Functional Exploration of the Adult Ovarian Granulosa Cell Tumor-Associated Somatic FOXL2 Mutation p.Cys134Trp (c.402CG) 英文参考文献.docVIP

FunctionalExplorationoftheAdultOvarianGranulosa CellTumor-AssociatedSomaticFOXL2Mutation p.Cys134Trp(c.402C.G) Be′re′niceA.Benayoun1,2.,SandrineCaburet1,2.,Aure′lieDipietromaria1,2,AdrienGeorges1,2,3 ,Barbara D’Haene4,P.J.EswariPandaranayaka5,DavidL’Ho?te1,2,Anne-LaureTodeschini1,2 ,Sankaran Krishnaswamy5,MarcFellous6,ElfrideDeBaere4,ReinerA.Veitia1,2* 1ProgrammedePathologieMole′culaireetCellulaire,InstitutJacquesMonod,Paris,France,2Universite′ParisDiderot/Paris7,Paris,France,3EcoleNormaleSupe′rieurede Paris, Paris, France, 4Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium, 5School of Biotechnology, Kamaraj University, Madurai, India, 6De′partementdeGe′ne′tiqueetDe′veloppement, InstitutCochin,Paris,France Abstract Background: The somatic mutation in the FOXL2 gene c.402C.G (p.Cys134Trp) has recently been identified in the vast majorityofadultovariangranulosacelltumors(OGCTs)studied.Inaddition,thismutationseemstobespecifictoadult OGCTsandislikelytobeadriverofmalignanttransformation.However,itspathogenicmechanismsremainelusive. Methodology/PrincipalFindings:WehavesequencedtheFOXL2openreadingframeinapaneloftumorcelllines(NCI-60, colorectalcarcinomacelllines,JEG-3,andKGNcells).WefoundtheFOXL2c.402C.GmutationintheadultOGCT-derived KGN cell line. All other cell lines analyzed were negative for the mutation. In order to gain insights into the pathogenic mechanismofthep.Cys134Trpmutation,thesubcellularlocalizationandmobilityofthemutantproteinwerestudiedand foundtobenodifferentfromthoseofthewildtype(WT).Furthermore,itstransactivationabilitywasinmostcasessimilar tothatoftheWTprotein,includinginconditionsofoxidativestress.Anotableexceptionwasanartificialpromoterknown to be coregulated by FOXL2 and Smad3, suggesting a potential modification of their interaction. We generated a 3D structuralmodelofthep.Cys134Trpvariantandouranalysissuggeststhathomodimerformationmightalsobedisturbed bythemutation. Conclusions/Significance:Here,weconfirmthespecificityofth