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Dual Regulation of Proliferation and Growth Arrest in Prostatic Stromal Cells by Transforming Growth Factor-ß1

Departments of Urology (W.Z., I.P., J.M.K., C.L., K.I.), Pathology (M.P.), and Preventive Medicine (B.J.), Northwestern University, Feinberg School of Medicine, Chicago, Illinois 60611; and Institute of Molecular Biology (J.Z.), Nankai University, Tainjing 300071, China

Address all correspondence and requests for reprints to: Dr. Chung Lee, Department of Urology, Tarry 16-733, 303 East Chicago Avenue, Chicago, Illinois 60611.

Abstract

In a preliminary study, we observed that TGF-ß1 induced both proliferation and growth arrest in prostatic stromal cells, depending on the concentration of TGF-ß1 used in the culture medium. In this study, we explored possible mechanisms of this dual effect of TGF-ß. Primary cultures of prostatic stromal cells, established from clinical surgical specimens and treated with low doses of TGF-ß1 (0.001–0.01 ng/ml), resulted in an increase in cell proliferation. The addition of neutralizing antibody against platelet-derived growth factor (PDGF)-BB, but not anti-PDGF-AA, abrogated this stimulatory effect of TGF-ß1. TGF-ß1 treatment resulted in a dose-related increase in PDGF-BB production as measured by ELISA. Cells underwent growth arrest at high concentrations of TGF-ß1 (1.0 and 10 ng/ml). An inhibitor of cyclin-dependent kinase (cdk), p15^INK4b, was up-regulated at both transcript and protein levels in these cultures by TGF-ß1 in a dose-related manner as determined by RT-PCR and Western blot analysis. The transcript, but not the protein, for another cdk inhibitor, p21^Cip1, was up-regulated with treatment of TGF-ß1 to these cells. Levels of other cdk inhibitors, such as p16^INK4a and p27^Kip1, were constitutively expressed in prostatic stromal cells and were not significantly affected by TGF-ß1 treatment. Finally, the growth arrest effect of TGF-ß1 was abrogated when antisense oligonucleotides to p15^INH4b, but not p21^Cip1, were added to the culture medium. These data indicate that the dual effect of TGF-ß1 is mediated, at least, by up-regulation of PDGF-BB and p15^INK4b, respectively.

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