Expression of forkhead transcription factors in human granulosa cells

Pisarska, Margareta D.; Kuo, Fang-Ting; Tang, Dahang; Zarrini, Parham; Khan, Sharmin; Ketefian, A.

doi:10.1016/j.fertnstert.2008.04.054

Cited by 28 publications

(23 citation statements)

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“…Regulation through phosphorylation has been shown to be an important mechanism for controlling the activities of transcription factors (28,37), including other forkhead transcription factors (38) expressed in both human and rodent granulosa cells (42,45). Protein kinase B/Akt phosphorylates the FOXO subfamily, leading to export from the nucleus and inhibition of transcriptional activities (6,9,30), whereas activation of the Ras-Ral pathway leads to phosphorylation of FOXO members and induces transcriptional activity (18,30).…”

Section: Discussionmentioning

confidence: 99%

LATS1 phosphorylates forkhead L2 and regulates its transcriptional activity

Pisarska

Kuo

Bentsi-Barnes

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

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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. large tumor suppressor gene 1 phosphorylation; transcriptional regulation; forkhead L2; granulosa cell; premature ovarian failure PREMATURE OVARIAN FAILURE (POF) is defined as a condition causing amenorrhea, hypoestrogenism, and elevated gonadotropins in women under 40 yr of age (1) and can be associated with failure to endow the follicle pool or an early loss of the fixed follicle pool following excess follicle recruitment and/or atresia. A genetic basis for selective cases of POF has been determined. Patients with blepharophimosis-ptosis-epicanthus inversus (BPES) syndrome type I exhibit POF in association with characteristic eyelid dysplasia, blepharophimosis, ptosis, and epicanthus inversus (60). Ovaries from BPES type I patients are histologically variable, ranging from the presence of some primordial follicles with atretic follicles to complete absence of follicles and scarring of the ovaries (23). The gene encoding the transcription factor forkhead L2 (FOXL2) (15) maps to the BPES locus on chromosome 3q22-3q23. FOXL2 is a member of the forkhead/hepatocyte nuclear factor 3 family of transcription factors (15), which is characterized by the presence of a conserved winged helix domain that is essential for DNA binding as well as more divergent transactivation or transrepression domains (12,29,33). FOXL2 mutations in indivi...

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Section: Discussionmentioning

confidence: 99%

LATS1 phosphorylates forkhead L2 and regulates its transcriptional activity

Pisarska

Kuo

Bentsi-Barnes

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

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“…Although FOXO1, FOXO3, and FOXO4 expression was observed in human MGCs (Pisarska et al 2009), mutations in the human FOXO1A and FOXO3A genes were identified in women with POF (Watkins et al 2006). Results from a recent study have indicated that depletion of Foxo1 and Foxo3 in mouse GCs reduced expression of Igf1 and Irs2 and resulted in an infertile phenotype.…”

Section: Pi3k/pten/akt and Tsc/mtor Pathways And Ovarian Somatic Cellsmentioning

confidence: 99%

PI3K/PTEN/Akt and TSC/mTOR signaling pathways, ovarian dysfunction, and infertility: an update

Makker

Goel

Mahdi

2014

Journal of Molecular Endocrinology

180

115

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Abnormalities in ovarian function, including defective oogenesis and folliculogenesis, represent a key female reproductive deficiency. Accumulating evidence in the literature has shown that the PI3K/PTEN/Akt and TSC/mTOR signaling pathways are critical regulators of ovarian function including quiescence, activation, and survival of primordial follicles, granulosa cell proliferation and differentiation, and meiotic maturation of oocytes. Dysregulation of these signaling pathways may contribute to infertility caused by impaired follicular development, intrafollicular oocyte development, and ovulation. This article reviews the current state of knowledge of the functional role of the PI3K/PTEN/Akt and TSC/mTOR pathways during mammalian oogenesis and folliculogenesis and their association with female infertility.

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“…62,63 In silico algorithms were used to hypothesize that miR-608 regulates FOXO4, which is one of the three FOXO family members expressed in human granulosa cells (available at http://www.targetscan.org and http:// www.microrna.org; accessed March 22, 2014), and that the FOXO class of transcription factors may play important roles in human folliculogenesis and luteinization. 64 The role of these miRNAs in the ovary or in folliculogenesis, however, remains to be elucidated. Interestingly, the miRNA polymorphisms showing associations with POI risk have also been associated 2.…”

Section: Discussionmentioning

confidence: 99%