Role of the PRb/E2F Pathway in TGF Beta-mediated Tumour Suppression

Download or read book Role of the PRb/E2F Pathway in TGF Beta-mediated Tumour Suppression written by Juliana Korah and published by . This book was released on 2014 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: "Tumour formation is characterized by a series of well-defined events that occur in virtually all human cancers, including the ability of cells to attain immortalization, sustain proliferation and evade apoptosis. These cell growth and cytostatic processes are normally regulated by various growth factors that act in concert to maintain proper cellular homeostasis. As a result, deregulation of these growth factor signalling pathways leads to uncontrolled cell growth and tumour formation. In particular, transforming growth factor-[beta] (TGF[beta]) exerts a central role in preventing tumour formation in virtually all cell types and tissues. TGF[beta] tumour suppressive effects are mainly illustrated by its ability to inhibit cell growth, induce cell death and prevent cell immortalization. TGF[beta]-mediated prevention of cell immortalization relies on inhibition of telomerase activity. While expression of hTERT, the protein component of telomerase, is increased in most cancer cells, studies from our laboratory revealed that TGF[beta] efficiently represses hTERT gene expression in both normal and cancer cells through multiple signalling pathways. We further found that the inhibition of hTERT by TGF[beta] requires the synthesis of an intermediate molecule that we identified as the transcription factor E2F1, and showed that interfering with E2F1 activity impedes the TGF[beta] inhibitory effect on telomerase activity. The E2F family of transcription factors plays a central role in regulating cell-cycle progression. Deregulation of these factors is a common event in most human cancers. Interestingly, E2F1 has been shown to have the ability to induce both cell cycle progression and apoptosis, though the mechanisms of E2F-mediated apoptosis have not been fully elucidated. TGF[beta] itself is a potent pro-apoptotic factor, as it modulates the expression of multiple apoptotic genes in various tissues. However, a common and central signalling pathway, acting downstream of TGF[beta] and leading to cell death, had yet to be uncovered. Interestingly, recent work from our laboratory highlighted E2F1 as a central factor downstream of TGF[beta]-induced apoptosis in cancer cells. Using the E2F1 knockout mouse model, we found E2F1 to be required for TGF[beta]-mediated apoptosis in normal cells as well. 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 pro-apoptotic target gene promoters, thereby activating their transcription. These findings define a novel process of gene activation by the TGF[beta]-E2F1 signalling axis, and uncover the pRb/E2F1 pathway as a wide-ranging and critical mediator of the TGF[beta] apoptotic programme in multiple target tissues. We further determined that TGF[beta] induces pRb/E2F1-dependent transcriptional activation of several autophagy-related genes, potentially leading to autophagic cell death. Together, our studies support a role for the pRb/E2F pathway as a potent co-transducer of TGF[beta] signalling and highlight the pivotal role for pRb/E2F in mediating TGF[beta] tumour-suppressive effects." --