NovelantitumoractivityofFAM193Aprotein
Understandingtheprocessofcancerdevelopmentiscriticalfordesigningeffective,personalized cancertreatmentsForyears,researchershaveknownthatcancerbeginswithcertaintypesofgenetic mutationsOnetypeofcancergeneiscalleda"tumorsuppressorgene"Whenworkingproperly,tumor suppressorgenesstopmalignantcellsfromundergoinguncontrolledcellproliferationandinitiatea processofcelleliminationcalledapoptosis,aformofcelldeathMutationsintumorsuppressorgenes cancausethesegenestolosefunction,ultimatelyleadingtothedevelopmentofcancer
InastudyrecentlypublishedinCellReports,researchersattheUniversityofColoradoAnschutz SchoolofMedicinedescribethediscoveryandcharacterizationofanovelproteininvolvedinthe mechanismofsuppressionofdifferenttypesoftumors.
ThetumorsuppressorgeneknownasTP53,whicheffectivelylimitsthedevelopmentandgrowthof manydifferenttypesoftumorsinthebody,isthemostfrequentlymutatedtumorsuppressorgenein humancancers.Thisgeneencodesaproteincalledp53,whichisbothapotentinhibitorofcell proliferationandaninducerofapoptosis
DrZdenekAndrysik,assistantresearchprofessorofpharmacologyattheUniversityofColorado SchoolofMedicineandco-authorofthepaper,said:"Inmorethanhalfofallcancercases,TP53isnot mutated,butliesdormantAsaresult,muchresearchefforthasbeendevotedtodevelopdrugsto reactivatethislatentformofp53forcancertherapyHowever,mostcancersrespondtop53activation andthesedrugscauseatransientblockincellproliferationAbetterresponsetothesedrugsisthe eliminationofcancercellsthroughapoptosisTherefore,itiscrucialforustounderstandwhatother factorsarerequiredforeffectivep53-targetedcancertherapy"
Toaddressthisknowledgegap,MariaSzwarc,PhD,andAnnaGuarnieri,PhD,former pharmacologypostdoctoralfellowandco-leadauthoronthepaper,tookamultidisciplinary experimentalapproach,includinggeneticscreeningusingCRISPRtechnologytoindividuallydisrupt allgenesinthehumangenomeandidentifywhichgenesrequirep53tobefullyactivatedAsaresult, thescreenidentifiedaproteincalledFAM193Athatisapotentandbroadpositiveregulatorofp53 activity,whichispoorlyunderstood
"Ourfollow-upstudiesshowedthatFAM193Aisrequiredforthestabilizationofthep53proteinand itsfunction,"explainsDr.Szwarc."ItturnsoutthatFAM193Ainterfereswithcytokinesthatnormally inhibitp53function,theMDM2andMDM4proteins,whichareoftenoveractiveincancerWefound thatFAM193AcanantagonizetheMDM4protein,whichunleashesp53'sabilitytopreventcancercell proliferationandsurvivalConsistentwiththesefindings,wedocumentthathighlevelsofFAM193A foundincertaintumortypesareassociatedwithbetterprognosisincancerpatients”
"WhenwefoundFAM193Atobeapartnerofp53inageneticscreen,therewaslittlequestionaboutits function,"saidJoaquinEspinosa,PhD,“Thereislittle,ifany,informationavailableHowever, advancedcomputationalanalyzesoflarge-scaledatasetsofhundredsofcancercelltypesandhuman tumorshaverevealedaclearfunctionallinkbetweenp53andFAM193AThesefindingsbringusone
stepclosertoeffectivep53-basedcancertherapy,andFAM193Ashouldbeconsidered.Futureresearch willfocusonfindingwaystoenhancetheactivityofthesepartnerfactorstoeffectivelysuppress tumors.”