This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Driving Biological Project 2: Proteolytic Regulation of HIF-lalpha: An Ancient ProteasePathway Regulates the Von Hippel-Lindau Angiogenesis Network Patients with von Hippel-Lindau syndrome present with highly vascularized tumors of the CNS and theeye, because of a pro-angiogenic defect in the proteasome pathway. The von Hippel-Lindauprotein is part of an E3 ubiquitin-protein ligase complex. This complex targets hypoxia-induciblefactor (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 stonehypothesis, namely that these three proteins are linked in a proteolytic network involved inregulating HIF-lalpha. Our work will include attempts to identify the substrates for each protease, andefforts to test their role in the HIF-lalpha pathway
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