The FKBP52 Cochaperone Acts in Synergy with β-Catenin to Potentiate Androgen Receptor Signaling.
The FKBP52 Cochaperone Acts in Synergy with β-Catenin to Potentiate Androgen Receptor Signaling.
复制标题
FKBP52联酮与β-catenin的协同作用可增强雄激素受体信号传导。
DOI：
10.1371/journal.pone.0134015
复制
发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Cox MB
中科院分区：
文献类型：
--
作者：
Storer Samaniego C;Suh JH;Chattopadhyay A;Olivares K;Guy N;Sivils JC;Dey P;Yumoto F;Fletterick RJ;Strom AM;Gustafsson JÅ;Webb P;Cox MB
近年来，FKBP 52和β-连环蛋白已成为前列腺癌治疗的有吸引力的靶点。β-连环蛋白直接与雄激素受体（AR）相互作用，并且已被表征为AR介导的转录的共激活因子。FKBP 52是细胞和整体动物模型中AR的正调节因子，并且是雄激素依赖性组织发育所必需的。我们先前表征了称为MJC 13的AR抑制剂，其靶向AR BF 3表面以特异性抑制FKBP 52调节的AR信号传导。预测模型表明β-连环蛋白与BF 3重叠表面上的AR激素结合结构域相互作用。在这里，我们证明了FKBP 52和β-连环蛋白在体外直接相互作用，并协同作用以促进非依赖性和依赖性AR信号的协同上调。我们的数据表明，FKBP 52促进β-连环蛋白与AR的相互作用，并且是前列腺癌细胞中AR活性的β-连环蛋白共激活所必需的。MJC 13有效地阻断β-连环蛋白与AR LBD的相互作用以及FKBP 52和β-连环蛋白对AR的协同上调。我们的数据表明，FKBP 52和β-连环蛋白对AR的共调节不需要FKBP 52 PPI酶催化活性，也不需要FKBP 52与Hsp 90结合。然而，突出于PPIase口袋的FKBP 52富含脯氨酸的环对于协同作用至关重要。
FKBP52 and β-catenin have emerged in recent years as attractive targets for prostate cancer treatment. β-catenin interacts directly with the androgen receptor (AR) and has been characterized as a co-activator of AR-mediated transcription. FKBP52 is a positive regulator of AR in cellular and whole animal models and is required for the development of androgen-dependent tissues. We previously characterized an AR inhibitor termed MJC13 that putatively targets the AR BF3 surface to specifically inhibit FKBP52-regulated AR signaling. Predictive modeling suggests that β-catenin interacts with the AR hormone binding domain on a surface that overlaps with BF3. Here we demonstrate that FKBP52 and β-catenin interact directly in vitro and act in concert to promote a synergistic up-regulation of both hormone-independent and -dependent AR signaling. Our data demonstrate that FKBP52 promotes β-catenin interaction with AR and is required for β-catenin co-activation of AR activity in prostate cancer cells. MJC13 effectively blocks β-catenin interaction with the AR LBD and the synergistic up-regulation of AR by FKBP52 and β-catenin. Our data suggest that co-regulation of AR by FKBP52 and β-catenin does not require FKBP52 PPIase catalytic activity, nor FKBP52 binding to Hsp90. However, the FKBP52 proline-rich loop that overhangs the PPIase pocket is critical for synergy.