Functional Exploration of the Adult Ovarian Granulosa Cell Tumor-Associated Somatic FOXL2 Mutation p.Cys134Trp (c.402C>G) - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Article Dans Une Revue PLoS ONE Année : 2010

Functional Exploration of the Adult Ovarian Granulosa Cell Tumor-Associated Somatic FOXL2 Mutation p.Cys134Trp (c.402C>G)

Résumé

Background : The somatic mutation in the FOXL2 gene c.402C.G (p.Cys134Trp) has recently been identified in the vast majority of adult ovarian granulosa cell tumors (OGCTs) studied. In addition, this mutation seems to be specific to adult OGCTs and is likely to be a driver of malignant transformation. However, its pathogenic mechanisms remain elusive. Methodology : Principal Findings:We have sequenced theFOXL2open reading frame in a panel of tumor cell lines (NCI-60,colorectal carcinoma cell lines, JEG-3, and KGN cells). We found theFOXL2c.402C.G mutation in the adult OGCT-derivedKGN cell line. All other cell lines analyzed were negative for the mutation. In order to gain insights into the pathogenicmechanism of the p.Cys134Trp mutation, the subcellular localization and mobility of the mutant protein were studied andfound to be no different from those of the wild type (WT). Furthermore, its transactivation ability was in most cases similarto that of the WT protein, including in conditions of oxidative stress. A notable exception was an artificial promoter knownto be coregulated byFOXL2and Smad3, suggesting a potential modification of their interaction. We generated a 3Dstructural model of the p.Cys134Trp variant and our analysis suggests that homodimer formation might also be disturbedby the mutation. Conclusions/Significance : Here, we confirm the specificity of theFOXL2c.402C.G mutation in adult OGCTs and begin the exploration of its molecular significance. This is the first study demonstrating that the p.Cys134Trp mutant does not have astrong impact on FOXL2 localization, solubility, and transactivation abilities on a panel of proven target promoters, behaving neither as a dominant-negative nor as a loss-of-function mutation. Further studies are required to understand the specific molecular effects of this outstanding FOXL2 mutation.
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hal-02116167 , version 1 (30-04-2019)

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Bérénice Benayoun, Sandrine Caburet, Aurélie Dipietromaria, Adrien Georges, Barbara d'Haene, et al.. Functional Exploration of the Adult Ovarian Granulosa Cell Tumor-Associated Somatic FOXL2 Mutation p.Cys134Trp (c.402C>G). PLoS ONE, 2010, 5 (1), pp.e8789. ⟨10.1371/journal.pone.0008789⟩. ⟨hal-02116167⟩
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