Abstract
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.
Highlights
Transforming growth factor-b (TGFb) ligands signal through serine/threonine kinase receptors that, once activated by ligand binding, recruit and phosphorylate the canonical downstream mediators, Smad[2] and Smad[3]
E2F1 mutants that are unable to promote cell-cycle progression retain their ability to induce programmed cell death, indicating that induction of the cell cycle and apoptosis are separable functions of E2F1.18 Given our previous findings that E2F1 is required for TGFb-mediated inhibition of hTERT11 and that TGFb promotes increased E2F-DNA-binding activity in pre-apoptotic hepatoma cell nuclear extracts,[19] we investigated whether E2F1 could mediate another arm of the TGFb tumor-suppressive response and regulate apoptosis
We found that the effect of TGFb on cell viability (Figure 1c) and early apoptosis (Figure 1d) in all the cell lines tested was almost completely prevented when E2F1 expression was silenced, indicating that E2F1 is required for mediating the TGFb pro-apoptotic response in multiple cell lines of various origins
Summary
TGFb ligands signal through serine/threonine kinase receptors that, once activated by ligand binding, recruit and phosphorylate the canonical downstream mediators, Smad[2] and Smad[3]. Smad[2] and Smad[3] interact with Smad[4] to translocate to the nucleus where the Smad complex associates with diverse DNA-binding factors to regulate expression of target genes in a cell- and tissue-specific manner These partner proteins, which act as co-activators or co-repressors, are differentially expressed in different cell types and are thought to provide a basis for tissue and cell type-specific functions for TGFb ligands.[3]. Our results underline E2F1 as a central mediator of the TGFb pro-apoptotic response and highlight the E2F1–pRb–P/CAF signaling pathway as a critical regulator of TGFb-mediated cell death
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