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Oncology: Theory & Practice
Title
Oncology: Theory & Practice
Editor
iConcept Press
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USD$109.99
ISBN
978-1-922227-80-5
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26767

Chapter 3

Oncology: Theory & Practice

Role of the pRb-E2F Pathway in TGFβ-Mediated Tumour Suppression

by Juliana Korah and Jean-Jacques Lebrun

Viewed: 1467

Abstract

The process of 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-β (TGFβ) exerts a central role in preventing tumour formation by acting as a potent tumour suppressor in virtually all cell types and tissues. TGFβ tumour suppressive effects are mainly illustrated by its ability to inhibit cell growth, induce apoptosis and prevent cell immortalization. TGFβ-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 TGFβ efficiently represses hTERT gene expression in both normal and cancer cells through multiple signalling pathways. We further found that the inhibition of hTERT by TGFβ requires the synthesis of an intermediate molecule that we identified as the transcription factor E2F1, and showed that interfering with E2F1 activity impedes the TGFβ inhibitory effect on telomerase activity. The E2F family of transcription factors play 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. TGFβ 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 TGFβ and leading to cell death, had yet to be uncovered. Interestingly, recent work from our laboratory highlighted E2F1 as a central factor downstream of TGFβ-induced apoptosis in cancer cells.. Using the E2F1 knockout mouse model, we found E2F1 to be required for TGFβ-mediated apoptosis in normal cells as well. 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 pro-apoptotic target gene promoters, thereby activating their transcription. These findings define a novel process of gene activation by the TGFβ-E2F1 signalling axis, and uncover the pRb–E2F1–P/CAF pathway as a wide-ranging and critical mediator of the TGFβ apoptotic programme in multiple target tissues. Together, our studies support a role for E2F1 as a potent co-transducer of TGFβ signalling and highlight the crucial role for the pRb-E2F pathway in regulating TGFβ tumour-suppressive effects.

Author Details

Juliana Korah
Department of Surgical Research Division of Medical Oncology, Faculty of Medicine, McGill University, Canada
Jean-Jacques Lebrun
Division of Medical Oncology, Faculty of Medicine, McGill University, Canada

Citation

Juliana Korah and Jean-Jacques Lebrun. Role of the pRb-E2F Pathway in TGFβ-Mediated Tumour Suppression. In Oncology: Theory & Practice. ISBN:978-1-922227-80-5. iConcept Press. 2014.

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