ANDROGEN EFFECTS MEDIATED BY AR AND PROTO-ONCOPROTEINS

类固醇激素，诱导和维持分化。一个最好的例子 其中包括雄激素，一种正常情况下绝对需要的类固醇激素 发展和维持男性的性别特征。这些戏剧性的 雄激素对性分化的影响是通过 雄激素受体(AR)，核受体超家族成员。 像所有的核受体一样，AR通过结合其特定的配体来发挥作用， 雄激素，并导致其DNA转录速度增加 靶基因。然而，与其他核受体不同的是， 被原癌蛋白cJun抑制，AR实际上是由 Cjun.事实上，我的实验室最近的结果有力地证明了cjun是一种 AR介导的反式激活的辅助激活剂。这些结果是 总结如下：i)外源性和内源性cJun均介导AR 激活；ii)cjun可以缓解AR自我抑制；iii)cjun DNA结合缺陷的突变体仍可介导AR反式激活； IV)反义cJun缺失突变体可特异性阻断cJun介导的 AR转录激活。因此，我们建议对这部小说进行进一步的研究 CJun的活性，我们称之为反式共激活。这件事会做到的 通过研究Har-cJun相互作用的以下几个方面。第一, 我们将寻找cJun在各种雄激素调节中的作用- 反应基因，它将检测启动子和染色质的影响 在任何cJun活动中。其次，君家的其他成员和 Fos家族的成员将在cJun中接受角色审查 与Har共激活。第三，我们将更仔细地研究一些 Har和cJun中的功能域对于Har- CJun共激活。第四，我们将确定cjun的级别 效果，在实现这一具体目标时，我们将审查配体或 Har与DNA结合，或Har之间直接的蛋白质-蛋白质相互作用 和cjun。最后，在最后一个具体目标中，我们提出了实验来 研究截断形式的cjun的作用机制，在 反义定向，可以特异性地完全阻断cjun 与Har共激活。鉴于应收账款可能涉及 前列腺癌与心脏病及cJun在治疗中的重要性 通过成功实现特定目标来调节细胞生长 在这个项目中，我们将开辟一个新的重要领域 分子生物学将对两者的研究产生广泛的影响 正常发育和患病状态。

Steroid hormones, induce and maintain differentiation. A prime example of this is androgen, a steroid hormone absolutely required for normal development and maintenance of male sex characteristics. These dramatic effects of androgens on sexual differentiation are mediated by the androgen receptor (AR), a member of the nuclear receptor superfamily. Like all nuclear receptors, the AR acts by binding its specific ligand, androgen, and causing an increase in the rate of DNA transcription of its target genes. However, unlike other nuclear receptors, which are inhibited by the proto-oncoprotein cJun, AR is actually stimulated by cJun. Indeed, recent results from my lab argue strongly that cJun is a coactivator for AR-mediated transactivation. These results are summarized below: i) both exogenous and endogenous cJun mediate AR transactivation; ii) cJun can relieve AR self-squelching; iii) cJun mutant deficient in DNA binding can still mediate AR transactivation; and iv) anti-sense cJun deletion mutant can specifically block cJun-mediated AR transactivation. Therefore, we propose to further study this novel activity of cJun, which we call trans-coactivation. This will be done by studying the following aspects of the hAR-cJun interaction. First, we will look for a cJun role in the regulation of various androgen- responsive genes, which will examine both promoter and chromatin effects on any cJun activity. Secondly, other members of the Jun family and members of the Fos family will be examined for a role in the cJun coactivation with hAR. Thirdly, we will look more closely at some functional domains within hAR and cJun that are essential for the hAR- cJun coactivation. Fourthly, we will determine at what level the cJun effect, and in carrying out this specific aim, we will examine ligand or DNA binding by hAR, or a direct protein-protein interactions between hAR and cJun. Finally, in the last specific aim, we propose experiments to study the mechanism of action of a truncated form of cJun, which, in the anti-sense orientation, can specifically and completely block cJun coactivation with hAR. In view of the potential involvement of AR in prostate cancer and heart disease and the importance of cJun in regulating cell growth, by successfully carrying out the specific aims of this project, we would be opening up a new and important field of molecular biology which will have broad implications to the study of both normal development and the diseased state.