Hypoxia(orlowO2levels)affectsvariouspathologies.First,tissueischemia,avariationinO2tensioncausedbyhypoxia/reoxygenation,canleadtoendothelialcellchanges.Forexample,longperiodsofischemiaresultinendothelialchanges,suchasvascularleakage,resultinginvaricoseveins.Inmoreseveresituations,ischemiacanleadtomyocardialorcerebralinfarctionandretinalvesselocclusion.Ofinterest,HIF-1isstABIlizedpriortoinductionofvascularendothelialgrowthfactor(VEGF)expressionduringacuteischemiainthehumanheart.Second,pulmonaryhypertensionassociatedwithchronicrespiratorydisordersresultsfrompersistentvasoconstrictionandvascularremodeling.Third,hypoxicgrADIentscreatedinenlargingsolidtumorstriggerexpressionofgenescontaininghypoxiaresponseelement(HRE)ssuchasthoseinvolvedinangiogenesis.ThisallowssubsequentdeliveryofO2,nutrients,andfurthertumorgrowth.VascularremodelingisanimportantcomponenttotumOrigenesis;withoutproperbloodsupply,deliveryofoxygenmayoccurbydiffusion,butbecomesinefficientintumorsgreaterthan1mmindiameter.Short-termhypoxiacanalsoelevateplateletnumbers,whileprolongedexposuremaycausesomedegreeofthrombocytopeniainresponsetoincreasedlevelsoferythropoetin(EPO).Anotherdisorderinvolvinginadequateresponsestohypoxiaispreeclampsia,apathologyofpregnancythoughttobecausedbyimproperdifferentiationofplacentaltrophoblastcellsduetopoorlycontrolledO2tensionorimproperhypoxia-inducIBLefactor(HIF)-mediatedresponses.TheprimarymolecularmechanismofgeneactivationduringhypoxiaisthroughHIF-1.Severalgenesinvolvedincellulardifferentiationaredirectlyorindirectlyregulatedbyhypoxia.TheseincludeEPO,LDH-A,ET-1,transferrin,transferrinreceptor,VEGF,Flk-1,Flt-1,platelet-derivedgrowthfactor-?(PDGF-?),basicfibroblastgrowthfactor(bFGF),andothersgenesaffectingglycolysis.HIF-1isamemberofthebasichelix-loop-helix(bHLH)-PASfamilyoftranscriptionfactorsknowntoinducegeneexpressionbybindingtoa~50-bpHREcontainingacore5"-ACGTG-3"sequence.bHLH-PASproteinsheterodimerizetoformtranscriptioncomplexesthatregulateO2homeostasis,circadianrhythms,neurogenesis,andtoxinmetabolism.ThreebHLH-PASproteinsinvertebratesrespondtohypoxia:HIF-1,EPAS(HIF-2),andHIF-3.ThesedimerizewithARNT(arylhydrocarbonreceptornucleartranslocatorprotein),ARNT-2,orARNT-3.HIF-1isubiquitinatedandsubsequentlydegradedinlessthan5minutesundernormoxicconditions.AlthoughseveralcandidateO2-sensingmoleculeshaveemergedintheliterature,themolecularbasisofhowcellssenseO2levelsispoorlycharacterized.pVHL,theproteinproductofatumor-suppressorgeneresponsibleforvonHippelLindaudisease,isimplicatedinthisO2-sensingsystembyitsassociationwithHIF-1,targetingitforubiquitin-mediateddegradation.Similarly,F-box-containingproteinsrecognizesubstratesoftheubiquitinligases,targetingthemforphosphorylation-dependentubiquitinationandproteosomaldegradation.InadditiontoF-boxes,mostoftheseproteinsalsocontainaWD40oraleucine-richrepeat(LLR)domainthatpresumablyfunctionsasaSer/Thrbindingmodule.AsecondfamilyofproteinsassistingtheubiquitinligasessharearegiondesignatedSOCS-box(originallyfromthesuppressorofcytokinesignalingproteinsSOCS).UnderlowO2(<5% o2)="" hif-1="" is="" stabilized="" leading="" to="" the="" formation="" of="" a="" functional="" transcription="" factor="" complex="" with="" arnt.="" this="" complex="" is="" the="" master="" regulator="" of="" o2="" homeostasis="" and="" induces="" a="" network="" of="" genes="" involved="" in="" angiogenesis,="" erythropoiesis,="" and="" glucose="">

Contributor:KosiGramatikoff,PhD

REFERENCES:HarrisA.L.vonHippel-Lindausyndrome:targetforanti-vascularendothelialgrowthfactor(VEGF)receptortherapy.Oncologist.2000;5Suppl1:32-6.Review.KrebsDL,HiltonDJ.SOCSproteins:negativeregulatorsofcytokinesignaling.StemCells.2001;19(5):378-87.Review.Ramirez-BergeronDL,SimonMC.Hypoxia-induciblefactorandthedevelopmentofstemcellsofthecardiovascularsystem.StemCells2001;19(4):279-86Review.SemenzaGL.HIF-1andmechanismsofhypoxiasensing.CurrOpinCellBiol.2001Apr;13(2):167-71.Review.YaffeMB,EliaAE.Phosphoserine/threonine-bindingdomains.CurrOpinCellBiol.2001Apr;13(2):131-8.Review.

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