Mechanisms of action of androgen receptor and cofactors

雄激素受体和辅助因子的作用机制

基本信息

批准号：
7220662
负责人：
ZHENGXIN WANG
金额：
$ 26.49万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-07-15 至 2009-04-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The androgen receptor (AR), a member of a superfamily of ligand-activated nuclear transcription factors, mediates the biological functions of androgens in prostate development, growth, function, tumorigenesis, and cancer progression. Androgen ablation therapy, while effective at early androgen-dependent stages, fails at the androgen-independent stages of advanced prostate cancer. Although these tumors are clinically androgen-independent, they appear to remain androgen receptor-dependent through mechanisms that are not effectively blocked by androgen deprivation therapy. Androgen-independent progression has been associated with mutations and amplification of the androgen receptor gene and with activation of intracellular signaling pathways that stimulate androgen receptor function. A detailed understanding of the molecular mechanisms by which androgen receptor activates/represses key target genes would provide insights into the role of androgens in growth and development of the prostate and in development and progression of prostate cancer. Androgen receptor direct target genes that play key regulatory roles in prostate development, maintenance, and tumorigenesis are poorly defined. The general objective of this proposal is to identify AR direct target genes as a basis for understanding AR functions in survival, differentiation, and proliferation of cells of the prostate, as well as early events leading to prostate cancer, and to investigate the mechanism of action of AR and various identified AR cofactors on these genes. Toward this objective we will (i) identify genes that are targeted directly by AR; (ii) determine the gene specificity of various identified AR cofactors; (iii) investigate AR and cognate cofactor functions in cell-free transcription systems reconstituted with general initiation factors. This approach may provide insights into development of new drugs that target the androgen receptor pathway downstream of the point of ligand-receptor interaction.

描述（由申请人提供）：雄激素受体（AR）是配体激活的核转录因子超家族的成员，介导了雄激素在前列腺发育，生长，功能，肿瘤发生和癌症进展中的生物学功能。雄激素消融疗法虽然在早期雄激素依赖性阶段有效，但在晚期前列腺癌的雄激素独立阶段失败。尽管这些肿瘤在临床上是与雄激素无关的，但它们似乎通过不受雄激素剥夺疗法有效阻断的机制仍然依赖雄激素受体依赖性。雄激素非依赖性进展与雄激素受体基因的突变和扩增有关，并激活刺激雄激素受体功能的细胞内信号传导途径。对雄激素受体激活/抑制关键靶基因的分子机制的详细理解将为雄激素在前列腺生长和发育以及前列腺癌的发展和发展中的作用提供见解。雄激素受体直接靶基因在前列腺发育，维持和肿瘤发生中起关键调节作用的定义很差。该提案的一般目标是将AR直接靶基因识别为理解AR在前列腺细胞的生存，分化和扩散以及导致前列腺癌的早期事件中的基础，并研究AR和各种鉴定出AR辅助因子在这些基因上的作用机理。为了实现这一目标，我们将（i）确定直接由AR靶向的基因；（ii）确定各种已鉴定的AR辅因子的基因特异性；（iii）研究与一般起始因子重构的无细胞转录系统中的AR和同源辅因子的功能。这种方法可以提供有关针对配体 - 受体相互作用下游的雄激素受体途径的新药物发展的洞察力。