Control of Prostate Growth and Tumor Progression

控制前列腺生长和肿瘤进展

• 批准号: 6951753
• 负责人: ROBERT J. MATUSIK
• 金额: $ 3.78万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6951753
• 关键词: SCID mouse; androgens; developmental genetics; gene expression; hormone regulation /control mechanism; matrix assisted laser desorption ionization; neoplastic process; prostate; prostate neoplasms; protein structure function; reproductive development; transcription factor

DESCRIPTION (provided by applicant): We have identified HNF3alpha , a member of the HNF3 forkhead family that bind to a consensus DNA sequence, as a new AR co-activator that is involved in androgen regulation and prostate-specific expression of the probasin (PB). HNF3alpha is expressed in the normal rodent prostate, our transgenic mouse models that develop preneoplastic lesions and in adenocarcinoma, and in all human prostate cancers examined. The closely related HNF3( forkhead protein was not expressed in the normal rodent prostate but was expressed in an androgen independent mouse neuroendocrine (NE) prostate cancer model and a subset of human prostate cancers. Expression of HNF3alpha in cell culture will increased androgen dependent AR activation of the PB and human Prostate Specific Antigen (PSA) promoters. Most importantly, co-expression of the HNF3beta gene with the PSA promoter-reporter in cell culture will activate the PSA promoter in an androgen-independent manner. Our Hypothesis is that HNF3alpha is key to normal prostate development and the expression of HNF3beta will switch androgen regulated genes to behave in an "androgen independent" manner. Our three Specific Aims are as follows: Aim 1: To characterize the HNF3 expression in the mouse UGS and prostate; Aim 2: To test the functional role of HNF3 proteins in prostate development; and Aim 3: To determine the role of HNF3alpha and HNF3beta in tumor development and progression. The overall goals of this grant are to establish the importance of the HNF3alpha in the normal development of the prostate and in androgen dependent tumor growth and the role of HNF3beta in rostate tumor progression to androgen-independence.

描述（由申请人提供）： 我们已经确定了与共有DNA序列结合的HNF3叉子家族的HNF3Alpha，是一种参与雄激素调节和前列腺特异性表达（PB）的新AR共激活剂。 HNF3Alpha在正常的啮齿动物前列腺，我们的转基因小鼠模型中表达，这些小鼠模型和腺癌腺瘤以及所有研究的人类前列腺癌中都表达。密切相关的HNF3（叉头蛋白未在正常啮齿动物前列腺中表达，而是在雄激素独立的小鼠神经内分泌（NE）前列腺癌模型和人类前列腺癌的子集中表达。HNF3Alpha在细胞培养中的表达将增加细胞培养的PB和人类抗抗酸的抗酸性抗酸性抗酸性抗酸的抗酸性抗体（PS）。在细胞培养中，具有pSA启动子的HNF3BETA基因将以雄激素启动子的方式激活雄激素的启动子，我们的假设是HNF3Alpha是正常的前列腺发育的关键，而HNF3BETA的表达是HNF3BETA的表达，而hNF3BETA的表达将与我们的三个特定范围”。小鼠UGS和前列腺；目标2：测试HNF3蛋白在前列腺发育中的功能；该赠款的总体目标是确定HNF3Alpha在前列腺正常发育和雄激素依赖性肿瘤生长中的重要性，以及HNF3Beta在Rostate肿瘤进展到雄激素独立性中的作用。