Sumoylation of Forkhead L2 by Ubc9 is required for its activity as a transcriptional repressor of the Steroidogenic Acute Regulatory gene

Kuo, Fang-Ting; Bentsi-Barnes, Ikuko K.; Bae, Jang–Ho; Pisarska, Margareta D.

doi:10.1016/j.cellsig.2009.09.001

Cited by 33 publications

(43 citation statements)

References 72 publications

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“…Yeast two-hybrid screening was performed using human FOXL2 as bait, and plasmids from positive colonies were isolated, purified, and sequenced (31). The specific interaction between wild-type FOXL2 and large tumor suppressor gene 1 (LATS1) was confirmed on the basis of activation of the GAL1-HIS3 reporter gene.…”

Section: Methodsmentioning

confidence: 99%

“…A FLAG-tagged FOXL2 cDNA was generated as described previously (31). A 3.4-kb human LATS1 cDNA sequence was PCR amplified from human ovary cDNA (Ambion, Austin, TX), using the primers 5=-GTGGCGGCCGCATGAAGAG-GAGTGAAAA-3= and 5=-TCGCGATCTAGTATATGTTTAACTC-GAGTGA-3=, and subcloned into pcDNA3 and pcDNA3.1-HisXpress expression vectors using the NotI and XhoI restriction sites to generate LATS1 expression constructs.…”

Section: Methodsmentioning

confidence: 99%

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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: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

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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“…Several potentially SUMOylated FOXL2 residues have been identified and it is not certain that this modification affects any residue in particular. SUMOylation seems to stabilise FOXL2 and consequently increases its transcriptional (activation or repression) activity (Kuo et al 2009, Marongiu et al 2010. Another consequence of SUMOylation under overexpression conditions is an increased recruitment of FOXL2 to PML nuclear bodies.…”

Section: Regulation Of Foxl2 Expression and Functionmentioning

confidence: 99%

“…It has been suggested that infertility could be a side effect of the tumours (St John et al 1999). FOXL2 interacts directly with the SUMO ligases PIAS1 and UBC9 (Kuo et al 2009). Several potentially SUMOylated FOXL2 residues have been identified and it is not certain that this modification affects any residue in particular.…”

Section: Regulation Of Foxl2 Expression and Functionmentioning

confidence: 99%

FOXL2: a central transcription factor of the ovary

Georges¹,

Auguste²,

Bessière³

et al. 2013

Journal of Molecular Endocrinology

132

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Forkhead box L2 (FOXL2) is a gene encoding a forkhead transcription factor preferentially expressed in the ovary, the eyelids and the pituitary gland. Its germline mutations are responsible for the blepharophimosis ptosis epicanthus inversus syndrome, which includes eyelid and mild craniofacial defects associated with primary ovarian insufficiency. Recent studies have shown the involvement of FOXL2 in virtually all stages of ovarian development and function, as well as in granulosa cell (GC)-related pathologies. A central role of FOXL2 is the lifetime maintenance of GC identity through the repression of testis-specific genes. Recently, a highly recurrent somatic FOXL2 mutation leading to the p.C134W subtitution has been linked to the development of GC tumours in the adult, which account for up to 5% of ovarian malignancies. In this review, we summarise data on FOXL2 modulators, targets, partners and post-translational modifications. Despite the progresses made thus far, a better understanding of the impact of FOXL2 mutations and of the molecular aspects of its function is required to rationalise its implication in various pathophysiological processes.

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“…In addition to repressing Sox9, and consistent with its role in female sex maintenance, Foxl2 has been implicated in the regulation of steroidogenic genes such as Star and aromatase and of pivotal ovarian genes such as follistatin (Moumne et al 2008, Kuo et al 2009, Kashimada et al 2011. Other potential target genes in somatic cells including regulators of the cell cycle and apoptosis, which together with the observation that some granulosa cell tumors carry a p.Cys134Trp mutation in the FOXL2 protein sequence, may point to a potential role as a tumor suppressor (Shah et al 2009, Benayoun et al 2010.…”

Section: Transcriptional Targets Of Foxl2mentioning

confidence: 99%

Forkhead transcription factors in ovarian function

Uhlenhaut¹,

Treier²

2011

Reproduction

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Since the discovery of the conserved forkhead (Fkh) DNA binding domain more than 20 years ago, members of the Fkh or forkhead box (FOX) family of transcription factors have been shown to act as important regulators of numerous developmental and homeostatic processes. The human genome contains 44 Fkh genes, several of which have recently been reported to be essential for female fertility. In this review, we highlight the roles of specific FOX proteins in ovarian folliculogenesis and present our current understanding of their molecular function. In particular, we describe what we have learned from loss-of-function studies using mouse models as well as human genetics and illustrate how different stages of folliculogenesis, both in oocytes and in somatic granulosa and theca cells, are regulated by FOXC1, FOXL2, and FOXO subfamily members.

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Sumoylation of Forkhead L2 by Ubc9 is required for its activity as a transcriptional repressor of the Steroidogenic Acute Regulatory gene

Cited by 33 publications

References 72 publications

LATS1 phosphorylates forkhead L2 and regulates its transcriptional activity

LATS1 phosphorylates forkhead L2 and regulates its transcriptional activity

FOXL2: a central transcription factor of the ovary

Forkhead transcription factors in ovarian function

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