Date of Award

5-1-2013

Degree Type

Dissertation

University or Center

Clark Atlanta University(CAU)

School

School of Arts and Sciences

Degree Name

Ph.D.

Department

Biology

First Advisor

Dr. Shafiq A. Khan

Second Advisor

Dr. Jaideep Chaudhary

Third Advisor

Dr. Valerie Odero-Marah

Abstract

TGF-β signaling pathways contain both tumor suppressor and tumor promoting activities. Nodal, a TGF-β like growth factor, functions as an embryonic morphogen that maintains the pluripotency of embryonic stem cells. We demonstrated that Nodal and its receptors are expressed in prostate epithelial stem cells (WPE) and prostate cancer cells (LNCaP, LNCaP-C8 1, and DU145). Nodal also exerts differential effects on proliferation and migration in different prostate cell lines. First, we determined the comparative effects of Nodal and TGF-β on proliferation and migration under identical experimental conditions in selected prostate cell lines. Our results demonstrated that Nodal and TGF-β exerted similar biological effects on prostate cells; both inhibited proliferation in WPE, RWPE1, and DU145 cells while neither had any effect on the proliferation of LNCaP or PC3 cells. Interestingly, Nodal and TGF-β induced migration in PC3 cells, but not in DU145 cells. TGF-β induced predominantly phosphorylation of Smad3, while Nodal induced phosphorylation of only Smad2. We also determined the expression and differential role of Ski, a co-repressor of Smad2/3, in Nodal and TGF- β signaling in prostate cancer cells. Similar levels of Ski mRNA were found in several established prostate cell lines; however, high levels of Ski protein were only detected in prostate cancer cells and prostate cancer tissue samples. Exogenous Nodal and TGF- β had no effects on Ski mRNA levels. On the other hand, TGF- β induced a rapid degradation of Ski protein mediated by the proteasomal pathway while Nodal had no effect on Ski protein. Reduced Ski levels correlated with increased basal and TGF-β-induced Smad2/3 phosphorylation. Knockdown of endogenous Ski reduced proliferation in DU145 cells and enhanced migration of PC3 cells. We conclude that high levels of Ski expression in prostate cancer cells may be responsible for repression of TGF-β and Smad3 signaling,

but Ski protein levels do not influence Nodal and Smad2 signaling.

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