CORE 2 DB2: PROTEOLYTIC REGULATION OF HIF-1ALPHA

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。驱动生物学项目2：HIF-α的蛋白分解调节：一种古老的蛋白水解酶途径调节冯·希佩尔-林道血管生成网络由于蛋白酶体途径中的促血管生成缺陷，von Hippel-Lindau综合征患者表现为中枢神经系统和眼睛的高度血管化肿瘤。冯·希佩尔-林道蛋白是E3泛素-蛋白连接酶复合体的一部分。该复合体以缺氧诱导因子(HIF)-1α为靶点进行降解。我们对日本河豚(Fugu Rubripe)的计算分析揭示了一种古老的融合蛋白，由von Hippel-Lindau蛋白、两种蛋白酶、蛋氨酸氨基肽酶-2和一种类似LON的蛋白酶组成。我们计划测试Rosetta stone假说，即这三种蛋白质连接在一个蛋白分解网络中，参与调节HIF-α。我们的工作将包括尝试确定每种蛋白酶的底物，并努力测试它们在HIF-α途径中的作用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Driving Biological Project 2: Proteolytic Regulation of HIF-lalpha: An Ancient Protease Pathway Regulates the Von Hippel-Lindau Angiogenesis Network Patients with von Hippel-Lindau syndrome present with highly vascularized tumors of the CNS and the eye, because of a pro-angiogenic defect in the proteasome pathway. The von Hippel-Lindau protein is part of an E3 ubiquitin-protein ligase complex. This complex targets hypoxia-inducible factor (HIF)-1alpha for degradation. Our computational analysis of the Japanese pufferfish (Fugu rubripes) reveals an ancient fusion protein comprised of the von Hippel-Lindau protein, and two proteases, methionine aminopeptidase-2, and a LON-like protease. We plan to test the Rosetta stone hypothesis, namely that these three proteins are linked in a proteolytic network involved in regulating HIF-lalpha. Our work will include attempts to identify the substrates for each protease, and efforts to test their role in the HIF-lalpha pathway