Notch2 Signaling Sensitizes Endothelial Cells to Apoptosis by Negatively Regulating the Key Protective Molecule Survivin 英文参考文献.docVIP
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Notch2 Signaling Sensitizes Endothelial Cells to Apoptosis by Negatively Regulating the Key Protective Molecule Survivin 英文参考文献
Notch2SignalingSensitizesEndothelialCellsto
ApoptosisbyNegativelyRegulatingtheKeyProtective
MoleculeSurvivin
ThibautQuillard1,2,3¤a,JulieDevalliere1,2,3,MathiasChatelais1,2,3,FloraCoulon1,2,3,Ce′lineSe′veno4,
MathildeRomagnoli4¤b,SophieBarille′ Nion4,Be′atriceCharreau1,2,3*
1INSERM,UMR643,Nantes,France,2CHUNantes,InstitutdeTransplantationetdeRechercheenTransplantation,ITERT,Nantes,France,3Universite′ deNantes,Faculte′
deMe′decine,Nantes,France,4INSERM,UMR892,Nantes,France
Abstract
Background:Notchsignalingpathwaycontrolskeyfunctionsinvascularandendothelialcells(ECs)whereNotch4playsa
majorrole.However,littleisknownaboutthecontributionofotherNotchreceptors.Thisstudyinvestigatedregulationof
Notch2andfurtherexamineditsimplicationinECdysfunction.
Methodology/Principal Findings: Here, we provide evidence for a novel link between Notch and TNF signaling, where
Notch2isupregulatedandactivatedinresponsetoTNF.ForcedexpressionofNotch2intracellulardomaininculturedECs
promotesapoptosisandallowsthesignificantdownregulationofseveralcell-death-relatedtranscriptsinadose-dependent
manner.Inparticular,activationofNotch2ledtoarapiddecreaseinsurvivinmRNAandproteinexpression,whilesurvivin
upregulationwasobtainedbytheselectiveknockdownofNotch2inECs,indicatingthatsurvivinexpressioniscontrolledat
theNotchlevel.Moreover,Notch2silencingandectopicexpressionofsurvivin,butnotXIAPorBcl2,rescuedECsfromTNF
andNotch2-mediatedapoptosis,respectively.
Conclusions/Significance:Inconclusion,TNFsignalingactivatesNotch2thatsensitizesECstoapoptosisviamodulationof
the key apoptosis regulator survivin. Overall, our findings also indicate that specific Notch receptors control distinct
functionsinvascularcellsandinflammatorycytokinescontributetothisspecificity.
Citation: Quillard T, Devalliere J, Chatelais M, Coulon F, Se′veno C, et al. (2009) Notch2 Signaling Sensitizes Endothelial Cells to Apoptosis by Negatively
RegulatingtheKeyProtectiveMoleculeSurvivin.PLoSONE4(12):e8244.doi:10.1371/journal.pon
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