title: Discovery of novel protein partners of the transcription factor FOXL2 provides insights into its physiopathological roles.
abstract: FOXL2 transcription factor is responsible for the Blepharophimosis Ptosis Epicantus inversus Syndrome (BPES), a genetic disease involving craniofacial malformations often associated with ovarian failure. Recently, a somatic FOXL2 mutation (p.C134W) has been reported in >95% of adult-type granulosa cell tumors. Here, we have identified 10 novel FOXL2 partners by yeast-two-hybrid screening and co-immunoprecipitation. Most BPES-inducing mutated FOXL2 proteins display aggregation in cultured cells. Here, we show that two of the partners (NR2C1 and GMEB1) can be sequestered in such aggregates. This co-aggregation can contribute to the pathogenesis of FOXL2 mutations. We have also measured the effects of FOXL2 interactants on the transcriptional regulation of a series of target promoters. Some of the partners (CXXC4, CXXC5, BANF1) were able to repress FOXL2 activity indistinctively of the promoter. Interestingly, CREM-τ2α, which acted as a repressor on most promoters, increased wild-type (WT) FOXL2 activity on two promoters (PTGS2 and CYP19A1), but was unable to increase the activity of the oncogenic mutant p.C134W. Conversely, GMEB1, which also acted as a repressor on most promoters and increased WT FOXL2 activity on the Per2 promoter, increased to a greater extent the activity of the p.C134W variant. Interestingly, partners with intrinsic pro-apoptotic effect were able to increase apoptosis induction by WT FOXL2, but not by the p.C134W mutant, whereas partners with an anti-apoptotic effect decreased apoptosis induction by both FOXL2 versions. Altogether, these results suggest that the p.C134W mutated form fails to integrate signals through protein-protein interactions to regulate target promoter subsets and in particular to induce cell death.
authors.affiliation: Institut Jacques Monod, UMR 7592 CNRS-Université Paris Diderot, Paris 75205, France.
authors.forename: David
authors.initials: D
authors.lastname: L'Hôte
authors.forename: Adrien
authors.initials: A
authors.lastname: Georges
authors.forename: Anne Laure
authors.initials: AL
authors.lastname: Todeschini
authors.forename: Jae-Hong
authors.initials: JH
authors.lastname: Kim
authors.forename: Bérénice A
authors.initials: BA
authors.lastname: Benayoun
authors.forename: Jeehyeong
authors.initials: J
authors.lastname: Bae
authors.forename: Reiner A
authors.initials: RA
authors.lastname: Veitia
mesh_terms: D000818:Animals; D017209:Apoptosis; D016569:Blepharophimosis / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020125:Mutation, Missense; D006080:Ovarian Follicle / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D021381:Protein Transport; D012868:Skin Abnormalities / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D014564:Urogenital Abnormalities
chemical_list: C418221:CXXC4 protein, human; C540448:CXXC5 protein, human; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C421604:FOXL2 protein, human; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors; D014157:Transcription Factors