CORE 2 DB2: PROTEOLYTIC REGULATION OF HIF-1ALPHA

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心机构，不一定为研究者机构。驱动生物项目2：HIF-1 α的蛋白水解调节：一种古老的蛋白酶途径调节Von Hippel-Lindau血管生成网络von Hippel-Lindau综合征患者由于蛋白酶体途径中促血管生成缺陷，表现为CNS和眼部高度血管化的肿瘤。von Hippel-Lindau蛋白是E3泛素-蛋白连接酶复合物的一部分。该复合物靶向缺氧诱导因子（HIF）-1 α进行降解。我们的日本河豚（红鳍东方鲀）的计算分析揭示了一个古老的融合蛋白组成的冯希佩尔-林道蛋白，和两个蛋白酶，蛋氨酸氨肽酶-2，LON样蛋白酶。我们计划测试罗塞塔石碑假说，即这三种蛋白质连接在一个蛋白水解网络参与调节HIF-1 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-1 α通路中的作用。

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