SonicHedgehog(Shh)isasecretedproteinidentifiedgeneticallyasanimportantdevelopmentalfactor.ShhprovidesamorphogenicsignalinthedevelopingCNS,organizingthespatialpatterningofcellsinthemidbrainandinducingproliferationofneuronalprecursorcellsinthedevelopingcerebellum,neuraltubeandretina.ProliferativesignalingbyShhisinvolvedinthedevelopmentofcancer,includingspecificbrainandskincancerssuchasbasalcellcarcinomas.Sonichedgehogsignalingmayproceedbymorethanonemechanism.OnesignalingpathwayisactivatedbyShhbindingtoPatched(Ptc-1)whichreleasesinhibitionoftheGPCRSmoothened,activatingtheShhsignalingpathwayandallowingprogressionthroughtheG1phaseofthecellcycle.ShhcanalsoaffectprogressionthroughtheG2/Mtransition.PatchedbindstophosphorylatedCyclinB1,onecomponentoftheM-phasepromotingfactor(MPF),alongwiththekinaseCdc2.TheinteractionofCyclinB1withPatchedblocksMPFactivity,blockingprogressionthroughtheG2/Mtransition.ShhbindingleadstodegradationofPtc-1,releaseofCyclinB1,andentryofthecyclinB1intothenucleus.PatchedactsasatumorsuppressorbyblockingMPFactivity.BlockadeoftheHedgehogpathwaybycyclopaminedemonstratedthetherapeuticpotentialofHedgehoginhibitioninthetreatmentofsomecancers.

Contributor:KosiGramatikoff,PhD

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