Molecular Regulation of Androgen Receptor Activation

描述：（由申请人提供）当前的总体目标 建议是针对理解的分子机制， 晚期前列腺癌的激素不敏感性机制探讨 AR激活过程。非依赖性前列腺癌的出现 削弱了激素疗法的有效性。前列腺的一种机制 癌细胞规避激素治疗的方法是引入/选择突变体 雄激素受体（AR），最终将拮抗剂转化为激动剂， 在体内和体外都是明显的。其他的扰动导致了 非依赖性AR激活。例如，小窝蛋白的水平， 与小窝信号微区相关的蛋白质， 与前列腺癌的激素抵抗和转移有关我们展示在 细胞模型表明，小窝蛋白水平的调节显著改变了 AR对雄激素的敏感性。此外，瞬态和动态直接 AR和小窝蛋白在雄激素刺激下的相互作用， 演示。我们的工作假设是，AR激活可能是 通过与信号复合体的串扰来调节， 含有小窝蛋白的小窝。目前的提案旨在严格 评估AR和小窝蛋白-1在分子、细胞和 生理水平。近期目标是：（1）详细定义 AR和小窝蛋白-1在分子水平上相互作用;（2）功能上 研究雄激素受体中AR与caveolin-1的相互作用 （3）研究窖蛋白的生理功能 使用前列腺癌细胞培养模型在AR信号传导中的过表达; (4)为了表征小窝蛋白-1过表达对LNCap细胞的影响， 使用裸鼠异种移植物模型的致瘤性和转移。充分 表征AR和小窝蛋白之间的相互作用可以外推到 了解前列腺癌进展的病理生物学， 正常的前列腺上皮AR信号生理学。远景目标 是确定新的目标和机制，这可能是有用的，在未来 开发合理的药物靶点。

DESCRIPTION: (provided by the applicant) The overall objectives of the current proposal are directed at understanding the molecular mechanism underlying the hormone insensitivity in advanced prostate cancer by delineating the mechanism of AR activation process. The emergence of hormone-independent prostate cancer curtails the effectiveness of hormonal therapies. One mechanism for prostate cancer cells to circumvent the hormonal therapy is to introduce/select mutant androgen receptors (AR), which eventually turn an antagonist into an agonist as evident both in vivo and in vitro. Other perturbations are leading to hormone-independent AR activation. For example, levels of caveolin, a scaffold protein associated with caveolae signaling microdomains, have been correlated with hormone resistance and metastasis in prostate cancer. We demonstrate in cellular models that modulations in caveolin levels dramatically alter the sensitivity of AR to androgen. Furthermore, a transient and dynamic direct interaction between AR and caveolin in response to androgen stimulation is also demonstrated. Our working hypothesis is that AR activation is potentially regulated by a crosstalk with signal complexes associated with caveolin-containing caveolae. The current proposal is designed to rigorously evaluate the interaction between AR and caveolin-1 at molecular, cellular and physiological levels. The immediate goals are: (1) to define in detail the interaction between AR and caveolin-1 at molecular level; (2) to functionally characterize the interaction between AR and caveolin-1 in androgenic receptor activation; (3) to characterize the physiological role of caveolin overexpression in AR signaling using a prostate carcinoma cell culture model; (4) to characterize the effect of caveolin-1 overexpression on LNCap cell tumorigenicity and metastasis using a nude mouse xenograft model. Fully characterizing the interaction between AR and caveolin can be extrapolated to the understanding of the pathobiology of prostate cancer progression as well as the normal prostate epithelial physiology of AR signaling. The long-term goals are to identify novel targets and mechanisms, which could be useful in future development of rational drug targets.