Caveolin-1 interacts with androgen receptor - A positive modulator of androgen receptor mediated transactivation
Caveolin-1 interacts with androgen receptor - A positive modulator of androgen receptor mediated transactivation
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DOI：
10.1074/jbc.m006598200
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发表时间：
2001-04-20
影响因子：
4.8
通讯作者：
Richie, JP
中科院分区：
文献类型：
--
作者：
Lu, ML;Schneider, MC;Richie, JP
雄激素受体（AR）属于类固醇激素核受体超家族。它作为雄激素依赖性转录因子发挥作用，调节细胞增殖和分化的基因。小窝蛋白是小窝膜的主要成分，作为许多信号转导途径的支架蛋白。最近的结果将小鼠前列腺癌中的 Caveolin-1 表达与雄激素敏感性相关联。此外，患者标本的免疫组织化学染色表明，caveolin 表达可能是前列腺癌进展的独立预测因子。在本研究中，我们研究了 AR 信号传导与 Caveolin-1 之间的潜在相互作用，并证明 Caveolin-1 的过度表达可增强配体依赖性 AR 激活。相反，通过caveolin-1反义表达构建体下调caveolin-1表达可以下调配体依赖性AR激活。 AR 与通过平衡蔗糖梯度离心法分离的富含小窝蛋白的低密度膜组分的共定位也证明了这两个分子之间的关联。免疫共沉淀和谷胱甘肽 S-转移酶融合蛋白下拉实验表明 AR 和 Caveolin-1 之间的相互作用是雄激素依赖性过程，为这种相互作用的生理作用提供了进一步的证据。使用哺乳动物双杂交检测系统，我们确定 Caveolin-1 的 NH2 末端区域负责与 AR 的 NH2 末端结构域和配体结合结构域相互作用。
Androgen receptor (AR) belongs to the steroid hormone nuclear receptor superfamily. It functions as an androgen dependent transcriptional factor that regulates genes for cell proliferation and differentiation. Caveolin is a principal component of caveolae membranes serving as a scaffold protein of many signal transduction pathways. Recent results correlate caveolin-1 expression with androgen sensitivity in murine prostate cancer. Furthermore, immunohistochemical staining of patient specimens suggests that caveolin expression may be an independent predictor of progression of prostate cancer. In this study, we investigate the potential interactions between AR signaling and caveolin-1 and demonstrate that overexpression of caveolin-1 potentiates ligand-dependent AR activation. Conversely, down-regulation of caveolin-1 expression by a caveolin-1 antisense expression construct can downregulate ligand-dependent AR activation. Association between these two molecules is also demonstrated by co-localization of AR with caveolin-rich, low-density membrane fractions isolated by an equilibrium sucrose gradient centrifugation method. Co-immunoprecipitation and glutathione S-transferase fusion protein pull-down experiments demonstrate that interaction be tween AR and caveolin-1 is an androgen-dependent process, offering further evidence for a physiological role of this interaction. Using a mammalian two-hybrid assay system, we determine that the NH2 terminus region of caveolin-1 is responsible for the interaction with both the NH2-terminal domain and the ligand-binding domain of AR.