Hypoxicstress,likeDNAdamage,inducesp53proteinaccumulationandp53-dependentapoptosisinoncogenicallytransformedcells.UnlikeDNAdamage,hypoxiadoesnotinducep53-dependentcellcyclearrest,suggestingthatp53activityisdifferentiallyregulatedbythesetwostresses.Hypoxiainducesp53proteinaccumulation,butincontrasttoDNAdamage,hypoxiafailstoinduceendogenousdownstreamp53effectormRNAsandproteins,suchasp21,Bax,CIP1,WAF1etc.Hypoxiadoesnotinhibittheinductionofp53targetgenesbyionizingrADIation,indicatingthatp53-dependenttransactivationrequiresaDNAdamage-inducIBLesignalthatislackingunderhypoxictreatmentalone.Thephosphatidylinositol3-OH-kinase-Aktpathwayinhibitsp53-mediatedtranscriptionandapoptosis.Mdm2,aubiquitinligaseforp53,playsacentralroleinregulationofthestABIlityofp53andservesasagoodsubstrateforAkt.Mdm-2targetsthep53tumorsuppressorforubiquitin-dependentdegradationbytheproteasome,but,inaddition,thep53transcriptionfactorinducesMdm-2,thus,establishingafeedbackloop.HypoxiaorDNAdamagebyabrogatingbindingofHIF-1withVHLandp53withMdm-2,respectively,leadstostabilizationandaccumulationtranscriptionallyactiveHIF-1andp53.Atthemolecularlevel,DNAdamageinducestheinteractionofp53withthetranscriptionalactivatorp300aswellaswiththetranscriptionalcorepressormSin3A.Incontrast,hypoxiaprimarilyinducesaninteractionofp53withmSin3A,butnotwithp300.

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