VHL, Jade-1 and protein stability in renal cancer

修订摘要：肾癌是一种破坏性的恶性肿瘤，对 药物治疗。VHL肿瘤抑制基因在大多数成人肾脏中发生突变 癌症。然而，VHL抑制肿瘤的机制尚不清楚。使用 寻找肾脏中重要的VHL相互作用蛋白的定向方法 癌症，我们的实验室已经鉴定出JADE-1(细胞凋亡和 上皮细胞分化)作为一种特别强的VHL相互作用因子。 JADE-1是一种新的富肾、害虫和植物同源结构域蛋白，是一种 是一个新的蛋白质家族的成员。VHL稳定Jade-1蛋白，Jade-1是一种 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，伴有非肾癌导致的VHL错义突变 能够像野生型VHL一样稳定Jade-1。Jade-1稳定器是 因此，VHL活动第一次显示出与 肾癌的风险，这表明它与疾病有关。此外， VHL对JADE-1的稳定具有高度的特异性，因为它还没有 与已知或潜在的VHL合作伙伴进行观察。我们已经确立了 VHL-Jade-1关系的真实性也是令人信服的证据 作为玉石一号，S具有令人信服的生物学意义。我们提出以下建议 目标： 1.VHL-JADE-1蛋白-蛋白相互作用及JADE-1的表达 肾癌组织 2.VHL依赖的JADE-1的稳定和修饰 3.Jade-1在VHL诱导细胞凋亡及调控中的作用

Revised Abstract: 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-1, a novel,kidney-enriched, PEST and plant homeodomain protein, is a member of a new protein family. VHL 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. Moreover, stabilization of Jade-1 by VHL is highly specific, as it has not been observed with known or potential VHL partners. 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. Examination of the role of Jade-1 in apoptosis and modulation by VHL