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.
Amir
Avital L
AL
Cancer Biology Program, Hematology-Oncology Division, the Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
Barua
Moumita
M
McKnight
Nicole C
NC
Cheng
Shinta
S
Yuan
Xin
X
Balk
Steven P
SP
D000726:Androgen Antagonists / Q000378:metabolism / Q000494:pharmacology; D017373:Cyproterone Acetate / Q000378:metabolism / Q000494:pharmacology; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008297:Male; D011471:Prostatic Neoplasms; D011485:Protein Binding / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D051820:TCF Transcription Factors; D015534:Trans-Activators / Q000378:metabolism*; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000502:physiology; D014162:Transfection; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin
D000726:Androgen Antagonists; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D008024:Ligands; D011518:Proto-Oncogene Proteins; D011944:Receptors, Androgen; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D015534:Trans-Activators; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; D017373:Cyproterone Acetate