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