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: 7227198
• 负责人: HERBERT TOD COHEN
• 金额: $ 30.53万
• 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 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7227198
• 关键词: Adult; Anoikis; Apoptosis; Apoptotic; Biological; Cancer Etiology; Cell Adhesion; Cells; Chromatin; Clinical; Degradation Pathway; Development; Disease; Epithelial Cells; Epithelium; Gene Expression; Gene Proteins; Genes; Homeodomain Proteins; Hypoxia; Kidney; Knockout Mice; Laboratories; Life; Malignant Neoplasms; Malignant neoplasm of kidney; Mediating; Medical; Microarray Analysis; Missense Mutation; Modeling; Modification; Mutate; Nature; Nuclear; Oncogenes; Pathway interactions; Plants; Post-Translational Protein Processing; Proteasome Inhibitor; Protein Family; Proteins; Renal carcinoma; Resistance; Role; Stress; Suppressor Mutations; Techniques; Testing; Tissues; Tumor Suppression; Tumor Suppressor Proteins; Von Hippel-Lindau Tumor Suppressor Protein; base; biological adaptation to stress; cancer risk; cell growth; clinically relevant; design; member; monolayer; multicatalytic endopeptidase complex; novel; pro-apoptotic protein; protein protein interaction; therapeutic target; transcription factor; tumorigenesis

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

肾癌是一种对药物治疗具有高度抵抗力的毁灭性恶性肿瘤。VHL肿瘤 在大多数成人肾癌中抑制基因突变。然而，VHL肿瘤抑制的机制是 不知道。使用定向方法来寻找在肾癌中重要的VHL相互作用蛋白， 一个实验室已经鉴定出Jade-1（上皮细胞凋亡和分化基因）是一种特别的 强VHL相互作用。Jade-1是一种新的肾脏富集的PEST和植物同源结构域蛋白， 一个新的蛋白质家族。Jade-1是蛋白酶体降解的短寿命靶点 途径，是强烈的促凋亡，因为它减少细胞粘附，并直接促进 染色质致密化VHL阻断Jade-l诱导的细胞凋亡并稳定Jade-1蛋白，这是 新的VHL功能。此外，我们现在已经表明，Jade-1稳定化是VHL 突变依赖性，非肾癌引起的VHL错义突变能够稳定Jade-1 类似于野生型VHL。因此，Jade-1稳定化是第一个显示出显著的VHL活性的VHL活性。 与肾癌风险的相关性，表明它与疾病有关。Jade-1的稳定化 VHL是高度特异性的，因为它尚未与已知或潜在的VHL合作伙伴观察到。玉-1是 低氧诱导的VHL依赖性的方式，并显示改变的翻译后的证据 在条件性VHL缺失小鼠中的修饰。我们已经有了确凿的证据， VHL-Jade-1关系的真实性以及Jade-1引人注目的生物学意义。我们 提出以下目标： 1. VHL-Jade-1蛋白相互作用及Jade-1在肾癌组织中的表达 2. VHL依赖性Jade-1稳定化和修饰 3. Jade-1在细胞凋亡和细胞应激中的作用及VHL的调节作用 4. Jade-1作为转录因子与染色质致密化及VHL的调节