Nat Rev Drug Discov 2017从基础细胞凋亡发现到高级选择性BCL-2家族抑制.pdfVIP免费

TypeIprogrammedcelldeath,alsoknownasapopto­sis,wasfirstdefinedintheearly1970s1andisatightlycontrolledprocessthatiscrucialfortissuehomeostasis.Theabilitytoavertapoptosisisakeycharacteristicofcancercells2.Apoptosiscanbetriggeredbyextra­cellularorintracellularstimuli;inrecentdecades,themolecularmechanismsunderlyingtheintrinsic3andextrinsic4apoptoticpathwayshavebeenelucidated5.Theextrinsicpathwayisactivatedinresponsetothebindingofdeath­inducingligandstocell­surfacedeathreceptors.Cell­intrinsicapoptoticstimuliincludeDNAdamage,growthfactordeprivationandoxidativestress.Initiationoftheintrinsicpathway(FIG.1)leadstomito­chondrialdepolarization,whichallowsthereleaseofcytochromec.Inturn,cytochromecbindstoapoptosisprotease­activatingfactor1(APAF1)andprocaspase9,generatinganintracellular‘apoptosome’thatactivatescaspase9.Disruptedmitochondriaalsoproducesec­ondmitochondria­derivedactivatorofcaspase(SMAC;alsoknownasDIABLO),whichreleasescaspase3fromX­linkedinhibitorofapoptosis(XIAP)­mediatedinhibi­tion.Boththeextrinsicandintrinsicapoptosispathwaysconvergeoncaspase3andcaspase7,whichdrivetheterminaleventsofapoptosis5.TheBcelllymphoma2(BCL­2)genefamilyencodesmorethan20proteinsthatregulatetheintrinsicapopto­sispathway,andarefundamentaltothebalancebetweencellsurvivalanddeath6–8.BCL2wasinitiallydiscoveredaspartofthet(14;18)chromosomaltranslocation,whichoccursinpatientswithfollicularlymphomaanddiffuselargeBcelllymphoma(DLBCL),andleadstoelevatedBCL2transcription9,10.Althoughoriginallybelievedtoactasaclassicalgrowth­drivingoncogene,itwaslatershownthatBCL2insteadpromotesmalignantcellsurvivalbyattenuatingapoptosis11,12.MembersoftheBCL­2familyaregroupedtogether,astheycontainuptofourcon­servedBCL­2homology(BH)regions.Themultiregion(BH1–4)anti­apoptoticproteinsBCL­2,BCL­XL(alsoknownasBCL­2L1),BCL­W(alsoknownasBCL­2L2),myeloidcellleukaemia1(MCL1)andA1(alsoknownasBCL­2A1)antagonizepro­apoptoticBH3­onlyproteins,andtheyinhibittheessentialapoptosiseffectorsBCL­2antag...