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A direct beta-catenin-independent interaction between androgen receptor and T cell factor 4.

T cell factor (Tcf) proteins bind beta-catenin and are downstream effectors of Wnt/beta-catenin signals. A recently demonstrated interaction between beta-catenin and the androgen receptor (AR) ligand binding domain has suggested that AR may be a Tcf-independent Wnt/beta-catenin effector. This study demonstrates that there is a direct interaction between the AR DNA binding domain (DBD) and Tcf4. Tcf4 bound specifically to a glutathione S-transferase-ARDBD fusion protein and could be coimmunoprecipitated with beta-catenin and transfected AR or endogenous AR in prostate cancer cells. Transfected Tcf4 repressed the transcriptional activity of full-length AR and a VP16-ARDBD fusion protein, and this repression was only partially reversed by transfected beta-catenin. AR activation by cyproterone acetate, a partial agonist that did not support beta-catenin binding to the AR, was also repressed by Tcf4, further indicating that repression was not due to beta-catenin sequestration. Tcf4 could recruit beta-catenin to the AR DBD in vitro and to the cyproterone acetate-liganded AR in vivo. Chromatin immunoprecipitation experiments in LNCaP prostate cancer cells showed that endogenous AR was bound to a Tcf4-responsive element in the c-myc promoter. These findings indicate that AR and Tcf4 can interact directly and that this interaction may occur on the promoters or enhancers of particular genes. The direct AR-Tcf4 interaction, in conjunction AR- and Tcf4-beta-catenin binding, provides a mechanism for cooperative and selective gene regulation by AR and the Wnt/beta-catenin-Tcf pathway that may contribute to normal and neoplastic prostate growth.

Pubmed ID: 12799378

Authors

  • Amir AL
  • Barua M
  • McKnight NC
  • Cheng S
  • Yuan X
  • Balk SP

Journal

The Journal of biological chemistry

Publication Data

August 15, 2003

Associated Grants

None

Mesh Terms

  • Androgen Antagonists
  • Cyproterone Acetate
  • Cytoskeletal Proteins
  • Humans
  • Ligands
  • Male
  • Prostatic Neoplasms
  • Protein Binding
  • Proto-Oncogene Proteins
  • Receptors, Androgen
  • Signal Transduction
  • TCF Transcription Factors
  • Trans-Activators
  • Transcription Factor 7-Like 2 Protein
  • Transcription Factors
  • Transcriptional Activation
  • Transfection
  • Tumor Cells, Cultured
  • Wnt Proteins
  • Zebrafish Proteins
  • beta Catenin