期刊
MOLECULAR ENDOCRINOLOGY
卷 24, 期 5, 页码 1024-1036出版社
ENDOCRINE SOC
DOI: 10.1210/me.2009-0375
关键词
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资金
- Ministry of Education, Science, and Technology [2009-0066320, 2009-414-E00006]
- Ministry of Health, Welfare, and Family Affairs [A084923]
- Seoul RBD program [10543, 10550]
- National Research Foundation of Korea [2009-0066320, 2009-0093821] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Mutations in FOXL2 are responsible for blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) type I, in which affected women exhibit premature ovarian failure. FOXL2-null mice showed defects in granulosa cell development during folliculogenesis. We screened a rat ovarian yeast two-hybrid cDNA library to identify FOXL2-interacting proteins and found steroidogenic factor-1 (SF-1). Here, we show that human FOXL2 and SF-1 proteins interact in human granulosa cells and that FOXL2 negatively regulates the transcriptional activation of a steroidogenic enzyme, CYP17, by SF-1. Furthermore, FOXL2 mutants found in blepharophimosis-ptosis-epicanthus inversus syndrome type I patients lost the ability to repress CYP17 induction mediated by SF-1. Chromatin immunoprecipitation and EMSA results further revealed that FOXL2 inhibited the binding of SF-1 to the CYP17 promoter, whereas the FOXL2 mutants failed to block this interaction. Therefore, this study identifies a novel regulatory role for FOXL2 on a key steroidogenic enzyme and provides a possible mechanism by which mutations in FOXL2 disrupt normal ovarian follicle development. (Molecular Endocrinology 24: 1024-1036, 2010)
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