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标题：eIF2α phosphorylation bypasses premature senescence caused by oxidative stress and pro-oxidant antitumor therapies
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作者：Kamindla Rajesh ; Andreas I. Papadakis ; Urszula Kazimierczak 等
期刊名称：Aging
出版年度：2013
卷号：5
期号：12
页码：884-901
出版社：U.S.Department of Health & Human Service
摘要：Eukaryotic. cells. respond. to. various. forms. of. stress. by. blocking. mRNA. translation. initiation. via. thephosphorylation.of.the.alpha.(¦Á).subunit.of.eIF2.at.serine.51.(S51).(eIF¦ÁP)..An.important.role.of.eIF2¦ÁP.is.the.regulation.ofredox. homeostasis. and. adaptation. of. cells. to. oxidative. stress...Herein,. we. demonstrate. that. eIF2¦ÁP. guards. cells. fromintracellular..reactive. oxygen. species. (ROS). via. the. inhibition. of. senescence.. Specifically,. genetic. inactivation. of. eithereIF2¦ÁP. or. eIF2¦Á. kinase. PERK. in. primary. mouse. or. human. fibroblasts. leads. to. proliferative. defects. associated. withincreased.DNA.damage,.G2/M.accumulation.and.induction.of.premature.senescence..Impaired.proliferation.of.either.PERKor. eIF2¦ÁP©\deficient.primary. cells. is. caused. by. increased.ROS. and. restored. by. anti©\oxidant.treatment..Contrary.to. primarycells,.immortalized.mouse.fibroblasts.or.human.tumor.cells.become.tolerant.to.elevated.intracellular.ROS.levels.caused.byimpaired. eIF2¦ÁP..However,. eIF2¦ÁP©\deficient. human. tumor. cells. are. highly. susceptible. to. extrinsic. ROS. generated. by. thepro©\oxidant.drug. doxorubicin. by. undergoing. premature. senescence.. Our. work.demonstrates. that. eIF2¦ÁP. determines.celldestiny. through. its. capacity. to. control. senescence. in. response. to. oxidative. stress.. Also,. inhibition. of. eIF2¦ÁP. may. be. asuitable.means.to.increase.the.anti©\tumor.effects.of.pro©\oxidant.drugs.through.the.induction.of.senescence
关键词：eIF2;.protein.phosphorylation;.mRNA.translation;.reactive.oxygen.species;.DNA.damage;.cellular.senescence;.;doxorubicin.