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Live Cell Imaging of the TGF- β/Smad3 Signaling Pathway In Vitro and In Vivo Using an Adenovirus Reporter System
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The androgen receptor represses transforming growth factor-beta signaling through interaction with Smad3

Jerry E Chipuk1, Susan C Cornelius, Nicole J Pultz

  • 1Ireland Cancer Center Research Laboratories, Department of Pharmacology, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, Ohio 44106, USA.

The Journal of Biological Chemistry
|November 15, 2001
PubMed

Insights

Androgens, like dihydrotestosterone, inhibit transforming growth factor-beta (TGF-beta) signaling in prostate cells. Ligand-bound androgen receptor (AR) directly blocks Smad3 binding to DNA, repressing TGF-beta target gene expression.

Area of Science:

  • Molecular Endocrinology
  • Prostate Cancer Biology
  • Signal Transduction

Background:

  • Androgens are known to negatively regulate transforming growth factor-beta (TGF-beta) signaling components and Smad activation in the prostate via largely unknown mechanisms.
  • Understanding this cross-talk is crucial for elucidating prostate cancer development and progression, where TGF-beta signaling often plays a context-dependent role.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which androgens inhibit TGF-beta signaling in prostate cells.
  • To investigate the direct interaction between androgen receptor (AR) and components of the TGF-beta/Smad pathway.

Main Methods:

  • Utilized LNCaP and NRP-154 prostate cell lines to assess TGF-beta1-induced gene expression and promoter activity.
  • Employed reporter gene assays (3TP-luciferase, AP-1-luciferase, SBE4(BV)-luciferase) to measure transcriptional responses.
  • Performed co-transfection studies, immunoprecipitation, GST pull-down assays, and electrophoretic mobility shift assays (EMSA) to investigate protein-protein interactions and DNA binding.

Main Results:

  • Androgens (dihydrotestosterone, R1881) down-regulated TGF-beta1-induced expression of TGF-beta1, c-Fos, and Egr-1 in LNCaP cells.
  • Dihydrotestosterone (DHT) inhibited TGF-beta1-responsive promoter constructs and Smad activation, even with enforced receptor expression.
  • AR directly associates with Smad3, and ligand-bound AR inhibits Smad3 binding to the Smad-binding element (SBE), thereby repressing TGF-beta transcriptional responses.

Conclusions:

  • Ligand-bound androgen receptor (AR) directly represses TGF-beta transcriptional responses in prostate cells.
  • The mechanism involves the selective inhibition of Smad3 binding to the Smad-binding element (SBE) by the AR ligand-binding domain.
  • This study reveals a novel cross-regulatory mechanism between androgen and TGF-beta signaling pathways in the prostate.

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