ThetranscriptionalregulatorCREMplaysakeyroleinspermatogenesis,actingasacentraltranscriptionfactortriggeringacascadeoftranscriptionalactivationofpost-meioticgenesinvolvedinthisprocesssuchascalsperminandtestisangiotensin-convertingenzyme.ThekeyroleofCREMinspermformationisdemonstratedbythemalesterilityofmicelackingCREM,thefailureofspermatidstodevelopintomaturesperm,andalackofpost-meioticgeneexpressionintheseanimals.Priortomeiosis,splicevariantsofCREMactasantagoNISTsofcAMP-dependenttranscriptionalactivation,butcoordinatewithspermatogenesis,thepotenttranscriptionalactivatorCREMtausplicevariantishighlyexpressed.InothertissuesCREMactivatesgenesinresponsetocAMPthroughphosphorylationandCBPassociation,buttranscriptionalactivationbyCREMinmalegermcellsisCBPindependent.Stimulationofspermatidswithfollicle-stimulatinghormone(FSH)inducescAMPformation,andtheassociationofCREMwiththecoactivatorACT,althoughthemechanismregulatingtheinteractionofCREMwithACTisnotyetknown.Atwo-hybridscreenlookingforACTinteractingfactorsrevealedanothersurprisingcomponentregulatingCREM,thekinesinKif17b.Kinesinsaremolecularmotorsthatinteractwithmicrotubulestotransportorganellesandothermaterialwithinthecell.Kif17bisactivelyexportedfromthenucleusinaCrm1-dependentmanner,sowhenitisboundtoACTtheexportofKif17bexcludesCREM-ACTfromthenucleusandblockstranscriptionalactivationbythiscomplex.ThemechanismregulatingtheinteractionofKif17bwithACTtodriveCREMactivationisnotyetknown.Althoughtheregulationoftranscriptionbyakinesinissurprising,afunctionalconnectionbetweencytoskeletalelementsandtranscriptionalregulationisnotunprecedented,asdemonstratedbythetranscriptionfactorMIZ-1thatregulatestranscriptioninresponsetochangesinmicrotubulestructure.

Contributor:GlennCrostonPh.D.

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