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Stem Cells
2013 Dec 01;3112:2724-36. doi: 10.1002/stem.1514.
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FGFR1 signaling stimulates proliferation of human mesenchymal stem cells by inhibiting the cyclin-dependent kinase inhibitors p21(Waf1) and p27(Kip1).
Dombrowski C
,
Helledie T
,
Ling L
,
Grünert M
,
Canning CA
,
Jones CM
,
Hui JH
,
Nurcombe V
,
van Wijnen AJ
,
Cool SM
.
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Signaling through fibroblast growth factor receptor one (FGFR1) is a known inducer of proliferation in both embryonic and human adult mesenchymal stem cells (hMSCs) and positively regulates maintenance of stem cell viability. Leveraging the mitogenic potential of FGF2/FGFR1 signaling in stem cells for therapeutic applications necessitates a mechanistic understanding of how this receptor stimulates cell cycle progression. Using small interfering RNA (siRNA) depletion, antibody-inhibition, and small molecule inhibition, we establish that FGFR1 activity is rate limiting for self-renewal of hMSCs. We show that FGFR1 promotes stem cell proliferation through multiple mechanisms that unite to antagonize cyclin-dependent kinase (CDK) inhibitors. FGFR1 not only stimulates c-Myc to suppress transcription of the CDK inhibitors p21(Waf1) and p27(Kip1), thus promoting cell cycle progression but also increases the activity of protein kinase B (AKT) and the level of S-phase kinase-associated protein 2 (Skp2), resulting in the nuclear exclusion and reduction of p21(Waf1). The in vivo importance of FGFR1 signaling for the control of proliferation in mesenchymal progenitor populations is underscored by defects in ventral mesoderm formation during development upon inhibition of its signaling. Collectively, these studies demonstrate that FGFR1 signaling mediates the continuation of MSC growth and establishes a receptor target for enhancing the expansion of mesenchymal progenitors while maintaining their multilineage potential.
Amaya,
FGF signalling in the early specification of mesoderm in Xenopus.
1993, Pubmed,
Xenbase
Amaya,
FGF signalling in the early specification of mesoderm in Xenopus.
1993,
Pubmed
,
Xenbase
Amaya,
Expression of a dominant negative mutant of the FGF receptor disrupts mesoderm formation in Xenopus embryos.
1991,
Pubmed
,
Xenbase
Auld,
Hormonal induction of adipogenesis induces Skp2 expression through PI3K and MAPK pathways.
2007,
Pubmed
Baumbach,
Regulation of human histone gene expression: transcriptional and posttranscriptional control in the coupling of histone messenger RNA stability with DNA replication.
1987,
Pubmed
Bianchi,
Ex vivo enrichment of mesenchymal cell progenitors by fibroblast growth factor 2.
2003,
Pubmed
Blagosklonny,
The restriction point of the cell cycle.
2002,
Pubmed
Böttcher,
Fibroblast growth factor signaling during early vertebrate development.
2005,
Pubmed
Bracken,
E2F target genes: unraveling the biology.
2004,
Pubmed
Burgar,
Association of the signaling adaptor FRS2 with fibroblast growth factor receptor 1 (Fgfr1) is mediated by alternative splicing of the juxtamembrane domain.
2002,
Pubmed
Cantley,
Oncogenes and signal transduction.
1991,
Pubmed
Chandramohan,
c-Myc represses FOXO3a-mediated transcription of the gene encoding the p27(Kip1) cyclin dependent kinase inhibitor.
2008,
Pubmed
Cheng,
The p21(Cip1) and p27(Kip1) CDK 'inhibitors' are essential activators of cyclin D-dependent kinases in murine fibroblasts.
1999,
Pubmed
Coutu,
Inhibition of cellular senescence by developmentally regulated FGF receptors in mesenchymal stem cells.
2011,
Pubmed
Dombrowski,
Heparan sulfate mediates the proliferation and differentiation of rat mesenchymal stem cells.
2009,
Pubmed
el-Deiry,
WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis.
1994,
Pubmed
Fletcher,
The role of FGF signaling in the establishment and maintenance of mesodermal gene expression in Xenopus.
2008,
Pubmed
,
Xenbase
Gartel,
Myc represses the p21(WAF1/CIP1) promoter and interacts with Sp1/Sp3.
2001,
Pubmed
Giri,
Alterations in expression of basic fibroblast growth factor (FGF) 2 and its receptor FGFR-1 in human prostate cancer.
1999,
Pubmed
Harper,
The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases.
1993,
Pubmed
Hase,
Correlation of basic fibroblast growth factor expression with the invasion and the prognosis of oral squamous cell carcinoma.
2006,
Pubmed
Helledie,
A simple and reliable electroporation method for human bone marrow mesenchymal stem cells.
2008,
Pubmed
Isaacs,
eFGF regulates Xbra expression during Xenopus gastrulation.
1994,
Pubmed
,
Xenbase
Jacob,
Fibroblast growth factor receptor 1 signaling in the osteo-chondrogenic cell lineage regulates sequential steps of osteoblast maturation.
2006,
Pubmed
Jacob,
Expression and localization of Ski determine cell type-specific TGFbeta signaling effects on the cell cycle.
2008,
Pubmed
James,
Differential modification of p27Kip1 controls its cyclin D-cdk4 inhibitory activity.
2008,
Pubmed
Kitagawa,
The consensus motif for phosphorylation by cyclin D1-Cdk4 is different from that for phosphorylation by cyclin A/E-Cdk2.
1996,
Pubmed
Kouhara,
A lipid-anchored Grb2-binding protein that links FGF-receptor activation to the Ras/MAPK signaling pathway.
1997,
Pubmed
Kusakabe,
Xenopus FRS2 is involved in early embryogenesis in cooperation with the Src family kinase Laloo.
2001,
Pubmed
,
Xenbase
Lepique,
c-Myc protein is stabilized by fibroblast growth factor 2 and destabilized by ACTH to control cell cycle in mouse Y1 adrenocortical cells.
2004,
Pubmed
Liang,
PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest.
2002,
Pubmed
Ling,
Sulfated glycosaminoglycans mediate the effects of FGF2 on the osteogenic potential of rat calvarial osteoprogenitor cells.
2006,
Pubmed
Marie,
Fibroblast growth factor signaling controlling osteoblast differentiation.
2003,
Pubmed
Mohammadi,
Structures of the tyrosine kinase domain of fibroblast growth factor receptor in complex with inhibitors.
1997,
Pubmed
Motti,
Loss of p27 expression through RAS-->BRAF-->MAP kinase-dependent pathway in human thyroid carcinomas.
2007,
Pubmed
Müller,
E2Fs regulate the expression of genes involved in differentiation, development, proliferation, and apoptosis.
2001,
Pubmed
Norbury,
Animal cell cycles and their control.
1992,
Pubmed
Ornitz,
Receptor specificity of the fibroblast growth factor family.
1996,
Pubmed
Ornitz,
FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease.
2002,
Pubmed
Ozen,
Role of fibroblast growth factor receptor signaling in prostate cancer cell survival.
2001,
Pubmed
Pardee,
G1 events and regulation of cell proliferation.
1989,
Pubmed
Pines,
Isolation of a human cyclin cDNA: evidence for cyclin mRNA and protein regulation in the cell cycle and for interaction with p34cdc2.
1989,
Pubmed
Pledger,
Induction of DNA synthesis in BALB/c 3T3 cells by serum components: reevaluation of the commitment process.
1977,
Pubmed
Plumb,
Coordinate regulation of multiple histone mRNAs during the cell cycle in HeLa cells.
1983,
Pubmed
Polyak,
Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals.
1994,
Pubmed
Quarto,
Molecular mechanisms of FGF-2 inhibitory activity in the osteogenic context of mouse adipose-derived stem cells (mASCs).
2008,
Pubmed
Quarto,
FGF-2 inhibits osteogenesis in mouse adipose tissue-derived stromal cells and sustains their proliferative and osteogenic potential state.
2006,
Pubmed
Quarto,
Differential expression of specific FGF ligands and receptor isoforms during osteogenic differentiation of mouse Adipose-derived Stem Cells (mASCs) recapitulates the in vivo osteogenic pattern.
2008,
Pubmed
Rider,
Autocrine fibroblast growth factor 2 increases the multipotentiality of human adipose-derived mesenchymal stem cells.
2008,
Pubmed
Roberts,
Cyclins, Cdks, and cyclin kinase inhibitors.
1994,
Pubmed
Schlessinger,
Cell signaling by receptor tyrosine kinases.
2000,
Pubmed
Sears,
Multiple Ras-dependent phosphorylation pathways regulate Myc protein stability.
2000,
Pubmed
Seedorf,
Intracellular signaling by growth factors.
1995,
Pubmed
Sherr,
Inhibitors of mammalian G1 cyclin-dependent kinases.
1995,
Pubmed
Shimada,
Maternal-zygotic medaka mutants for fgfr1 reveal its essential role in the migration of the axial mesoderm but not the lateral mesoderm.
2008,
Pubmed
Slack,
The role of fibroblast growth factors in early Xenopus development.
1996,
Pubmed
,
Xenbase
Solchaga,
FGF-2 enhances the mitotic and chondrogenic potentials of human adult bone marrow-derived mesenchymal stem cells.
2005,
Pubmed
Tsutsumi,
Retention of multilineage differentiation potential of mesenchymal cells during proliferation in response to FGF.
2001,
Pubmed
Westendorf,
Runx2 (Cbfa1, AML-3) interacts with histone deacetylase 6 and represses the p21(CIP1/WAF1) promoter.
2002,
Pubmed
Woei Ng,
Osteogenic differentiation of murine embryonic stem cells is mediated by fibroblast growth factor receptors.
2007,
Pubmed
Xiong,
p21 is a universal inhibitor of cyclin kinases.
1993,
Pubmed
Zaidi,
Tyrosine phosphorylation controls Runx2-mediated subnuclear targeting of YAP to repress transcription.
2004,
Pubmed
Zaragosi,
Autocrine fibroblast growth factor 2 signaling is critical for self-renewal of human multipotent adipose-derived stem cells.
2006,
Pubmed
Zhang,
Direct cell cycle regulation by the fibroblast growth factor receptor (FGFR) kinase through phosphorylation-dependent release of Cks1 from FGFR substrate 2.
2004,
Pubmed
Zhang,
F-box protein Skp2: a novel transcriptional target of E2F.
2006,
Pubmed
Zhou,
Cytoplasmic localization of p21Cip1/WAF1 by Akt-induced phosphorylation in HER-2/neu-overexpressing cells.
2001,
Pubmed
