低氧细胞应激的HIF-1信号通路-王苹苹

[e-mail]∥．journals．zju．edu．cn/medDOI10．3785/j．issn．1008-9292．2011．05．017HIF-1310058hypoxiainduciblefactorHIFHIF-1αHIF-1β、。10HIF-1HIF-1α。1Q494A1008-9292201105-0559-08HIF-1signalpathwayincellularresponsetohypoxiaWANGPing-pingKONGFan-pingCHENXue-qunDUJi-zengDepartmentofBasicMedicalSciencesZhejiangUniversitySchoolofMedicineHangzhou310058ChinaAbstractHIF-1iscomposedofHIF-1αandHIF-1βsubunits．Itpromotestargetgenestranscriptionunderhypoxiaandplaysessentialrolesincelldevelopmentphysiologicaladaptationsandpathologicalprocesses．Inthepast10yearstheresearchonsignalingpathwaysofHIF-1inresponsetocellhypoxiastressespeciallyonHIF-1α-mediatedgenetranscriptionhasmadegreatprogress．KeywordsHypoxia-induciblefactor1HypoxiaResponseelementsTranscriptionfactorsJZhejiangUnivMedicalSci2011405559-566．。1。HIF-1α。10HIF-1α。HIF-1HIF-1hypoxiaresponseelementHRE。HIF。1HIF-11．1HIF-1HIF-1120kDHIF-1α91－94kDHIF-1βaryl4052011JOURNALOFZHEJIANGUNIVERSITYMEDICALSCIENCESVol40No52011hydrocarbonreceptornucleartranslocatorARNT222basichelix-loop-helixbHLH/PER-ARNT-SIMPAS3NbHLH/PAS。bHLHNPAS。HIF-1αoxygendependentdegradationdomainODDDC2transactivationdomainTADTAD-Naminoacids531-575TAD-Caminoacids786-8262TADinhibitorydomainIDaminoacids576-785TAD4。HIF-αHIF-1α、HIF-2αHIF-3α3HIF-αHIF-1β。HIF-1αHIF-2α48%DNA。HIF-2αHIF-1α5。HIF-3αHIFHIF-3α1bHLHPASIPASinhibitoryPASdomainproteinIPASHIFIPASHIF-1α6。1．2HIF-1αHIF-1α5minHIF-1α2HIF-1α①FIH-1factor-inhibitingHIF-1HIF-1αC803HIF-1αCBPCREB-bindingprotein/p300HIF-1α7。②prolylhydroxylasePHDsHIF-1α564HIF-2α531402vonhippel-lindauproteinpVHLHIF-1αODDDHIF-1α8。PHDsHIF。PHDsFIH-1HIF-1α。HIF-1αCNLSHIF-1α。HIF-1βHIF-1αNCBP/p300。HIF-1αSUMOsmallubiquitin-likemodifierSUMOSUMOSENPs。。HIF-1αHIF-1αSUMO9SUMOHIF-1αVHLHIF-1α。SENPsHIF-1αSUMO9。HIF-1βSUMO10。SUMOHIF-1βHIF-α。HIF-1α。HIF-1αNO11。90heatshockprotein90Hsp90HIF-1αPASHIF-1α。RACK1receptorforactivatedproteinCkinase1Hsp90HIF-1αPASHIF-1α。17-AAG17-allylaminogeldanamycinHsp90Hsp90HIF-1αRACK1HIF-1α12。·065·402HREHREHIF-1HIF-1bindingsiteHBSA/GCGTG13。HIF-1αβHIF-1HRE。HIFHREHRE14。100HBSHBSN－3N－2A/G－1C1G2T3G4。A－14．5T－34．213。HRE－2T＞G＞C。CACGTGHIF-1β。1endothelin-1ET-1HREAACGTGHBS－216。vascularendothelialgrowthfactorVEGF1kb5'286bpHRE。HREHBS5'ATCGTGGG3'HIF-1HIF-1ancillarysequenceHAS5'CACAG3'16。VEGFVEGF。EPO3'HIF-15'-TACGTGCT-3'EPO3。HepG21insulin-likegrowthfactorbindingproteinIGFBP-120%1%24hHIF-1IGFBP-1HBS。－1086/－1090HBS3'-ACGTG-5'－1099/－1103HAS3'-CAGGT-5'IGFBP-117。HASHRE8bpHIF-1IGFBP-1。HASHIF-1HREHIF-1。HAS。HRE2HBSsHRE23HBSs18。HBSHREHRE8。AlactatedehydrogenaseALDHAHRE1cAMP-1ATF-1/CREB-119。GATA2GATA-bindingtranscriptionfactor-2GATA-2AP-1ET-120。VEGFHREAP-1EPOHRE4hepaticnuclearfactor4HNF-421。HRE18。3HIF-1HIF-170HIF-122。3．1HIF-1HIF-1。HIF-1VEGFinduciblenitricoxidesynthaseiNOS、ET-11hemeoxygenase-1HO-1。HIF-1αVEGF23。HIF-1α、、24-26HIF-2α·165·5．HIF-127。HIFαHIF-1α。HIF-128。3．2HIF-1、HIF-1。HIF-1。ATP。HIFLDHA。HIF-11pyruvatedehydrogenasekinase-1PDK1PDKA29。HIF-1ATP29。HIF-1305-。HIF-1HIF-1RNADNA。3．3HIF-1HIF32。HIFVHLWntHIF32。HIFMyc、IGF、VEGF、EPO、/BNIP3、NIX、PDK1、LDHA、DNAGADD45A、MMP1、LOX、CXCR432。HIFαVHLHIF-2αHIF-1α32HIF-1αMyc33。HIF-1αp53p5334。HIF-2αp5335。HIF。3．4HIF-1＜3%＜0．1%。HIFHIF36-37。1%～3%HIFBNIP3NIXBNIP3LBeclin1Bcl-238。NIXWXXLLC3。BNIP3FOXO3FOXO3HIFSirt139。3．5HIF-1。。、HIF40。NF-κB。、HIFNF-κB40。PHD1IKKIκBNF-κB41。NF-κBHIF-1α。IKKHIF-1αNF-κBHIF-1αHIF-1αNF-κB。HIF-2αIKK42。HIF-1。3．6HIF-1HIFα·265·40HIFαEPO43-44。EPOPHD-2/VHL/HIF-2α。VHLHIF-1αEPO44。PHD-2/VHL/HIF-2α45-47SNPFIHPHDHIF-1αARNTHIF-1βHIF-1αNotchICDNotch。HIF-1αMycMXI1MAXMyc．1Notch、MycFig．1HypoxiasignalingpathwayscrosstalkwithNotchandMycpathwaysPHD-2HIF-2α。PHD-2HIF-2α。EPO。HIF-1αHIF-1αIGF-1、IGFBP-1LDH“”48HIF-1αHIF-1αGlut1Glut1mRNA49。4HIF。MycNotch1。Myc、、。Myc50。Myc3。HIF-1αMycMyc51。HIF-1αDNAMycMYCMYC52。MXI1MYC53。MXI1MYC·365·5．HIF-1MAXMYCMYC-MAX。HIF-1αHIF-2αMXI1MYC。HIF-2αMAXMYC33。Notch。NotchDLL1DLL4Notch54。HIF-1αNotchNotchICD。HIF-1αNotchICDNotchNotch52。HIF-1αNotchICDNotchICD。FIH-1HIF-1αNotchICD55。FIH-1NotchHIF-1αFIH-1NotchICDFIH-1HIF-1α56。HIF-1、。HIF-1HIF-αDNA、。References1HOCHACHKAPWLUTZPL．MechanismoriginandevolutionofanoxiatoleranceinanimalsJ．CompBiochemPhysiolBBiochemMolBiol20011304435-459．2WANGGLSEMENZAGL．Purificationandcharacterizationofhypoxia-induciblefactor1J．JBiolChem199527031230-1237．3WANGGLJIANGBHRUEEAetal．Hypoxia-induciblefactor1isabasic-helix-loop-helix-PASheterodimerregulatedbycellularO2tensionJ．ProcNatlAcadSciUSA199592125510-5514．4JIANGBHZHENGJZLEUNGSWetal．Transactivationandinhibitorydomainsofhypoxia-induciblefactor1alpha．Modulationoftrans-criptionalactivitybyoxygentensionJ．JBiolChem19972723119253-19260．5HOLMQUIST-MENGELBIERLFREDLUNDELOFSTEDTTetal．RecruitmentofHIF-1alphaandHIF-2alphatocommontargetgenesisdifferentiallyregulatedinneuroblastomaHIF-2alphapromotesanaggressivephenotypeJ．CancerCell2006105413-423．6MAKINOYCAORSVENSSONKetal．InhibitoryPASdomainproteinisanegativeregulatorofhypoxia-induciblegeneexpressionJ．Nature20014146863550-554．7LENDAHLULEEKLYANGHetal．Generatingspecificityanddiversityinthetranscriptionalresponsetohypoxia