aromatase is a direct target of foxl2 c134w in granulosa cell tumors via a single highly conserved binding site in the ovarian specific promoter芳香化酶是一个直接的目标foxl2 c134w颗粒细胞肿瘤中通过一个高度保守的结合位点的卵巢特定的启动子.pdfVIP

Aromatase Is a Direct Target of FOXL2: C134W in Granulosa Cell Tumors via a Single Highly Conserved Binding Site in the Ovarian Specific Promoter 1 1 1 1,2 1,2 Nicholas I. Fleming , Kevin C. Knower , Kyren A. Lazarus , Peter J. Fuller , Evan R. Simpson , Colin D. Clyne1,2* 1 Prince Henry’s Institute of Medical Research, Clayton, Victoria, Australia, 2 Department of Biochemistry and Molecular Biology, Monash University, Victoria, Australia Abstract Background: Granulosa cell tumors (GCT) of the ovary often express aromatase and synthesize estrogen, which in turn may influence their progression. Recently a specific point mutation (C134W) in the FOXL2 protein was identified in .94% of adult-type GCT and it is likely to contribute to their development. A number of genes are known to be regulated by FOXL2, including aromatase/CYP19A1, but it is unclear which are direct targets and whether the C134W mutation alters their regulation. Recently, it has been reported that FOXL2 forms a complex with steroidogenic factor 1 (SF-1) which is a known regulator of aromatase in granulosa cells. Methodology/Principal Findings: In this work, the human GCT-derived cell lines KGN and COV434 were heterozygous and wildtype for the FOXL2:C134W mutation, respectively. KGN had abundant FOXL2 mRNA expression but it was not expressed in COV434. Expression of exogenous FOXL2:C134W in COV434 cells induced higher expression of a luciferase reporter for the ovarian specific aromatase promoter, promoter II (PII) ( 2516bp) than expression of wildtype FOXL2, but did not alter induction of a similar reporter for the steroidogenic acute regulatory protein (StAR) promoter (21300bp). Co-