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《Free Radical Biology and Medicine》 0:1月13日 (2015)

CUL4B impedes stress-induced cellular senescence by dampening a p53-reactive oxygen species positive feedback loop

Wei, Zhao; Guo, Haiyang; Liu, Zhaojian; Zhang, Xiyu; Liu, Qiao; Qian, Yanyan; Gong, Yaoqin; Shao, Changshun

Abstract:

Tumor suppressorp53isknowntoregulatethelevelofintracellularreactiveoxygenspecies(ROS).Itcan either alleviateoxidativestressunderphysiologicalandmildlystressedconditionsorexacerbate oxidativestressunderhighlystressedconditions.Weherereportthatap53–ROSpositivefeedback loop drivesasenescenceprograminnormalhuman fibroblasts(NHFs)andthissenescence-drivingloop is negativelyregulatedbyCUL4B.CUL4B,whichcanassemblevariousubiquitinE3ligases,wasfoundto be downregulatedinstress-inducedsenescentcells,butnotinreplicativesenescentcells.Weobserved that p53-dependentROSproductionwassignificantly augmentedandstress-inducedsenescencewas greatlyenhancedwhenCUL4Bwasabsentordepleted.EctopicexpressionofCUL4B,ontheotherhand, blunted p53activation,reducedROSproduction,andattenuatedcellularsenescenceincellstreatedwith H2O2. CUL4Bwasshowntopromotep53ubiquitinationandproteosomaldegradationinNHFsexposed to oxidativestress,thusdampeningthep53-dependentcellularsenescence.Together,ourresults established acriticalroleofCUL4Binnegativelyregulatingthep53–ROSpositivefeedbackloopthat drivescellularsenescence.