Vascularendothelialgrowthfactor(VEGF)playsakeyroleinphysiologicalbloodvesselformationandpathologicalangiogenesissuchastumorgrowthandischemicdiseases.HypoxiaisapotentinducerofVEGFinvitro.TheincreaseinsecretedBIOLOGicallyactiveVEGFproteinfromcellsexposedtohypoxiaispartlybecauseofanincreasedtranscriptionrate,mediatedbybindingofhypoxia-inducIBLefactor-1(HIF1)toahypoxiaresponsiveelementinthe5"-flankingregionoftheVEGFgene.bHLH-PAStranscriptionfactorthatinteractswiththeAhreceptornucleartranslocator(Arnt),anditspredictedaminoacidsequenceexhibitssignificantsimilaritytothehypoxia-induciblefactor1alpha(HIF1a)product.HLFmRNAexpressioniscloselycorrelatedwiththatofVEGFmRNA..ThehighexpressionlevelofHLFmRNAintheO2deliverysystemofdevelopingembryosandadultorganssuggeststhatinanormoxicstate,HLFregulatesgeneexpressionofVEGF,variousglycolyticenzymes,andothersdrivenbytheHREsequence,andmaybeinvolvedindevelopmentofbloodvesselsandthetubularsystemoflung.VEGFexpressionisdramaticallyinducedbyhypoxiadueinlargeparttoanincreaseinthestABIlityofitsmRNA.HuRbindswithhighaffinityandspecificitytotheVRSelementthatregulatesVEGFmRNAstabilitybyhypoxia.Inaddition,aninternalribosomeentrysite(IRES)ensuresefficienttranslationofVEGFmRNAevenunderhypoxia.TheVHLtumorsuppressor(vonHippel-Lindau)regulatesalsoVEGFexpressionatapost-transcriptionallevel.ThesecretedVEGFisamajorangiogenicfactorthatregulatesmultipleendothelialcellfunctions,includingmitogenesis.CellularandcirculatinglevelsofVEGFareelevatedinhematologicmalignanciesandareadverselyassociatedwithprognosis.Angiogenesisisaverycomplex,tightlyregulated,multistepprocess,thetargetingofwhichmaywellproveusefulinthecreationofnoveltherapeuticagents.Currentapproachesbeinginvestigatedincludetheinhibitionofangiogenesisstimulants(e.g.,VEGF),ortheirreceptors,blockadeofendothelialcellactivation,inhibitionofmatrixmetalloproteinases,andinhibitionoftumorvasculature.Preclinical,phaseI,andphaseIIstudiesofbothmonoclonalantibodiestoVEGFandblockersoftheVEGFreceptortyrosinekinasepathwayindicatethattheseagentsaresafeandofferpotentialclinicalutilityinpatientswithhematologicmalignancies.

Contributor:KosiGramatikoff,PhD

REFERENCES:EmaMetal.,AnovelbHLH-PASfactorwithclosesequencesimilaritytohypoxia-induciblefactor1alpharegulatestheVEGFexpressionandispotentiallyinvolvedinlungandvasculardevelopment.ProcNatlAcadSciUSA.(1997)Apr29;94(9):4273-8.FogartyM.findingwaystostarvethecanserseed:angiogenesis,lymphangiogenesis,bonemetastasesarefocusesofintenseredearch.Thescientist,may27,2002GilesFJ.Thevascularendothelialgrowthfactor(VEGF)signalingpathway:atherapeutictargetinpatientswithhematologicmalignancies.Oncologist.(2001);6Suppl5:32-9.Review.GnarraJRetal.,Post-transcriptionalregulationofvascularendothelialgrowthfactormRNAbytheproductoftheVHLtumorsuppressorgene.ProcNatlAcadSciUSA.(1996)Oct1;93(20):10589-94.LevyNS,etal.,HypoxicstabilizationofvascularendothelialgrowthfactormRNAbytheRNA-bindingproteinHuR.JBiolChem.(1998)Mar13;273(11):6417-23.McMahonG.VEGFreceptorsignalingintumorangiogenesis.Oncologist.2000;5Suppl1:3-10.Review.SteinI,etal.,TranslationofvascularendothelialgrowthfactormRNAbyinternalribosomeentry:implicationsfortranslationunderhypoxia.MolCellBiol.(1998)Jun;18(6):3112-9.vascularendothelialgrowthfactor.Mini-reviews&technicalinformation.http://www.rndsystems.com

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