Access Type

Open Access Dissertation

Date of Award

1-1-1998

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Pathology

First Advisor

Yong Q. Chen, Ph.D.

Abstract

TGF-β is a potent growth inhibitor of epithelial cells. However, many transformed cells have lost their sensitivity to this growth inhibitory effect. The molecular mechanism of such insensitivity is not yet understood. Here, we have studied the TGF-β1 effect on normal human prostate and carcinoma cells. Our results showed that normal cells were sensitive to growth inhibition, whereas tumor cells were not or only minimally inhibited regardless of the concentration of TGF-β1 (20 to 80 pM) or time of exposure (1-5 days). P21WAF1/Cip1/Sdi1 and p15INK4B but not p27K1P1 were detectable by Western blotting in normal and tumor cells. TGF-β1 treatment increased the association of p21WAF1/Cip1/Sdi1 with the Cdk2/cyclin E complex in both normal and prostate tumor cells. However, there was no increase in the association of p15INK4B nor p27K1P1 with the Cdk/cyclin complexes. In normal cells, the increase in the association of p21WAF1/Cip1/Sdi1 with the Cdk2/cyclin E complex resulted in inhibition of the Cdk2 activity. In contrast, although there was an increase in the association of p21WAF1/Cip1/Sdi1 with the Cdk2/cyclin E complex in tumor cells, there was no inhibition of the Cdk2 activity. These results indicate that a lack of inhibition of the Cdk2 activity correlates with the insensitivity to TGF-β1 in prostate tumor cells.

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