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Submitted on May 6, 2003
Accepted on July 18, 2003
1
1 Departments of Urology, Pathology and Preventive Medicine, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, and Institute of Molecular Biology, Nankai University, Tainjing, China
* To whom correspondence should be addressed.
In a preliminary study, we observed that transforming growth factor-
1 (TGF-1) induced both proliferation and growth arrest in prostatic stromal cells, depending on the concentration of TGF-1 used in the culture medium. In this study, we explored possible mechanisms of this dual effect of TGF-. Primary cultures of prostatic stromal cells, established from clinical surgical specimens, treated with low doses of TGF-1 (0.001 - 0.01 ng/ml) resulted in an increase in cell proliferation. The addition of neutralizing antibody against platelet-derived growth factor-BB (PDGF-BB), but not anti-PDGF-AA, abrogated this stimulatory effect of TGF-1. TGF-1 treatment resulted in a dose-related increase in PDGF-BB production as measured by enzyme-linked immunoabsorbant assay. Cells underwent growth arrest at high concentrations of TGF-1 (1.0 and 10 ng/ml). An inhibitor of cyclin dependent kinase (cdk), p15INK4b, was up-regulated at both transcript and protein levels in these cultures by TGF-1 in a dose-related manner as determined by RT-PCR and by Western blot analysis. The transcript, but not the protein, for another cdk inhibitor, p21Cip1, was up-regulated with treatment of TGF-1 to these cells. Levels of other cdk inhibitors, such as p16INK4a and p27Kip1, were constitutively expressed in prostatic stromal cells and were not significantly affected by TGF-1 treatment. Finally, the growth arrest effect of TGF-1 was abrogated when antisense oligonucleotides to p15INH4b and, but not p21Cip1, was added to the culture medium. These data indicate that the dual effect of TGF-1 is mediated, at least, by up-regulation of PDGF-BB and p15INK4b, respectively.
•
Prostatic stromal cells •
PDGF-BB •
p15INK4b
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