Cyclin-dependentkinaseinhibitor-2A(CDKN2A)goesbythecolloquialdesignationp16,whichissometimesreferredtoasp16(INK4).ThealphatranscriptofCDKN2Ahasbeenshowntoencodep16(INK4a),arecognizedtumorsuppressorthatinducesaG1cellcyclearrestbyinhibitingthephosphorylationoftheRBproteinbythecyclin-dependentkinasesCDK4andCDK6.ThebetatranscriptofCDKN2Aencodesp14(ARF).Thepredicted132-aminoacidp14(ARF)isshorterthanthecorrespondingmouseprotein,p19(ARF),andthe2proteinsshareonly50%identity.However,bothproteinshavetheABIlitytoelicitap53response,manifestintheincreasedexpressionofbothCDKN1AandMDM2,andresultinginadistinctivecellcyclearrestinboththeG1andG2/Mphases.TwounrelatedproteinsencodedbytheINK4A-ARFlocusfunctionintumorsuppression.ARFbindstoMDM2andpromotestherapiddegradationofMDM2.ThisinteractionismediatedbytheE1-beta-encodedN-terminaldomainofARFandaC-terminalregionofMDM2.ARF-promotedMDM2degradationisassociatedwithMDM2modificationandconcurrentp53stabilizationandaccumulation.Thep19(Arf)tumorsuppressorinhibitsproductionofribosomalRNA,retardingprocessingof47/45Sand32Sprecursors.TheseeffectscorrelatewithbutdonotstrictlydependuponinhibitionofrRNAbiosynthesisorcellcyclearrest,arenotmimickedbyp53,andrequireneitherp53norMdm2.Arfmutantslackingconservedaminoacidresidues2-14donotblockrRNAsynthesisandprocessingorinhibitcellproliferation.EvolutionmayhavelinkedaprimordialnucleolarArffunctiontoMdm2andp53,creatingamoreefficientcheckpoint-signalingpathwayforcoordinatingribosomalbiogenesisandcellcycleprogression.

Contributor:KosiGramatikoff,PhD

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