TUMOR SUPPRESSOR PVHL FUNCTIONAL INTERACTION WITH CUL2

描述：pVHL的失活与 常见的和散发性的多血管肿瘤，包括肾细胞 癌(RCC)、中枢神经系统血管母细胞瘤和 嗜铬细胞瘤。PVHL抑制体内肿瘤形成，可能是通过 破坏低氧诱导的mRNAs的稳定性及其负性调节 相应的蛋白质。其中一些蛋白质是血管生成因子。 PVHL与Elongins C/B形成的复合体的结合 E3样泛素连接酶CUL-2是这种调节所必需的。这个 人pVHL/ElonginsC/B/CuL-2复合体可能由于其与 酵母cdc53/skp1/cdc34复合体，通过靶向破坏某些蛋白质 泛素依赖的蛋白分解。这些蛋白质中的一些可能对 低氧诱导基因的调控。这项提议的目标是 确定CuL-2在低氧诱导基因和/或调控中的作用 PVHL抑制肿瘤生长。申请者将描述内源性的 人CuL-2在常氧和低氧条件下的表达。我们将绘制CUL-2的地图 进入pVHL/ElonginsC/B/CuL-2复合体所需的残基，在 为了评估其在低氧诱导蛋白调控中的作用和 PVHL抑制肿瘤生长。通过以下方式进一步深入了解这一机制 哪个Cul-2参与了这一调控，细胞内的cul-2与 蛋白质将被鉴定和克隆。

DESCRIPTION: Inactivation of the pVHL is linked to the development of familiar and sporadic hypervascular neoplasms, including renal cell carcinomas (RCC), central nervous system hemangioblastomas and pheochromocytomas. pVHL suppresse tumor formation in vivo, likely by destabilizing hypoxia-inducible mRNAs and negatively regulating their corresponding proteins. Some of these proteins are angiogenic factors. Binding of pVHL to a complex formed between Elongins C/B and the putative E3-like ubiquitin ligase cul-2 is necessary for such a regulation. The human pVHL/ElonginsC/B/cul-2 complex may, by virtue of its homology to the yeast cdc53/skp 1/cdc34 complex, target certain proteins for destruction via ubiquitin-dependent proteolysis. Some of these proteins may be critical for the regulation of hypoxia-inducible genes. The goal of this proposal is to determine the role of cul-2 in regulation of hypoxia-inducible genes and/or tumor suppression by pVHL. The applicant will characterize the endogenous human cul-2 under conditions of normoxia and hypoxia. We will map the cul-2 residues required for its entrance into pVHL/ElonginsC/B/cul-2 complex, in order to assess its role in regulation of hypoxia-inducible proteins and tumor suppression by pVHL. To gain further insight into the mechanism by which cul-2 participates in this regulation, cellular cul-2 associated proteins will be identified and cloned.