Sox2 induction by FGF and FGFR2 activating mutations inhibits Wnt signaling and osteoblast differentiation

Mansukhani, Alka; Ambrosetti, Davide Carlo; Holmes, Greg; Cornivelli, Lizbeth; Basilico, Claudio

doi:10.1083/jcb.200409182

Cited by 208 publications

(238 citation statements)

References 54 publications

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“…Previous studies reported conflicting results on the role of FGFR2 in the control of osteoblast differentiation. Genetic manipulation in murine osteoblasts indicated that gain-of-function mutations of FGFR2 can either reduce (51,54) or increase osteoblast differentiation (55)(56)(57)(58). The present data provide novel evidence for a positive role of activated FGFR2 on osteogenic differentiation of murine mesenchymal cells in vitro.…”

Section: Discussionsupporting

confidence: 49%

Fibroblast Growth Factor Receptor 2 Promotes Osteogenic Differentiation in Mesenchymal Cells via ERK1/2 and Protein Kinase C Signaling

Miraoui

Oudina

Petite

et al. 2009

Journal of Biological Chemistry

138

134

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Mesenchymal stem cells (MSCs)3 have the potential to differentiate into different lineages, including osteoblasts, chondroblasts, and adipocytes (1-7). The osteoblast differentiation program of MSCs is characterized by cell recruitment, which is followed by timely expressed genes including Runx2, alkaline phosphatase (ALP), type I collagen (ColA1), and osteocalcin (OC), which is associated with extracellular matrix mineralization (8 -10). The program of MSC osteogenic differentiation can be induced by soluble molecules such as bone morphogenetic proteins (BMPs) or Wnt proteins that activate several signaling pathways to trigger osteoblast differentiation (11-15). Although various downstream signals are known to promote osteogenic differentiation (16 -20), the molecular mechanisms that control the early stages of MSC osteoblast differentiation are not fully elucidated.Fibroblast growth factors (FGFs) play an important major role in the control of cell proliferation, differentiation, and survival in several tissues including bone (21-24). Notably, FGF2 was found to promote cell growth and osteoblast differentiation in bone marrow-derived mesenchymal cells (25,26). Consistent with an important role of FGF signaling in the control of osteoprogenitor cells, deletion of FGF2 in mice results in decreased bone marrow stromal cell osteogenic differentiation and altered bone formation (27). The actions of FGFs are highly dependent on high affinity FGF receptors (FGFRs) (28). FGF binding to FGFRs leads to receptor dimerization and phosphorylation of intrinsic tyrosine residues, which leads to activation of several signal transduction pathways including phospholipase C␥ (PLC␥), mitogen-activated protein kinases (MAPK), and phosphatidylinositol 3-kinase (PI3K) (29,30). In bone, activation of extracellular-related kinase (ERK1/2) MAPK and protein kinase C (PKC) was found to enhance osteoblast gene expression (31, 32). The important role of FGFR signaling in bone formation is highlighted by the finding that gain-of-function mutations in FGFRs results in premature cranial osteogenesis (33, 34). FGFR1 was recently shown to be an important transducer of FGF signals in proliferating osteoblasts (35). In contrast, activated FGFR2 was shown to enhance osteoblast differentiation in Apert syndromic craniosynostosis (36 -41). However, the role of FGFR2 signaling in osteogenic differentiation of mesenchymal stem cells is yet to be elucidated.In the present study, we investigated the specific role of FGFR2 signaling on osteoblast commitment and differentiation

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Section: Discussionsupporting

confidence: 49%

Fibroblast Growth Factor Receptor 2 Promotes Osteogenic Differentiation in Mesenchymal Cells via ERK1/2 and Protein Kinase C Signaling

Miraoui

Oudina

Petite

et al. 2009

Journal of Biological Chemistry

138

134

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“…Downregulation of the cyclin D1 mRNA and upregulation of the p27 Kip1 mRNA were also observed after SOX2 overexpression (data not shown), indicating that these cell-cycle-regulating factors may be controlled by SOX2 at the transcriptional levels. It has been reported that b-catenin activates the transcription of cyclin D1 through TCF-binding sites within the promoter, resulting in a direct effect on cell proliferation in colon carcinoma cells (Tetsu and McCormick, 1999), whereas SOX2 associates with b-catenin in osteoblasts and inhibits the activity of a Wnt-responsive reporter plasmid in HEK293 cells (Mansukhani et al, 2005). It is, thus, possible that SOX2 may function in the cell cycle through interaction with Wnt signals in gastric epithelial cells.…”

Section: Roles Of Sox2 In Gastric Carcinogenesismentioning

confidence: 99%

SOX2 is frequently downregulated in gastric cancers and inhibits cell growth through cell-cycle arrest and apoptosis

Otsubo

Akiyama

Yanagihara³

et al. 2008

Br J Cancer

197

173

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SOX transcription factors are essential for embryonic development and play critical roles in cell fate determination, differentiation and proliferation. We previously reported that the SOX2 protein is expressed in normal gastric mucosae but downregulated in some human gastric carcinomas. To clarify the roles of SOX2 in gastric carcinogenesis, we carried out functional characterisation of SOX2 in gastric epithelial cell lines. Exogenous expression of SOX2 suppressed cell proliferation in gastric epithelial cell lines. Flow cytometry analysis revealed that SOX2-overexpressing cells exhibited cell-cycle arrest and apoptosis. We found that SOX2-mediated cell-cycle arrest was associated with decreased levels of cyclin D1 and phosphorylated Rb, and an increased p27Kip1 level. These cells exhibited further characteristics of apoptosis, such as DNA laddering and caspase-3 activation. SOX2 hypermethylation signals were observed in some cultured and primary gastric cancers with no or weak SOX2 expression. Among the 52 patients with advanced gastric cancers, those with cancers showing SOX2 methylation had a significantly shorter survival time than those without this methylation (P ¼ 0.0062). Hence, SOX2 plays important roles in growth inhibition through cell-cycle arrest and apoptosis in gastric epithelial cells, and the loss of SOX2 expression may be related to gastric carcinogenesis and poor prognosis.

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“…Importantly, the Wnt/β-catenin pathway is active in the early developing ovary and inactive in the early developing testis (Chassot et al, 2008). Furthermore, a number of SOX proteins, such as SOX1, SOX2, SOX3, SOX7, SOX9 and SOX17 inhibit the canonical Wnt/β-catenin signaling in different models of chondrocyte, neuronal and intestinal differentiation; however the mechanism of their action is still unclear (Akiyama et al, 2004, Bastide et al, 2007, Kan et al, 2004, Mansukhani et al, 2005, Sinner et al, 2007, Takash et al, 2001, Zorn et al, 1999. Here we investigated whether SRY could inhibit the canonical Wnt/β-catenin pathway.…”

Section: Introductionmentioning

confidence: 99%

Human SRY inhibits β-catenin-mediated transcription

Bernard

Sim

Knower

et al. 2008

The International Journal of Biochemistry & Cell Biology

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In most mammals, sex is determined by the presence or absence of the SRY gene. SRY encodes a DNA binding HMG-box transcription factor which, during embryogenesis, is the initial trigger of testis differentiation from the bipotential gonad, yet its precise mode of function remains unclear. In ovarian development, R-spondin1 and Wnt4 act through the Wnt/β-catenin signaling pathway to regulate TCF-dependent expression of unknown target genes and repress testis development. Conversely, SRY may be necessary to prevent the development of ovaries by inhibiting the action of ovarian-determining genes. We hypothesize that SRY prevents Wnt/β-catenin signaling, thereby inhibiting ovarian development. In HEK293T cells, SRY repressed β-catenin-mediated TCFdependent gene activation in the presence of a specific GSK3β inhibitor or an activated β-catenin mutant, suggesting that SRY inhibits Wnt signaling at the level of β-catenin. Three SRY mutant proteins with nuclear localization defects, encoded by XY male-to-female patients, failed to inhibit β-catenin; surprisingly four SRY sex reversed mutants with defective DNA binding activity showed near wild-type SRY inhibitory activity. Moreover the potent transactivator SRY-VP16 fusion protein also showed wild-type SRY inhibitory activity. Thus SRY inhibition of β-catenin involves neither DNA binding nor transactivation functions of SRY. β-catenin and SRY interact in-vitro and SRY expression triggered β-catenin localization into specific nuclear bodies in NT2/D1 and Hela cells. We conclude that SRY inhibits β-catenin-mediated Wnt signaling by a novel nuclear function of SRY that could be important in sex determination.

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Sox2 induction by FGF and FGFR2 activating mutations inhibits Wnt signaling and osteoblast differentiation

Cited by 208 publications

References 54 publications

Fibroblast Growth Factor Receptor 2 Promotes Osteogenic Differentiation in Mesenchymal Cells via ERK1/2 and Protein Kinase C Signaling

Fibroblast Growth Factor Receptor 2 Promotes Osteogenic Differentiation in Mesenchymal Cells via ERK1/2 and Protein Kinase C Signaling

SOX2 is frequently downregulated in gastric cancers and inhibits cell growth through cell-cycle arrest and apoptosis

Human SRY inhibits β-catenin-mediated transcription

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