The mutations and potential targets of the forkhead transcription factor FOXL2

Moumné, Lara; Batista, Frank; Benayoun, Bérénice A.; Jeyabalan, Nallathambi; Fellous, Marc; Sundaresan, Periasamy; Veitia, Reiner A.

doi:10.1016/j.mce.2007.11.006

Cited by 66 publications

(43 citation statements)

References 85 publications

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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: 91%

Forkhead transcription factors in ovarian function

Uhlenhaut¹,

Treier²

2011

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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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Section: Transcriptional Targets Of Foxl2mentioning

confidence: 91%

Forkhead transcription factors in ovarian function

Uhlenhaut¹,

Treier²

2011

Reproduction

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“…We identified another exact match in the FOXG1 gene, which encodes a forkhead transcription factor. Not only was the FOXM1 transcription factor network cited as significantly altered in 87% of samples in the previous TCGA study (The Cancer Genome Atlas Research Network 2011), but, additionally, some forkhead transcription factors were previously identified as therapeutic targets (Moumne et al 2008;Wang et al 2010b).…”

Section: Cosmic/omim Querymentioning

confidence: 98%

MuSiC: Identifying mutational significance in cancer genomes

Dees¹,

Zhang²,

Kandoth³

et al. 2012

Genome Res.

605

565

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Massively parallel sequencing technology and the associated rapidly decreasing sequencing costs have enabled systemic analyses of somatic mutations in large cohorts of cancer cases. Here we introduce a comprehensive mutational analysis pipeline that uses standardized sequence-based inputs along with multiple types of clinical data to establish correlations among mutation sites, affected genes and pathways, and to ultimately separate the commonly abundant passenger mutations from the truly significant events. In other words, we aim to determine the Mutational Significance in Cancer (MuSiC) for these large data sets. The integration of analytical operations in the MuSiC framework is widely applicable to a broad set of tumor types and offers the benefits of automation as well as standardization. Herein, we describe the computational structure and statistical underpinnings of the MuSiC pipeline and demonstrate its performance using 316 ovarian cancer samples from the TCGA ovarian cancer project. MuSiC correctly confirms many expected results, and identifies several potentially novel avenues for discovery.

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“…In early postnatal Foxl2-null ovaries, the expression of some genes increases, e.g., nuclear receptor subfamily 0, group B, member 1 (Nr0b1; also known as Dax1) and Wnt4, while the expression of others decreases, e.g., nuclear receptor subfamily 5, group A, member 2 (Nr5a2; also known as Lrh1), aromatase (Cyp19a1), Fst, and Apoa1. Additional genes regulated in the ovary by FOXL2 at later stages of follicle development include inhibin βB subunit (the product of which forms either inhibin B when in complex with inhibin α subunit or activin B when it homodimerizes), Nr5a2, sterol regulatory element-binding transcription factor 1 (Srebf1), PPARγ coactivator 1α (Ppargc1a), cholesterol side chain cleavage (Cyp11a1), and steroidogenic acute regulatory protein (Star) (48)(49)(50). These results indicate that in addition to its role in embryonic ovarian development, FOXL2 likely affects specific basic metabolic aspects required for the proliferation and differentiation of somatic cells in the postnatal ovary.…”

Section: Introductionmentioning

confidence: 99%

The ovary: basic biology and clinical implications

Richards

Pangas²

2010

J. Clin. Invest.

425

276

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The classical view of ovarian follicle development is that it is regulated by the hypothalamic-pituitary-ovarian axis, in which gonadotropin-releasing hormone (GnRH) controls the release of the gonadotropic hormones follicle-stimulating hormone (FSH) and luteinizing hormone (LH), and that ovarian steroids exert both negative and positive regulatory effects on GnRH secretion. More recent studies in mice and humans indicate that many other intra-ovarian signaling cascades affect follicular development and gonadotropin action in a stage-and context-specific manner. As we discuss here, mutant mouse models and clinical evidence indicate that some of the most powerful intraovarian regulators of follicular development include the TGF-β/SMAD, WNT/FZD/β-catenin, and RAS/ERK1/2 signaling pathways and the FOXO/FOXL2 transcription factors. IntroductionThe ovary is a highly organized composite of germ cells (oocytes or eggs) and somatic cells (granulosa cells, thecal cells, and stromal cells) whose interactions dictate formation of oocyte-containing follicles, development of both oocytes and somatic cells as follicles, ovulation, and formation of the corpus luteum (the endocrine structure that forms from the ovarian follicle after ovulation and is required for establishing and maintaining pregnancy) (Figure 1). Many events in the adult ovary are controlled by two hormones, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), secreted from the anterior pituitary gland under the control of pulses of gonadotropin-releasing hormone (GnRH) from the hypothalamus (Figure 1). Low-frequency GnRH pulses stimulate a slight increase in FSH levels early in a woman's menstrual cycle, enhancing follicle growth, while high-frequency GnRH pulses lead to a sharp rise in levels of LH just before mid-cycle (an event known as the "LH surge"), triggering ovulation and formation of the corpus luteum (Figure 1). The ovary also has a key role in these processes, ensuring the timely release of fertilizable oocytes and the maintenance of luteal cell function, a necessity for pregnancy, by directing feedback mechanisms to the hypothalamus and pituitary. For example, estrogen produced by the cells of the developing follicle both inhibits GnRH production in the hypothalamus and elicits elevated GnRH pulses, which trigger the mid-cycle LH surge that initiates ovulation. Thus, fertility depends on highly orchestrated endocrine events involving multiple organ systems.Disruption of this finely controlled network can lead to many clinical syndromes including premature ovarian failure (POF), polycystic ovarian syndrome (PCOS), ovarian hyperstimulation syndrome, ovulation defects, poor oocyte quality, and cancer. The goal of this Review is to cover some of the advances in our understanding of the basic biology of the mammalian ovary that may shed light on specific ovarian dysfunctions that lead to infertility. We primarily focus on recent developments using mouse genetic models to study follicle growth and ovarian function because of the inherent di...

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The mutations and potential targets of the forkhead transcription factor FOXL2

Cited by 66 publications

References 85 publications

Forkhead transcription factors in ovarian function

Forkhead transcription factors in ovarian function

MuSiC: Identifying mutational significance in cancer genomes

The ovary: basic biology and clinical implications

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