| Summary: | FOXL2 is an essential transcription factor that is required for proper development of
the ovary and eyelid. Mutations in FOXL2 cause an autosomal dominant genetic disorder,
blepharophimosis-ptosis-epicanthus inversus syndrome (BPES). BPES type I patients have
eyelid malformation and premature ovarian failure leading to infertility, whereas women
with type II BPES are fertile or subfertile. In the present study, we evaluated and
compared apoptotic and antiproliferative activities of wild-type (WT) and mutant FOXL2
proteins found in BPES type I and II in human granulosa cell tumor-derived KGN cells.
Ectopic expression of WT FOXL2 induced apoptosis and inhibited cell cycle progression in
human granulosa cells. In contrast, mutated FOXL2s found in BPES type I significantly
reduced these activities, whereas mutated FOXL2s in BPES type II showed intermediate
activities. Furthermore, mutant FOX L2 proteins were defective in activating transcription
of target genes including Caspase 8, TNF-R1,
FAS, p21, and BMP4, which regulate
apoptosis, proliferation, and differentiation of granulosa cells. Thus, decreased
apoptotic and antiproliferative activities caused by mutant forms of FOXL2 found in BPES
patients may at least partially contribute to the pathophysiology of ovarian
dysfunction.
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