Smad6/7 as Sex Steroid Hormone Receptor Corepressors

Smad6/7 作为性类固醇激素受体辅阻遏物

• 批准号: 6747653
• 负责人: Xu Cao
• 金额: $ 25.38万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6747653
• 关键词: androgen receptor; apoptosis; athymic mouse; biological signal transduction; cell proliferation; gene expression; gene induction /repression; growth factor receptors; growth inhibitors; immunoprecipitation; neoplastic process; prostate neoplasms; protein protein interaction; steroid hormone receptor; tissue /cell culture; transcription factor; transforming growth factors; yeast two hybrid system

DESCRIPTION (provided by applicant): Castration and antiandrogens have been used to prevent prostate cancer growth at all stages. However, androgen withdrawal by chemical or surgical castration only slows tumor progression as prostate cancer eventually becomes hormone-independent, resumes growth and kills the patient. This suggests other growth factors are involved in the process. TGF-beta is one of few classes of endogenous inhibitors of cell growth. Loss of responsiveness to TGF-beta is believed to be a major factor in tumor formation. In prostate cancer, the TGF-beta pathway is often inactive with loss expression of TGF-beta receptor. In our preliminary studies, we find that: 1) Smad7, a TGF-beta antagonist, directly interacts with androgen receptor (AR) and inhibits AR-induced gene transcription. Importantly, Smad7 was immunocoprecipitated with histone deacetylase (HDAC), indicating its potential role as a transcription repressor. 2) Smad6, the other antagonist, interacts with Tip6O and RIP 140 androgen receptor coactivators and also inhibits AR-mediated gene expression. Our findings suggest the interaction between antagonist Smads and AR/coactivators serve as a novel cross-talk mechanism between TGF-beta and androgen, since expression of Smad7 and Smad6 are turned on by TGF-beta signaling. In prostate cancers, defect TGF-beta signaling results in deficiency of both Smad7 and Smad6, which may in turn shut down the antagonist Smads capability in down-regulating AR-enhanced gene expression and prostate cell proliferation. Therefore, we hypothesize that the interaction of antagonist Smads with AR and its coactivators such as RIP 140, regulates AR transcription activity and inhibits AR-induced prostate cell growth. Characterization of the cross-talk mechanisms will be helpful in understanding TGF-beta mediated inhibition of prostate cancer growth. We will pursue the following specific aims:1) Characterize the interactions of Smad7 with AR and Smad6 with an AR coactivator, RIP140. 2) Examine function of Smad7and Smad6 on androgen-induced cellular response. 3) Determine the molecular mechanism underlying Smad7 and Smad6 induced alternation of AR activity. 4) Characterize the effects Smad7 and smad6 on prostate cancer progression in nude mice. We believe that characterization of the cross-talk mechanism between TGF-beta and androgen would enable development of a TGF-beta based therapeutic strategy for the treatment of prostate cancer and improve anti-androgen treatment for prostate patients.

说明(申请人提供)：去势和抗雄激素已用于预防前列腺癌生长的所有阶段。然而，通过化学或手术去势来撤除雄激素只会减缓肿瘤的进展，因为前列腺癌最终变得不依赖激素，恢复生长并杀死患者。这表明，其他增长因素也参与了这一过程。转化生长因子-β是为数不多的内源性细胞生长抑制因子之一。对转化生长因子-β的反应性丧失被认为是肿瘤形成的主要因素。在前列腺癌中，转化生长因子-β途径通常是不活跃的，转化生长因子-β受体的表达缺失。在我们的初步研究中，我们发现：1)转化生长因子-β拮抗剂Smad7直接与雄激素受体(AR)相互作用，抑制AR诱导的基因转录。重要的是，Smad7与组蛋白脱乙酰酶(HDAC)免疫共沉淀，表明其作为转录抑制因子的潜在作用。2)另一种拮抗剂Smad6与Tip6O和RIP140雄激素受体共激活剂相互作用，并抑制AR介导的基因表达。我们的发现提示，Smad7和Smad6的表达是通过Smad7和Smad6的表达而启动的，因此，拮抗剂Smads和AR/辅活化子之间的相互作用是一种新的转化生长因子-β与雄激素之间的串扰机制。在前列腺癌中，转化生长因子-β信号的缺陷导致Smad7和Smad6的缺失，这可能反过来关闭拮抗剂Smads下调AR增强的基因表达和前列腺细胞增殖的能力。因此，我们假设拮抗剂Smads与AR及其辅激活剂如RIP 140相互作用，调节AR的转录活性，并抑制AR诱导的前列腺细胞生长。串扰机制的表征将有助于理解转化生长因子-β介导的前列腺癌生长抑制作用。我们将追求以下具体目标：1)表征Smad7与AR以及Smad6与AR共激活子RIP140的相互作用。2)检测Smad7和Smad6在雄激素诱导的细胞反应中的作用。3)确定Smad7和Smad6引起AR活性改变的分子机制。4)研究Smad7和Smad6对前列腺癌裸鼠移植瘤生长的影响。我们相信，表征转化生长因子-β与雄激素之间的相互作用机制将有助于开发基于转化生长因子-β的前列腺癌治疗策略，并改进前列腺癌患者的抗雄激素治疗。