VHL, Jade-1 and protein stability in renal cancer

超出所提供的空间。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肿瘤抑制基因在大多数成人肾癌中发生突变。然而，VHL肿瘤抑制的机制尚不清楚。我们的实验室使用定向方法来寻找在肾癌中重要的VHL相互作用蛋白，已经将Jade-1（上皮细胞凋亡和分化基因）鉴定为特别强的VHL相互作用因子。Jade-1是一种新的肾脏富集的PEST和植物同源结构域蛋白，是一个新的蛋白质家族的成员。Jade-1是蛋白酶体降解途径的短寿命靶标，并且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致密化。VHL阻断Jade-1诱导的细胞凋亡并稳定Jade-1蛋白，这是一种新的VHL功能。此外，我们现在已经表明，Jade-1稳定是VHL突变依赖性的，非肾癌引起的VHL错义突变能够稳定Jade-1像野生型VHL。因此，Jade-1稳定是第一个显示与肾癌风险实质相关的VHL活性，表明它与疾病有关。Jade-1通过VHL的稳定是高度特异性的，因为它还没有被观察到与已知的或潜在的VHL合作伙伴。Jade-1以VHL依赖性方式是低氧诱导的，并且在条件性VHL缺失小鼠中显示改变的翻译后修饰的证据。因此，我们已经建立了令人信服的证据VHL-玉-1关系的真实性以及玉-1的令人信服的生物学意义。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VHL依赖的Jade-1稳定和修饰3. Jade-1在细胞凋亡和细胞应激中的作用及VHL 4的调节作用Jade-1作为转录因子和染色质致密化，以及VHL性能位点的调节==

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===========================================