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Dual regulation of proliferation and growth arrest in prostatic stromal cells by transforming growth factor-beta1

Wei Zhou1, Irwin Park, Michael Pins

  • 1Department of Urology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois 60611, USA.

Endocrinology
|September 10, 2003
PubMed

Insights

Transforming growth factor-beta1 (TGF-beta1) uniquely influences prostatic stromal cells, promoting proliferation at low doses via platelet-derived growth factor-BB (PDGF-BB) and growth arrest at high doses through p15INK4b upregulation.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Prostate Cancer Research

Background:

  • Prostatic stromal cells play a crucial role in prostate tissue homeostasis.
  • Transforming growth factor-beta1 (TGF-beta1) exhibits complex regulatory functions in various cell types.
  • Previous observations indicated a dual effect of TGF-beta1 on prostatic stromal cell proliferation and growth arrest.

Purpose of the Study:

  • To elucidate the underlying mechanisms of TGF-beta1's dual effect on prostatic stromal cells.
  • To investigate the role of platelet-derived growth factor (PDGF) in TGF-beta1-induced proliferation.
  • To identify the specific cyclin-dependent kinase (cdk) inhibitors involved in TGF-beta1-mediated growth arrest.

Main Methods:

  • Primary cultures of human prostatic stromal cells were established.
  • Cells were treated with varying concentrations of TGF-beta1.
  • Enzyme-linked immunosorbent assay (ELISA) measured PDGF-BB production.
  • Reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analyzed cdk inhibitor expression.
  • Neutralizing antibodies and antisense oligonucleotides were used to probe signaling pathways.

Main Results:

  • Low doses of TGF-beta1 (0.001-0.01 ng/ml) stimulated prostatic stromal cell proliferation, an effect abrogated by anti-PDGF-BB but not anti-PDGF-AA antibodies.
  • TGF-beta1 treatment led to a dose-dependent increase in PDGF-BB production.
  • High doses of TGF-beta1 (1.0 and 10 ng/ml) induced growth arrest.
  • TGF-beta1 upregulated both transcript and protein levels of the cdk inhibitor p15INK4b in a dose-dependent manner.
  • The growth arrest induced by TGF-beta1 was reversed by antisense oligonucleotides targeting p15INK4b, but not p21Cip1.

Conclusions:

  • TGF-beta1 exerts a concentration-dependent dual effect on prostatic stromal cells.
  • TGF-beta1-induced proliferation is mediated by the upregulation of PDGF-BB.
  • TGF-beta1-induced growth arrest is primarily mediated by the upregulation of the cdk inhibitor p15INK4b.

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