Prof . Shafiq Khan

MoSE 3201A
Thursday, January 23, 2020 - 11:00am to 12:00pm

Disruption of TGF-β Signaling leads to Initiation of Carcinogenesis in the Prostate

The development of epithelial tissues depends on cell proliferation followed by functional differentiation. Transforming growth factor-β (TGFβ), acting through Smad2/Smad3 signaling, promotes G1 cell cycle arrest leading to inhibition of cell proliferation and induces cell differentiation. Loss of inhibitory effects of TGFβ on cell proliferation leads to pathological lesions including hyperplasia, benign tumor growth and carcinogenesis. The intracellular mechanisms involved in the development of resistance to inhibitory effects of TGFβ on cell proliferation remain largely unknown. We have recently identified a novel mechanism by which TGFβ induces cell cycle arrest and disruption of this mechanism leads to development of resistance to TGFβ effects on cell proliferation. We have shown that JunD, a member of AP-1 family of transcription factors, is essential for proliferation in human prostate and other epithelial cells. Treatment with TGFβ leads to specific proteasomal degradation of JunD, leading to inhibition of cell proliferation. We have identified COP1 as a candidate E3-ligase which is required for TGFβ dependent proteasomal degradation of JunD. In accordance with its essential role in cell proliferation, specific knockdown of JunD in prostate cancer cells leads to significant reduction in the expression of several genes which are required for cell cycle regulation including c-MYC, CDK2 and CDK4. The reduction of c-MYC was observed at both mRNA and protein levels under different experimental conditions suggesting that c-MYC expression is regulated by JunD at both transcriptional and translational levels. We hypothesize that JunD plays an essential role in cell proliferation in prostate epithelial cells by inducing the expression of genes which are required for the progression of cell cycle and the inhibitory effects of TGFβ on cell proliferation depend upon proteasomal degradation of JunD

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Host: Prof Mostafa El-Sayed (
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