Normal Proliferation and Tumorigenesis but Impaired Pancreatic Function in Mice Lacking the Cell Cycle Regulator Sei1 英文参考文献.docVIP

NormalProliferationandTumorigenesisbutImpaired PancreaticFunctioninMiceLackingtheCellCycle RegulatorSei1 PabloJ.Fernandez-Marcos1,CristinaPantoja1,AguedaGonzalez-Rodriguez2,3,NicholasMartin4, JuanaM.Flores5,AngelaM.Valverde2,3,EijiHara4,ManuelSerrano1* 1TumorSuppressionGroup,SpanishNationalCancerResearchCentre(CNIO),Madrid,Spain,2InstituteofBiomedicineAlbertoSols(CSIC/UAM),Madrid,Spain,3Centro deInvestigacio′nBiome′dica enReddeDiabetesyEnfermedadesMetabo′licasAsociadas(CIBERDEM),ISCIII,Madrid,Spain,4CancerInstituteoftheJapaneseFoundation forCancerResearch,Tokyo,Japan,5DepartmentofAnimalSurgeryandMedicine,ComplutenseUniversityofMadrid,Madrid,Spain Abstract Sei1 is a positive regulator of proliferation that promotes the assembly of Cdk4-cyclin D complexes and enhances the transcriptionalactivityofE2f1. ThepotentialoncogenicroleofSei1isfurthersuggested byitsoverexpressioninvarious types of human cancers. To study the role of Sei1, we have generated a mouse line deficient for this gene. Sei1-null fibroblasts did not show abnormalities regarding proliferation or susceptibility to neoplastic transformation, nor did we observe defects on Cdk4 complexes or E2f activity. Sei1-null mice were viable, did not present overt pathologies, had a normal lifespan, and had a normal susceptibility to spontaneous and chemically-induced cancer. Pancreatic insulin- producingcellsareknowntobeparticularlysensitivetoCdk4-cyclinDandE2factivities,andwehaveobservedthatSei1is highlyexpressedinpancreaticisletscomparedtoothertissues.Interestingly,Sei1-nullmicepresentlowernumberofislets, decreased b-cell area, impaired insulin secretion, and glucose intolerance. These defects were associated to nuclear accumulationofthecell-cycleinhibitorsp21Cip1andp27Kip1inisletcells.WeconcludethatSei1playsanimportantrolein pancreaticb-cells,whichsupportsafunctionallinkbetweenSei1andthecorecellcycleregulatorsspecificallyinthecontext ofthepancreas. Citation: Fernandez-Marcos PJ, Pantoja C, Gonzalez-Rodrigu