Mutant Forkhead L2 (FOXL2) Proteins Associated with Premature Ovarian Failure (POF) Dimerize with Wild-Type FOXL2, Leading to Altered Regulation of Genes Associated with Granulosa Cell Differentiation
Mutant Forkhead L2 (FOXL2) Proteins Associated with Premature Ovarian Failure (POF) Dimerize with Wild-Type FOXL2, Leading to Altered Regulation of Genes Associated with Granulosa Cell Differentiation
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DOI：
10.1210/en.2010-0989
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发表时间：
2011-10-01
期刊：
影响因子：
4.8
通讯作者：
Pisarska, Margareta D.
中科院分区：
文献类型：
--
作者：
Kuo, Fang-Ting;Bentsi-Barnes, Ikuko K.;Pisarska, Margareta D.
常染色体显性遗传病眼睑下垂-下垂-上皮性卵巢早衰是由于编码叉头L2 （FOXL2）基因的突变，产生假定的截断蛋白。我们之前证明FOXL2是类固醇急性调节（StAR）、P450SCC （CYP11A）、p450芳香化酶（CYP19）和细胞周期蛋白D2 （CCND2）基因的转录抑制因子，这些基因是卵巢卵泡增殖和分化的标志。此外，我们发现FOXL2的突变可能调节野生型FOXL2，导致CYP19转录抑制的丧失，类似于StAR。然而，这些卵巢早衰相关突变的调控机制在很大程度上仍然未知。因此，我们研究了FOXL2突变蛋白对全长蛋白对CYP19启动子转录抑制的影响。我们发现突变体FOXL2对野生型FOXL2对CYP19的抑制具有显性负向作用。野生型和突变型FOXL2都可以形成同源和异源二聚体。我们发现了一个最小的-57 bp的人类CYP19启动子包含两个潜在的FOXL2结合区域，并发现野生型和突变型FOXL2都可以结合到这些区域中的任何一个。突变分析显示，任何一个位点都足以抑制野生型FOXL2的转录，以及突变FOXL2的显性负作用，但当两个位点发生突变时，这些都被消除了。这些发现证实，突变型FOXL2对野生型FOXL2作为卵泡分化关键基因的转录抑制因子的活性产生显性负向影响，这可能是由于异源二聚体的形成，也可能是由于DNA结合的竞争。（内分泌学152:3917-3929,2011）
Premature ovarian failure in the autosomal dominant disorder blepharophimosis-ptosis-epican-thus inversus is due to mutations in the gene encoding Forkhead L2 (FOXL2), producing putative truncated proteins. We previously demonstrated that FOXL2 is a transcriptional repressor of the steroidogenic acute regulatory (StAR), P450SCC (CYP11A), P450aromatase (CYP19), and cyclin D2 (CCND2) genes, markers of ovarian follicle proliferation and differentiation. Furthermore, we found that mutations of FOXL2 may regulate wild-type FOXL2, leading to loss of transcriptional repression of CYP19, similar to StAR. However, the regulatory mechanisms underlying these premature ovarian failure-associated mutations remain largely unknown. Therefore, we examined the effects of a FOXL2 mutant protein on the transcriptional repression of the CYP19 promoter by the full-length protein. We found that mutant FOXL2 exerts a dominant-negative effect on the repression of CYP19 by wild-type FOXL2. Both wild-type and mutant FOXL2 and can form homo-and heterodimers. We identified a minimal -57-bp human CYP19 promoter containing two potential FOXL2-binding regions and found that both wild-type and mutant FOXL2 can bind to either of these regions. Mutational analysis revealed that either site is sufficient for transcriptional repression by wild-type FOXL2, and the dominant-negative effect of mutant FOXL2, but these are eliminated when both sites are mutated. These findings confirm that mutant FOXL2 exerts a dominant-negative effect on wild-type FOXL2's activity as a transcriptional repressor of key genes in ovarian follicle differentiation and suggest that this is likely due to heterodimer formation and possibly also competition for DNA binding. (Endocrinology 152: 3917-3929, 2011)