FOXL2 posttranslational modifications mediated by GSK3β determine the growth of granulosa cell tumours

Kim, Jae Hong; Kim, Yong‐Hak; Kim, Hong-Man; Park, Ho-Oak; Ha, Nam‐Chul; Kim, Tae Heon; Park, Soo‐Jin; Lee, Kangseok; Bae, Jang–Ho

doi:10.1038/ncomms3936

Cited by 35 publications

(52 citation statements)

References 37 publications

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“…The pGEX4T1-FHL2 plasmid was cloned using the following primers: FHL2 WT-F (5′-ACGGAATTCATGACTGAGCGCTTTGAC-3′) with FHL2 WT-R. Generation of the pCDNA3 FLAG-tagged or HA-tagged IER3, pCMV-HA Ubiquitin and pCDNA3-MDM2 encoding plasmids were described in previous studies. 15, 45, 46 E3 ligase-coding plasmids were generous gifts from Dr In Kyoung Lim (Ajou University; Flag-SKP2) and Dr Kang Yell Choi (Yonsei University; Flag-β-TrCP). The pCDNA4 6xHis-Ub plasmid was a generous gifts from Dr Chin Ha Chung (Seoul National University).…”

Section: Methodsmentioning

confidence: 99%

Scaffold protein FHL2 facilitates MDM2-mediated degradation of IER3 to regulate proliferation of cervical cancer cells

Jin

Lee

et al. 2016

Oncogene

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The expression of immediate early response 3 (IER3), a protein with a short half-life, is rapidly induced by various cellular stimuli. We recently reported that IER3 induces the apoptosis of cervical cancer cells and that its expression is downregulated in patients with cervical cancer. However, the molecular mechanism involved in the rapid degradation of IER3 remains unknown. Here, we demonstrate that MDM2 is an E3 ligase that interacts with IER3 and promotes its ubiquitination, followed by proteasomal degradation. Polyubiquitination of the conserved lysine 60 of IER3 is essential for its degradation. In addition, four and a half LIM domains protein 2 (FHL2) binds to both IER3 and MDM2, allowing for efficient MDM2-mediated IER3 degradation by facilitating an association between MDM2 and IER3. Moreover, IER3 induces cell cycle arrest in cervical cancer cells and its activity is further enhanced in cells in which FHL2 or MDM2 was silenced, thereby preventing IER3 degradation. The E6 and E7 oncoproteins of human papilloma virus 18 regulated IER3 expression. FHL2 expression was significantly higher in the squamous epithelium of cervical carcinoma tissues than in non-cancerous cervical tissues, whereas cervical carcinoma expression of IER3 was downregulated in this region. Thus, we determined the molecular mechanism responsible for IER3 degradation, involving a ternary complex of IER3, MDM2 and FHL2, which may contribute to cervical tumor growth. Furthermore, we demonstrated that FHL2 serves as a scaffold for E3 ligase and its substrate during the ubiquitination reaction, a function that has not been previously reported for this protein.

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Section: Methodsmentioning

confidence: 99%

Scaffold protein FHL2 facilitates MDM2-mediated degradation of IER3 to regulate proliferation of cervical cancer cells

Jin

Lee

et al. 2016

Oncogene

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“…In AGCTs, the mechanism how the FOXL2 mutation causes tumor formation remains an area of active investigation. At the molecular level, the C134W mutation is not linked to alterations in the protein structure (40), but instead it causes a change in the posttranslational modification (ubiquitination) leading to impaired interactions of FOXL2 with other transcription factors (41). The current evidence suggests that a key event in AGCT pathogenesis is a failure of the mutant FOXL2 to form specific protein-protein interactions leading to subtle changes in the transcription of target genes (42).…”

Section: Molecular Pathogenesismentioning

confidence: 98%

Pathogenesis and treatment of adult-type granulosa cell tumor of the ovary

et al. 2017

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Adult-type granulosa cell tumor is a clinically and molecularly unique subtype of ovarian cancer. These tumors originate from the sex cord stromal cells of the ovary and represent 3-5% of all ovarian cancers. The majority of adult-type granulosa cell tumors are diagnosed at an early stage with an indolent prognosis. Surgery is the cornerstone for the treatment of both primary and relapsed tumor, while chemotherapy is applied only for advanced or non-resectable cases. Tumor stage is the only factor consistently associated with prognosis. However, every third of the patients relapse, typically in 4-7 years from diagnosis, leading to death in 50% of these patients. Anti-Müllerian Hormone and inhibin B are currently the most accurate circulating biomarkers. Adult-type granulosa cell tumors are molecularly characterized by a pathognomonic somatic missense point mutation 402C->G (C134W) in the transcription factor FOXL2. The FOXL2 402C->G mutation leads to increased proliferation and survival of granulosa cells, and promotes hormonal changes. Histological diagnosis of adult-type granulosa cell tumor is challenging, therefore testing for the FOXL2 mutation is crucial for differential diagnosis. Large international collaborations utilizing molecularly defined cohorts are essential to improve and validate new treatment strategies for patients with high-risk or relapsed adult-type granulosa cell tumor. Key Messages: Adult-type granulosa cell tumor is a unique ovarian cancer with an indolent, albeit unpredictable disease course. Adult-type granulosa cell tumors harbor a pathognomonic somatic missense mutation in transcription factor FOXL2. The key challenges in the treatment of patients with adult-type granulosa cell tumor lie in the identification and management of patients with high-risk or relapsed disease.

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“…This differential activity is likely dependent on specific FOXL2 binding partners that constitute the transcriptional complex leading to gene regulation (Fleming et al, 2010; Pisarska et al, 2010, 2011; Georges et al, 2013) as well as post-translational modifications (PTMs) and variant alternative FOXL2 binding sites (see below). A variety of protein binding partners of FOXL2 have been reported, including DEAD box-containing protein (DP103; Lee et al, 2005), SMAD3 (Blount et al, 2009), ER alpha, (Kim et al, 2009), Steroidogenic factor-1 (SF-1; Park et al, 2010), UBC9, PIAS1 (Marongiu et al, 2010), LATS1 (Pisarska et al, 2010), FOXL2 itself (Kuo et al, 2011), CXXC4, CXXC5, CREM, GMEB1, NR2C1, SP100, RPLP1, BANF1, XRCC6, SIRT1 L’Hôte et al, 2012), GSK3β, MDM2 (Kim et al, 2014) and NOBOX (Bouilly et al, 2014). …”

Section: Introductionmentioning

confidence: 99%

“…As PTMs, sumoylation, phosphorylation and acetylation, have all been shown to modulate FOXL2 activity (Kuo et al, 2009; Marongiu et al, 2010; Pisarska et al, 2010; Georges et al, 2011; Kim et al, 2014). Recent evidence indicates that such modifications can even drive FOX factors to bind to particular target genes in response to environmental signals (Benayoun et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Novel action of FOXL2 as mediator of Col1a2 gene autoregulation

Marongiu

Deiana

Marcia

et al. 2016

Developmental Biology

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FOXL2 belongs to the evolutionarily conserved forkhead box (FOX) superfamily and is a master transcription factor in a spectrum of developmental pathways, including ovarian and eyelid development and bone, cartilage and uterine maturation. To analyse its action, we searched for proteins that interact with FOXL2. We found that FOXL2 interacts with specific C-terminal propeptides of several fibrillary collagens. Because these propeptides can participate in feedback regulation of collagen biosynthesis, we inferred that FOXL2 could thereby affect the transcription of the cognate collagen genes. Focusing on COL1A2, we found that FOXL2 indeed affects collagen synthesis, by binding to a DNA response element located about 65Kb upstream of this gene. According to our hypothesis we found that in Foxl2−/− mouse ovaries, Col1a2 was elevated from birth to adulthood. The extracellular matrix (ECM) compartmentalizes the ovary during folliculogenesis, (with type I, type III and type IV collagens as primary components), and ECM composition changes during the reproductive lifespan. In Foxl2−/− mouse ovaries, in addition to up-regulation of Col1a2, Col3a1, Col4a1 and fibronectin were also upregulated, while laminin expression was reduced. Thus, by regulating levels of extracellular matrix components, FOXL2 may contribute to both ovarian histogenesis and the fibrosis attendant on depletion of the follicle reserve during reproductive aging and menopause.

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FOXL2 posttranslational modifications mediated by GSK3β determine the growth of granulosa cell tumours

Cited by 35 publications

References 37 publications

Scaffold protein FHL2 facilitates MDM2-mediated degradation of IER3 to regulate proliferation of cervical cancer cells

Scaffold protein FHL2 facilitates MDM2-mediated degradation of IER3 to regulate proliferation of cervical cancer cells

Pathogenesis and treatment of adult-type granulosa cell tumor of the ovary

Novel action of FOXL2 as mediator of Col1a2 gene autoregulation

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