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Mol Endocrinol. 2011 Oct;25(10):1677-88. doi: 10.1210/me.2011-1023. Epub 2011 Sep 1.

The beta-catenin binding protein ICAT modulates androgen receptor activity.

Author information

1
Department of Urology, Stanford University School of Medicine, Stanford, California 94305-5328, USA.

Abstract

Androgens have important roles in the development of the prostate gland and in prostate cancer. Since the finding that β-catenin is a cofactor of the androgen receptor (AR) and can augment AR signaling, several proteins have been found to affect AR signaling through their interaction with β-catenin. Here, we investigated inhibitor of β-catenin and T-cell factor (ICAT), a β-catenin binding protein that inhibits the canonical Wnt/β-catenin signaling pathway, in AR signaling. We demonstrated that expression of ICAT in two AR positive prostate cancer cell lines, LNCaP and LAPC4, augments ligand-dependent AR-mediated transcription. In contrast, short hairpin RNA knockdown of ICAT and β-catenin specifically blocks enhanced AR-mediated transcription by ICAT. Using both stable expression of ICAT and short hairpin RNA knockdown of ICAT expression approaches, we further showed that ICAT enhances expression of endogenous PSA and KLK2, two androgen response genes, and ligand-induced cell growth. In addition, we identified that ICAT and AR can form a ternary complex with β-catenin using in vitro glutathione S-transferase protein pulldown assays. Moreover, we detected the endogenous protein complex containing ICAT, AR, and β-catenin in prostate cancer cells using immunoprecipitation assays. Recruitment of endogenous ICAT onto the promoter region of the human PSA gene, an AR downstream target promoter, was also identified in LNCaP cells. Finally, using in vitro protein binding assays, we examined the effect of full-length and truncated ICAT on the AR-β-catenin interaction and observed that addition of full-length ICAT retained the interaction between β-catenin and AR proteins. Intriguingly, the truncated ICAT comprising the N-terminal helical domain showed a more pronounced effect on β-catenin binding to AR proteins. Our findings suggest a novel molecular mechanism underlying the cross talk between androgen and Wnt signaling pathways.

PMID:
21885566
PMCID:
PMC3182419
DOI:
10.1210/me.2011-1023
[Indexed for MEDLINE]
Free PMC Article

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