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LATS1 phosphorylates forkhead L2 and regulates its transcriptional activity
- Source :
- American Journal of Physiology-Endocrinology and Metabolism. 299:E101-E109
- Publication Year :
- 2010
- Publisher :
- American Physiological Society, 2010.
-
Abstract
- Forkhead L2 (FOXL2) is expressed in the ovary and acts as a transcriptional repressor of the steroidogenic acute regulatory (StAR) gene, a marker of granulosa cell differentiation. Human FOXL2 mutations that produce truncated proteins lacking the COOH terminus result in blepharophimosis/ptosis/epicanthus inversus (BPES) syndrome type I, which is associated with premature ovarian failure (POF). In this study, we investigated whether FOXL2's activity as a transcriptional repressor is regulated by phosphorylation. We found that FOXL2 is phosphorylated at a serine residue and, using yeast two-hybrid screening, identified LATS1 as a potential FOXL2-interacting protein. LATS1 is a serine/threonine kinase whose deletion in mice results in an ovarian phenotype similar to POF. Using coimmunoprecipitation and kinase assays, we confirmed that LATS1 binds to FOXL2 and demonstrated that LATS1 phosphorylates FOXL2 at a serine residue. Moreover, we found that FOXL2 and LATS1 are coexpressed in developing mouse gonads and in granulosa cells of small and medium follicles in the mouse ovary. Last, we demonstrated that coexpression with LATS1 enhances FOXL2's activity as a repressor of the StAR promoter, and this results from the kinase activity of LATS1. These results provide novel evidence that FOXL2 is phosphorylated by LATS1 and that this phosphorylation enhances the transcriptional repression of the StAR gene, a marker of granulosa cell differentiation. These data support our hypothesis that phosphorylation of FOXL2 may be a control mechanism regulating the rate of granulosa cell differentiation and hence, follicle maturation, and its dysregulation may contribute to accelerated follicular development and POF in BPES type I.
- Subjects :
- Forkhead Box Protein L2
endocrine system
medicine.medical_specialty
Transcription, Genetic
Physiology
Endocrinology, Diabetes and Metabolism
Granulosa cell
Repressor
CHO Cells
Primary Ovarian Insufficiency
Protein Serine-Threonine Kinases
Biology
Transfection
Mice
Cricetulus
Cricetinae
Two-Hybrid System Techniques
Physiology (medical)
Internal medicine
Transcriptional regulation
medicine
Animals
Phosphorylation
Kinase activity
Granulosa cell differentiation
Regulation of gene expression
Reverse Transcriptase Polymerase Chain Reaction
Forkhead Transcription Factors
Articles
Immunohistochemistry
Forkhead box L2
Endocrinology
Gene Expression Regulation
Mutagenesis, Site-Directed
RNA
Female
Subjects
Details
- ISSN :
- 15221555 and 01931849
- Volume :
- 299
- Database :
- OpenAIRE
- Journal :
- American Journal of Physiology-Endocrinology and Metabolism
- Accession number :
- edsair.doi.dedup.....3a536c71fec46b95519c1563e30b2502