VHL, Jade-1 and protein stability in renal cancer

肾癌中的 VHL、Jade-1 和蛋白质稳定性

• 批准号: 6919315
• 负责人: HERBERT TOD COHEN
• 金额: $ 32.2万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6919315
• 关键词: DNA binding protein; apoptosis; athymic mouse; chemical stability; chromatin; clinical research; gene expression; genetic regulation; human subject; human tissue; immunoprecipitation; kidney neoplasms; ligase; point mutation; posttranslational modifications; protein binding; protein degradation; protein localization; protein protein interaction; protein structure function; transcription factor; tumor suppressor proteins; ubiquitin

EXCEED THE SPACE PROVIDED. Renal cancer is a devastating malignancy that is highly resistant to medical therapy. The VHL tumor suppressor is mutated in most adult renal cancers. Yet, the mechanism of VHL tumor suppression is not known. Using a directed approach to find VHL-interacting proteins important in renal cancer, our laboratory has identified Jade-1 (gene for Apoptosis and Differentiation in Epithelia) as a particularly strong VHL interactor. Jade-l, a novel, kidney-enriched, PEST and plant homeodomain protein, is a member of a new protein family. Jade-1 is a short-lived target of the proteasome degradation pathway and is strongly pro-apoptotic, as it decreases cellular adhesion and directly promotes chromatin compaction. VHL blocks Jade-l-induced apoptosis and stabilizes Jade-1 protein, which is a new VHL function. Moreover, we have now shown that Jade-1 stabilization is VHL mutation-dependent, with non-renal cancer-causing VHL missense mutations able to stabilize Jade-1 like wild-type VHL. Jade-1 stabilization is therefore the first VHL activity to show substantial correlation with renal cancer risk, suggesting it has a disease relationship. Stabilization of Jade-1 by VHL is highly specific, as it has not been observed with known or potential VHL partners. Jade-1 is hypoxia-inducible in a VHL dependent manner and shows evidence of altered post-translational modification in conditional VHL null mice. Thus, we have established convincing evidence of the VHL-Jade-1 relationship's authenticity as well as Jade-1 's compelling biological significance. We propose the following Aims: 1. The VHL-Jade-1 protein-protein interaction, and Jade-1 expression in renal cancer tissue 2. VHL-dependent Jade-1 stabilization and modification 3. Jade-1 in apoptosis and cell stress, and modulation by VHL 4. Jade-1 as a transcription factor and in chromatin compaction, and modulation by VHL PERFORMANCE SITE ========================================Section End===========================================

超出所提供的空间。肾癌是一种对药物治疗具有高度耐药性的恶性肿瘤。VHL肿瘤抑制因子在大多数成人肾癌中发生突变。然而，VHL抑制肿瘤的机制尚不清楚。我们的实验室使用定向方法寻找在肾癌中重要的VHL相互作用蛋白，发现Jade-1（上皮细胞凋亡和分化基因）是一个特别强的VHL相互作用因子。jade - 1是一种新的、富含肾脏的、PEST和植物同源结构域蛋白，是一个新蛋白家族的成员。Jade-1是蛋白酶体降解途径的短期靶标，具有强烈的促凋亡作用，因为它降低细胞粘附并直接促进染色质压实。VHL阻断Jade-1诱导的细胞凋亡，稳定Jade-1蛋白，是VHL的新功能。此外，我们现在已经证明Jade-1的稳定是VHL突变依赖的，非肾癌的VHL错义突变能够稳定Jade-1样野生型VHL。因此，Jade-1稳定是第一个显示与肾癌风险显著相关的VHL活动，表明它与疾病有关。VHL对Jade-1的稳定是高度特异性的，因为它没有在已知或潜在的VHL伙伴中观察到。Jade-1以VHL依赖的方式缺氧诱导，并在条件VHL缺失小鼠中显示出翻译后修饰改变的证据。因此，我们已经建立了令人信服的证据，证明VHL-Jade-1关系的真实性，以及Jade-1令人信服的生物学意义。我们提出以下目标：VHL-Jade-1蛋白-蛋白相互作用及Jade-1在肾癌组织中的表达依赖vhl的Jade-1稳定和修改Jade-1在细胞凋亡和细胞应激中的作用及vhl4的调节作用。Jade-1转录因子和染色质压实,和调制VHL网站性能 ======================================== 节结束 ===========================================