Linking beta-catenin to androgen-signaling pathway.
The androgen-signaling pathway is important for the growth and progression of prostate cancer cells. The growth-promoting effects of androgen on prostate cells are mediated mostly through the androgen receptor (AR). There is increasing evidence that transcription activation by AR is mediated through interaction with other cofactors. beta-Catenin plays a critical role in embryonic development and tumorigenesis through its effects on E-cadherin-mediated cell adhesion and Wnt-dependent signal transduction. Here, we demonstrate that a specific protein-protein interaction occurs between beta-catenin and AR. Unlike the steroid hormone receptor coactivator 1 (SRC1), beta-catenin showed a strong interaction with AR but not with other steroid hormone receptors such as estrogen receptor alpha, progesterone receptor beta, and glucocorticoid receptor. The ligand binding domain of AR and the NH(2) terminus combined with the first six armadillo repeats of beta-catenin were shown to be necessary for the interaction. Through this specific interaction, beta-catenin augments the ligand-dependent activity of AR in prostate cancer cells. Moreover, expression of E-cadherin in E-cadherin-negative prostate cancer cells results in redistribution of the cytoplasmic beta-catenin to the cell membrane and reduction of AR-mediated transcription. These data suggest that loss of E-cadherin can elevate the cellular levels of beta-catenin in prostate cancer cells, which may directly contribute to invasiveness and a more malignant tumor phenotype by augmenting AR activity during prostate cancer progression.
Yang
Fajun
F
Department of Surgery and Department of Genetics, Stanford University School of Medicine, Stanford, California 94305-5328, USA.
Li
Xiaoyu
X
Sharma
Manju
M
Sasaki
Carl Y
CY
Longo
Dan L
DL
Lim
Bing
B
Sun
Zijie
Z
D000728:Androgens / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008297:Male; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D011944:Receptors, Androgen / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators; D014407:Tumor Cells, Cultured; D020798:Two-Hybrid System Techniques; D051176:beta Catenin
D000728:Androgens; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D008024:Ligands; D011944:Receptors, Androgen; D015534:Trans-Activators; D051176:beta Catenin