The role of FoxO1 on FSHβ gene regulation in the pituitary

Abstract

The importance of FoxO proteins in reproductive endocrinology is emphasized by the FoxO3a KO mouse model that shows age-dependent infertility due to abnormal granulosa cell proliferation. In addition, FoxO3a mouse showed increased FSH and LH hormone levels, but the FoxO proteins role on pituitary, higher organ of gonad in reproductive axis, has not been defined. In the anterior pituitary, FoxO3a were detected in gonadotrope and corticotrope, but FoxO1 expression is completely co-localized with FSHβ. Over-expression of constitutively active FoxO1 (CA-FoxO1) decreased FSHβ gene expression in primary cell culture. Similarly, FoxO1 was decreased hFSHβ promoter activity in non-gonadotropic HEK293 cells and gonadotrope cells and it was bound to FoxO binding element (FBE) at-119/-124 in hFSHβ promoter. Furthermore CA-FoxO1 decreased GnRH-stimulated hFSHβ promoter activity and gene expression. Since PI3K pathway is main regulator for FoxO protein, phosphorylation of FoxO1 at Thr24 was investigated by GnRH treatment. GnRH increased phosphorylated FoxO1, showing similar pattern with phosphorylated AKT. In addition, GnRH treatment showed increasing cytoplasmic FoxO1 and when PI3K pathway was blocked by LY294002, cytoplasmic amount of FoxO1 was decreased. Following this result, FSHβ gene expression and promoter activity was blocked by LY294002. We conclude that FoxO1 was detected only in gonadotrope and acted as a transcriptional repressor for FSHβ gene expression by binding its FBE in FSHβ promoter. GnRH stimulated FSHβ gene expression via PI3K dependent inhibition of FoxO1 by regulating its localization.