Regulation and Cytoprotective Role of Hexokinase III 英文参考文献.docVIP

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Regulation and Cytoprotective Role of Hexokinase III 英文参考文献.doc

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Regulation and Cytoprotective Role of Hexokinase III 英文参考文献

RegulationandCytoprotectiveRoleofHexokinaseIII EugeneWyatt1,RongxueWu1,WaelRabeh2,Hee-WonPark2,3,MohsenGhanefar1,HosseinArdehali1* 1DivisionofCardiology,DepartmentofMedicine,NorthwesternUniversityFeinbergSchoolofMedicine,Chicago,Illinois,UnitedStatesofAmerica,2StructuralGenomics Consortium,UniversityofToronto,Toronto,Canada,3DepartmentofPharmacology,UniversityofToronto,Toronto,Canada Abstract Background: Hexokinases (HKs) catalyze the first step in glucose metabolism. Of the three mammalian 100-kDa HK isoforms,HKIandIIcanbindtomitochondriaandprotectagainstcelldeath.HKIIIdoesnotbindmitochondria,andlittleis knownaboutitsregulationorcytoprotectiveeffects.WestudiedtheregulationofHKIIIatthetranscriptionalandprotein levelsandinvestigateditsroleincellularprotection. Methodology/PrincipalFindings:WeshowthatlikeHKII,HKIIIexpressionisregulatedbyhypoxia,butotherfactorsthat regulate HKIIexpression haveno effect on HKIII levels. This transcriptional regulation is partially dependenton hypoxia- induciblefactor(HIF)signaling.Wealsodemonstrateregulationattheproteinlevel,asmutationsinputativeN-terminal substrate binding residues altered C-terminal catalytic activity, suggesting that HKIII activity is governed, in part, by interactionsbetweenthesetwodomains.OverexpressionofHKIIIreducedoxidant-inducedcelldeath,increasedATPlevels, decreased the production of reactive oxygen species (ROS), and preserved mitochondrial membrane potential. HKIII overexpressionwasalsoassociatedwithhigherlevelsoftranscriptionfactorsthatregulatemitochondrialbiogenesis,and greatertotalmitochondrialDNAcontent.AttemptstotargetHKIIItothemitochondriabyreplacingitsN-terminal32-amino- acidsequencewiththemitochondrial-targetingsequenceofHKIIledtoproteinaggregation,suggestingthatthisregionis necessarytomaintainproperproteinfoldingandsolubility. Conclusions/Significance: These results suggest that HKIII is regulated by hypoxia and there are functional interactions between its two halves. Furthermore, HKIII exerts pro