FOXL2C134W-Induced CYP19 Expression via Cooperation With SMAD3 in HGrC1 Cells

Endocrinology
Martina BelliShunichi Shimasaki

Abstract

Germline knockout studies in female mice demonstrated an essential role for forkhead box L2 (FOXL2) in early follicle development, whereas an inducible granulosa cell (GC)-specific deletion of Foxl2 in adults has shown ovary-to-testis somatic sex reprogramming. In women, over 120 different germline mutations in the FOXL2 gene have been shown to cause blepharophimosis/ptosis/epicantus inversus syndrome associated with or without primary ovarian insufficiency. By contrast, a single somatic mutation (FOXL2C134W) accounts for almost all adult-type GC tumors (aGCTs). To test the hypothesis that FOXL2C134W differentially regulates the expression of aGCT markers, we investigated the effect of FOXL2C134W on inhibin B and P450 aromatase expression using a recently established human GC line (HGrC1), which we now show to bear two normal alleles of FOXL2. Neither FOXL2wt nor FOXL2C134W regulate INHBB messenger RNA (mRNA) expression. However, FOXL2C134W selectively displays a 50-fold induction of CYP19 mRNA expression dependent upon activin A. Mechanistically, the CYP19 promoter is activated in a similar way by FOXL2C134W interaction with SMAD3, but not by FOXL2wt. SMAD2 had no effect. Moreover, FOXL2C134W interactions with SMAD3 and with t...Continue Reading

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Citations

Apr 21, 2020·Journal of the Endocrine Society·Ulla-Maija HaltiaAnniina Färkkilä
Nov 9, 2019·Journal of the Endocrine Society·Martina BelliShunichi Shimasaki
Jul 10, 2020·Cancer Research·Annaïck CarlesMartin Hirst
Jul 10, 2020·Cancer Research·Stine E Weis-BankePaul A C Cloos
Mar 1, 2021·Journal of Translational Medicine·Christian SecchiShunichi Shimasaki

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