathway, acting downstream of TGFβ and leading to cell death, has yet to be uncovered. Here, we show that TGFβ-induced apoptosis in cancer cells requires the transcription factor E2F1 (E2 promoter-binding factor 1). Using the E2F1 knockout mouse model, we also found E2F1 to be required for TGFβ-mediated apoptosis in normal cells. Moreover, we found TGFβ to increase E2F1 protein stability, acting at the post-translational level. We further investigated the molecular mechanisms by which E2F1 contributes to TGFβ-mediated apoptosis and found that TGFβ treatment led to the formation of a transcriptionally active E2F1-pRb-P/CAF complex on multiple TGFβ pro-apoptotic target gene promoters, thereby activating their transcription. Together, our findings define a novel process of gene activation by the TGFβ-E2F1 signaling axis and highlight E2F1 as a central mediator of the TGFβ apoptotic program.
Division of Medical Oncology, Department of Medicine, McGill University Health Center, Montreal, Canada.
J
J
Korah
N
N
Falah
A
A
Lacerte
J J
JJ
Lebrun
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D050687:E2F1 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic / Q000187:drug effects; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
D050687:E2F1 Transcription Factor; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein; D016212:Transforming Growth Factor beta; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor