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1、LeadingEdgeReviewTheRegulationofINK4/ARFinCancerandAgingWilliamY.Kim1andNormanE.Sharpless1,*1DepartmentsofMedicineandGenetics,TheUniversityofNorthCarolinaSchoolofMedicine,ChapelHill,NC27599,USA*Contact:nes@med.unc.eduDOI10.1016/j.cell.2006.10.003LossoftheINK4a/ARF/INK4blocusonchromosome9p21isamong
2、themostfrequentcytogeneticeventsinhumancancer.Theproductsofthelocus—p15INK4b,p16INK4a,andARF—playwidespreadandindependentrolesintumorsuppression.Recentdataalsosuggestthatexpressionofp16INK4ainducesanage-dependentdecreaseintheproliferativecapacityofcertaintissue-specificstemcellsandunipotentprogeni
3、tors.Here,wediscusstheregulationandroleofp16INK4a,ARF,andp15INK4bincancerandaging.Regulatedcellularproliferationisrequiredformamma-commonsecondandthirdexon.Althoughexons2and3lianhomeostasis,butuncontrolledproliferationisthearesharedbyp16INK4aandARF,theproteinsareencodedhallmarkofcancer.Therefore,a
4、nimportantquestionininalternativereadingframes.Asaconsequencep16INK4acancerbiologyishowatumorsuppressorproteindis-andARFarenotisoformsanddonotshareanyaminotinguishesmalignantfromphysiologicalgrowth?Thisisacidhomology(Figure1).nomeanfeat.PhysiologicgrowthcanhavemanyoftheTheINK4classofcell-cycleinhi
5、bitorsp15INK4b,p16INK4a,propertiesassociatedwiththeworstmalignancies:itp18INK4c,andp19INKd(thelatternottobeconfusedwithcanberapid,disordered,unexpected,andinvasive(forp19ARF)arehomologousinhibitorsofthecyclin-dependentexample,aninflammatoryresponsetoawound).Cellskinases,CDK4andCDK6,whichpromotepro
6、liferation.Inharboringoncogenicmutationsinvivooftenrespondbyparticular,p15INK4bandp16INK4aare85%similarattheaminoactivatingexpressionoftheINK4a/ARF/INK4blocus,acidlevelandlittlebiochemicaldistinctionhasbeenmadewhichencodescriticaltumorsuppressorproteins.Thisbetweentheseproteins(reviewedinSharpless
7、,2005).TheindicatesthatcellsunderstandataveryearlystageofbindingoftheINK4proteinstoCDK4andCDK6inducestransformationthatsomethinghasgoneawry.Under-anallostericchangethatabrogatesthebindingofthesestandinginmolecula
