Differential apoptotic activities of wild-type FOXL2 and the adult-type granulosa cell tumor-associated mutant FOXL2 (C134W)

Kim, Jae‐Hun; Yoon, Sang-Wook; Park, M; Ho, Park Chan; Jj, Ko; Lee, Kyung Hwa; Bae, Jang–Ho

doi:10.1038/onc.2010.541

Cited by 95 publications

(92 citation statements)

References 37 publications

(43 reference statements)

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“…14,15 It has been recently reported that wild-type FOXL2 and its mutant may have differential regulatory activities of the apoptosis. According to Kim et al,17 FOXL2 mutant induces a lower number of apoptotic cells due to deregulation of the caspase activation. In this context, we reported for the first time that FOXL2 gene mutation may also have a bad prognostic impact in vivo.…”

Section: Discussionmentioning

confidence: 99%

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Prognostic significance of FOXL2 mutation and mRNA expression in adult and juvenile granulosa cell tumors of the ovary

et al. 2011

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Recently, mutation of the FOXL2 gene has been consistently identified in adult granulosa cell tumors of the ovary. The purpose of this study is to investigate whether the FOXL2 mutation and mRNA expression have a role in the pathogenesis of juvenile and adult granulosa cell tumors and influence tumor progression. Thirty-four adult granulosa cell tumors and 20 juvenile granulosa cell tumors were examined for the presence of the FOXL2 (C402G) mutation. Expression levels were studied by quantitative PCR and immunohistochemistry. We found that FOXL2 (C402G) mutation was present in 19/27 (70%) of the adult type tumors but in none of the juvenile granulosa cell tumors (0/18). No correlation was encountered between the presence of FOXL2 mutation and various clinicopathologic parameters except for the presence of a different sex-cord component, which was more frequently found in the subgroup of wild-type adult granulosa cell tumors than in the mutated tumors. Patients with tumors harboring the FOXL2 (C402G) mutation had a worse disease-free survival than those with the wild-type gene. Expression levels of FOXL2 mRNA had an impact on disease-free survival in both adult and juvenile granulosa cell tumors. We also found that the mutated tumors had a higher immunohistochemical expression of the FOXL2 protein, and there was a linear correlation between mRNA and immunohistochemical FOXL2 expression in both adult and juvenile granulosa cell tumors. Patients with juvenile granulosa cell tumors and higher FOXL2 protein expression had worse overall survival and disease-free survival than those with negative or weakly immunoreactive tumors. Our data suggest that FOXL2 mutation and mRNA expression are of prognostic importance in both adult and juvenile granulosa cell tumors.

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Section: Discussionmentioning

confidence: 99%

“…10,16 Recently, mutant FOXL2 has been found to induce lower levels of apoptosis compared with wild-type FOXL2. 17 The purpose of this investigation was to find out whether FOXL2 mutation and expression levels have a role in the pathogenesis of juvenile and adult granulosa cell tumors as well as its potential value as a prognostic factor.…”

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confidence: 99%

Prognostic significance of FOXL2 mutation and mRNA expression in adult and juvenile granulosa cell tumors of the ovary

et al. 2011

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“…Indeed, the C134W mutation does not cause a general loss of function in vitro and the mutated protein can activate normally most target promoters under conditions of overexpression (Benayoun et al 2010). However, FOXL2 C134W has a decreased pro-apoptotic capacity when overexpressed in GCT-derived cultured cells (Kim et al 2011). It has recently been suggested that deregulation of the expression of gonadotrophin-releasing hormone receptor (GNRHR) could contribute to the impairment in induction of apoptosis (Cheng et al 2013).…”

Section: Foxl2: a Key Player In Gc Proliferation And Tumorigenesismentioning

confidence: 99%

“…Its overexpression in GCT-derived cells upregulates pro-apoptotic genes, such as TNF-R1, FAS or TRAIL-R, receptors of proapoptotic ligands (Kim et al 2011). FOXL2 also activates the expression of the GNRH receptor in human and mouse GCs, which may play a pro-apoptotic role (Escudero et al 2010, Cheng et al 2013.…”

Section: Foxl2: a Key Player In Gc Proliferation And Tumorigenesismentioning

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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“…Through whole-transcriptome paired-end RNA sequencing of only 4 GCTs, a somatic FOXL2 missense mutation c.402C>G (p.C134W) was found in all of them [43]. The presence of this unique recurrent somatic mutation in more than 95% of adult GCTs has been confirmed by several follow-up studies [44,45,46,47,48,49,50,51,52]. Localization of the mutated protein was found to be normal [43,44].…”

Section: Foxl2 Impairment In Granulosa Cell Tumorsmentioning

confidence: 69%

<i>FOXL2 </i>Impairment in Human Disease

Verdin¹,

Baere²

2012

Horm Res Paediatr

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FOXL2 encodes a forkhead transcription factor that plays important roles in the ovary during development and in post-natal, adult life. Here, we focus on the clinical consequences of FOXL2 impairment in human disease. In line with other forkhead transcription factors, its constitutional genetic defects and a somatic mutation lead to developmental disease and cancer, respectively. More than 100 unique constitutional mutations and regulatory defects have been found in blepharophimosis syndrome (BPES), a complex eyelid malformation associated (type I) or not (type II) with premature ovarian failure (POF). In agreement with the BPES phenotype, FOXL2 is expressed in the developing eyelids and in fetal and adult ovaries. Two knock-out mice and at least one natural animal model, the Polled Intersex Syndrome goat, are known. They recapitulate the BPES phenotype and have provided many insights into the ovarian pathology. Only a few constitutional mutations have been described in nonsyndromic POF. Moreover, a recurrent somatic mutation p.C134W was found to be specific for adult ovarian granulo-sa cell tumors. Functional studies investigating the consequences of FOXL2 mutations or regulatory defects have shed light on the molecular pathogenesis of the aforementioned conditions, and contributed considerably to genotype-phenotype correlations. Recently, a conditional knock-out of Foxl2 in the mouse induced somatic transdifferentiation of ovary into testis in adult mice, suggesting that Foxl2 has an anti-testis function in the adult ovary. This changed our view on the ovary and testis as terminally differentiated organs in adult mammals. Finally, this might have potential implications for the understanding and treatment of frequent conditions such as POF and polycystic ovary syndrome.

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Differential apoptotic activities of wild-type FOXL2 and the adult-type granulosa cell tumor-associated mutant FOXL2 (C134W)

Cited by 95 publications

References 37 publications

Prognostic significance of FOXL2 mutation and mRNA expression in adult and juvenile granulosa cell tumors of the ovary

Prognostic significance of FOXL2 mutation and mRNA expression in adult and juvenile granulosa cell tumors of the ovary

FOXL2: a central transcription factor of the ovary

<i>FOXL2 </i>Impairment in Human Disease

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