A transcriptionally active pRb-E2F1-P/CAF signaling pathway is central to TGFβ-mediated apoptosis

Transforming growth factor-beta (TGF beta) modulates the expression of multiple apoptotic target genes; however, a common and central signaling pathway, acting downstream of TGF beta and leading to cell death, has yet to be uncovered. Here, we show that TGF beta-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 TGF beta-mediated apoptosis in normal cells. Moreover, we found TGF beta to increase E2F1 protein stability, acting at the post-translational level. We further investigated the molecular mechanisms by which E2F1 contributes to TGF beta-mediated apoptosis and found that TGF beta treatment led to the formation of a transcriptionally active E2F1-pRb-P/CAF complex on multiple TGF beta pro-apoptotic target gene promoters, thereby activating their transcription. Together, our findings define a novel process of gene activation by the TGF beta-E2F1 signaling axis and highlight E2F1 as a central mediator of the TGF beta apoptotic program. Cell Death and Disease (2012) 3, e407; doi:10.1038/cddis.2012.146; published online 11 October 2012