Repression of androgen receptor mediated transcription by the ErbB-3 binding protein, Ebp1.
Members of the ErbB family of receptors have been implicated in regulation of androgen receptor (AR) activity. Ebp1, an ErbB-3 binding protein recently cloned in our laboratory, possesses an LXXLL motif important in mediating interactions with nuclear hormone receptors. Therefore, we sought to determine if Ebp1 could bind AR and influence AR transcriptional activation potential. We demonstrate in this study that Ebp1 bound to AR in vitro and in vivo, and that this binding was increased by androgen treatment. The C terminal 79 amino acids of Ebp1 were sufficient to bind AR. The N terminal domain of AR was responsible for binding Ebp1. Ligand-mediated transcriptional activation of both artificial and natural AR regulated promoters was inhibited by ectopic expression of ebp1 in transient transfection systems. Ebp1 deletion mutants that either lacked the C terminal AR binding region or had a mutated LXXLL motif failed to inhibit AR activated transcription. PSA expression from its endogenous promoter was also decreased in LNCaP prostate cancer cells overexpressing Ebp1. The growth of AR positive LNCaP cells was inhibited by ectopic expression of ebp1, but mutants that failed to repress transcription did not inhibit cell growth. These studies suggest that Ebp1 may play a role in the function of the AR and provide a link between ErbB receptors and the AR.
Zhang
Yuexing
Y
Greenebaum Cancer Center, University of Maryland, Baltimore, Maryland, MD 21201, USA.
Fondell
Joseph D
JD
Wang
Qianben
Q
Xia
Xianmin
X
Cheng
Aiwu
A
Lu
Michael L
ML
Hamburger
Anne W
AW
D048868:Adaptor Proteins, Signal Transducing; D015152:Blotting, Northern; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism*; D015536:Down-Regulation / Q000502:physiology*; D005786:Gene Expression Regulation; D005809:Genes, Regulator / Q000235:genetics*; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D008156:Luciferases / Q000235:genetics; D008297:Male; D009154:Mutation / Q000235:genetics; D011233:Precipitin Tests; D017430:Prostate-Specific Antigen / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins; D020239:Receptor Cross-Talk / Q000502:physiology*; D020893:Receptor, ErbB-3 / Q000235:genetics* / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism*; D045165:Testosterone Congeners / Q000494:pharmacology; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C101633:PA2G4 protein, human; D016601:RNA-Binding Proteins; D011944:Receptors, Androgen; D045165:Testosterone Congeners; D008156:Luciferases; D005982:Glutathione Transferase; D020893:Receptor, ErbB-3; D017430:Prostate-Specific Antigen