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• W2089016492 abstract "Fibroblast growth factor (FGF)/FGF receptor (FGFR) signaling induces the expression of Runx2, a key transcription factor in osteoblast differentiation, but little is known about the molecular signaling mechanisms that mediate this. Here we examined the role of the protein kinase C (PKC) pathway in regulating Runx2 gene expression and its transactivation function. Treatment with FGF2 or FGF4, or transfection with a vector expressing a mutant FGFR2 that is constitutively activated in the absence of ligand, strongly stimulates Runx2 expression. Electrophoretic mobility shift assays also showed that FGF2 treatment increases the specific binding of Runx2 to the cognate response element in the osteocalcin gene promoter. Blocking PKC completely inhibited FGF2-induced Runx2 expression, whereas mitogen-activate protein kinase inhibitors had no effect. The FGF/FGFR-stimulated 6xOSE2 promoter activity was also blocked by inhibiting PKC, as was the FGF2 stimulation of the DNA-binding activity of Runx2. Experiments with PKC isoform-specific inhibitors and dominant negative isoforms of PKC indicate that PKCδ is one of key isoforms involved in the FGF2-stimulated Runx2 expression. In addition, experiments with Runx2-knockout cells showed that, although the PKC pathway largely regulates FGF2-stimulated Runx2 activity by up-regulating Runx2 expression, it also modifies Runx2 protein post-translationally and thereby increases its transcriptional activity. Thus, we show for the first time that FGF/FGFR signaling stimulates the DNA-binding and transcriptional activities of Runx2 as well as its expression, and these are largely regulated by the PKC pathway. Fibroblast growth factor (FGF)/FGF receptor (FGFR) signaling induces the expression of Runx2, a key transcription factor in osteoblast differentiation, but little is known about the molecular signaling mechanisms that mediate this. Here we examined the role of the protein kinase C (PKC) pathway in regulating Runx2 gene expression and its transactivation function. Treatment with FGF2 or FGF4, or transfection with a vector expressing a mutant FGFR2 that is constitutively activated in the absence of ligand, strongly stimulates Runx2 expression. Electrophoretic mobility shift assays also showed that FGF2 treatment increases the specific binding of Runx2 to the cognate response element in the osteocalcin gene promoter. Blocking PKC completely inhibited FGF2-induced Runx2 expression, whereas mitogen-activate protein kinase inhibitors had no effect. The FGF/FGFR-stimulated 6xOSE2 promoter activity was also blocked by inhibiting PKC, as was the FGF2 stimulation of the DNA-binding activity of Runx2. Experiments with PKC isoform-specific inhibitors and dominant negative isoforms of PKC indicate that PKCδ is one of key isoforms involved in the FGF2-stimulated Runx2 expression. In addition, experiments with Runx2-knockout cells showed that, although the PKC pathway largely regulates FGF2-stimulated Runx2 activity by up-regulating Runx2 expression, it also modifies Runx2 protein post-translationally and thereby increases its transcriptional activity. Thus, we show for the first time that FGF/FGFR signaling stimulates the DNA-binding and transcriptional activities of Runx2 as well as its expression, and these are largely regulated by the PKC pathway. fibroblast growth factor FGF receptor mitogen-activated protein kinase extracellular signal-regulated kinase MAPK/Erk kinase protein kinase C Runt-related transcription factor 2 bovine serum albumin α-minimal essential medium Dulbecco's modified Eagle's medium fetal bovine serum phosphate-buffered saline 3-[morpholino]propanesulfonic acid osteoblast-specific core binding sequences diacylglycerol Fibroblast growth factors (FGFs)1 are important autocrine/paracrine signaling molecules involved in intramembranous and endochondral bone formation. They include FGF2, which is a strong mitogen for bone-derived cells (1Globus R.K. Plouet J. Gospodarowicz D. Endocrinology. 1988; 124: 1539-1547Crossref Scopus (266) Google Scholar, 2Long M.W. Robin J.A. Ashcraft E.A. Mann K.G. J. Clin. Invest. 1995; 95: 881-887Crossref PubMed Google Scholar, 3Pitaru S. Kotev-Emeth S. Noff D. Kaffuler S. Savion N. J. Bone Miner. Res. 1993; 8: 919-929Crossref PubMed Scopus (183) Google Scholar, 4Rodan S.B. Wesolowski G. Thomas K.A. Yoon K. Rodan G.A. Conn. Tissue Res. 1989; 20: 283-288Crossref PubMed Scopus (118) Google Scholar, 5Cannalis E. Centrella M. MacCarthy T.L. J. Clin. Invest. 1988; 81: 1572-1577Crossref PubMed Scopus (327) Google Scholar). Disruption of theFGF2 gene results in decreased bone formation (6Montero A. Okada Y. Tomita M. Ito M. Tsurukami H. Nakamura T. Doetschman T. Coffin J.D. Hurley M.M. J. Clin. Invest. 2000; 105: 1085-1093Crossref PubMed Scopus (400) Google Scholar), whereas overexpression of FGF2 in transgenic mice causes achondroplasia, the premature transformation of cartilage to bone (7Coffin J.D. Florkiewicz R.Z. Neumann J. Mort-Hopkins T. Dorn 2nd, G.W. Lightfoot P. German R. Howles P.N. Kier A. O'Toole B.A. Mol. Biol. Cell. 1995; 6: 1861-1873Crossref PubMed Scopus (259) Google Scholar). Constitutive active mutations of FGF receptors (FGFR) 1, 2, and 3 caused a congenital abnormality, craniosynostosis, which is characterized by premature osseous obliteration of cranial suture (8Muenke M. Schell U. Hehr A. Robin N.H. Losken H.W. Schinzed A. Pulleyn L.J. Nat. Genet. 1994; 8: 269-273Crossref PubMed Scopus (537) Google Scholar, 9Reardon W. Winter R.M. Rutland P. Pulleyn L.J. Jones B.M. Malcolm S. Nat. Genet. 1994; 8: 98-103Crossref PubMed Scopus (608) Google Scholar). In osteoblasts, the interaction of FGFs like FGF2 with their FGFRs induces receptor dimerization and autophosphorylation of receptors, which in turn activates multiple signal transduction pathways, including those involving mitogen-activated protein kinases (MAPKs) and protein kinase C (PKC) (10Chaudhary L.R. Avioli L.V. Biochem. Biophys. Res. Commun. 1997; 238: 134-139Crossref PubMed Scopus (70) Google Scholar, 11Kozawa O. Tokuda H. Matsuno H. Uematsu T. J. Cell. Biochem. 1999; 74: 479-485Crossref PubMed Scopus (48) Google Scholar, 12Suzuki A. Palmer G. Bonjour J.P. Caverzasio J. J. Bone Miner. Res. 2000; 15: 95-102Crossref PubMed Scopus (62) Google Scholar, 13Debiais F. Lemonnier J. Hay E. Delannoy P. Caverzasio J. Marie P.J. J. Cell. Biochem. 2001; 81: 68-81Crossref PubMed Scopus (71) Google Scholar). However, the signaling pathways that mediate the biological actions of FGF/FGFR in osteoblasts remain unclear.Runt-related transcription factor 2 (Runx2), previously known asCbfa1/Pebp2αA/AML3, plays an essential role in osteoblast differentiation (14Ducy P. Zhang R. Geoffroy V. Ridall A.L. Karsenty G. Cell. 1997; 89: 747-754Abstract Full Text Full Text PDF PubMed Scopus (3607) Google Scholar, 15Komori T. Yagi H. Nomura S. Yamaguchi A. Sasaki K. Deguchi K. Shimizu Y. Bronson R.T. Gao Y.H. Inada M. Sato M. Okamoto R. Kitamura Y. Yoshiki S. Kishimoto T. Cell. 1997; 89: 755-764Abstract Full Text Full Text PDF PubMed Scopus (3599) Google Scholar, 16Otto F. Thornell A.P. Crompton T. Denzel A. Gilmour K.C. Rosewell I.R. Stamp G.W. Beddington R.S. Mundlos S. Olsen B. Selby P.B. Owen M.J. Cell. 1997; 89: 765-771Abstract Full Text Full Text PDF PubMed Scopus (2378) Google Scholar).Runx2-knockout animals display complete bone loss because of arrested osteoblast maturation (15Komori T. Yagi H. Nomura S. Yamaguchi A. Sasaki K. Deguchi K. Shimizu Y. Bronson R.T. Gao Y.H. Inada M. Sato M. Okamoto R. Kitamura Y. Yoshiki S. Kishimoto T. Cell. 1997; 89: 755-764Abstract Full Text Full Text PDF PubMed Scopus (3599) Google Scholar) while heterozygotes develop cleidocranial dysplasia, which is characterized by delayed ossification (16Otto F. Thornell A.P. Crompton T. Denzel A. Gilmour K.C. Rosewell I.R. Stamp G.W. Beddington R.S. Mundlos S. Olsen B. Selby P.B. Owen M.J. Cell. 1997; 89: 765-771Abstract Full Text Full Text PDF PubMed Scopus (2378) Google Scholar, 17Mundlos S. Otto F. Mundlos C. Mulliken J.B. Aylsworth A.S. Albright S. Lindhout D. Cole W.G. Henn W. Knoll J.H.M. Owen M.J. Mertelsmann R. Zabel B.U. Olsen B.R. Cell. 1997; 89: 773-779Abstract Full Text Full Text PDF PubMed Scopus (1264) Google Scholar). Several reports show that Runx2 regulates the expression of bone marker genes during osteoblast differentiation (14Ducy P. Zhang R. Geoffroy V. Ridall A.L. Karsenty G. Cell. 1997; 89: 747-754Abstract Full Text Full Text PDF PubMed Scopus (3607) Google Scholar, 18Banerjee G. McCabe L.R. Choi J.Y. Hiebert S.W. Stein J.L. Stein G.S. Lian J.B. J. Cell. Biochem. 1997; 66: 1-8Crossref PubMed Scopus (396) Google Scholar, 19Ji C. Casinghino S. Chang D.J. Chen Y. Javed A. Ito Y. Hiebert S.W. Lian J.B. Stein G.S. McCarthy T.L. Centrella M. J. Cell. Biochem. 1998; 69: 353-363Crossref PubMed Scopus (87) Google Scholar). In our previous report, we investigated the expression pattern of Runx2 during intramembranous bone formation and found that Runx2 expression is needed for all steps of osteoblast differentiation, namely, from the commitment to differentiate through to the final differentiation event (20Park M.H. Shin H.I. Choi J.Y. Nam S.H. Kim Y.J. Kim H.J. Ryoo H.M. J. Bone Mineral. Res. 2001; 16: 885-892Crossref PubMed Scopus (73) Google Scholar). Taken together, these observations clearly indicate that Runx2 plays a key role in osteoblast differentiation.In humans, a mutation in FGFR1 that causes its constitutive activation is associated with Pfeiffer syndrome, one of the syndromes that comprise craniosynostosis as a phenotype. In mice, gene replacement with a constitutively active FGFR1 mutant results in increased expression of Runx2 and premature suture closure that is the representative phenotype of human craniosynostosis (21Zhou Y.X., Xu, X. Chen L., Li, C. Brodie S.G. Deng C.X. Hum. Mol. Genet. 2000; 9: 2001-2008Crossref PubMed Scopus (199) Google Scholar). This suggests that Runx2 may be a downstream target gene in FGF/FGFR signaling during bone formation. However, the mechanisms by which activated FGFRs increase Runx2 expression are not yet understood. In this report, we demonstrate for the first time that FGF/FGFR stimulation of Runx2 expression, which leads to the transactivation of downstream genes, is mediated by the PKC pathway. Fibroblast growth factors (FGFs)1 are important autocrine/paracrine signaling molecules involved in intramembranous and endochondral bone formation. They include FGF2, which is a strong mitogen for bone-derived cells (1Globus R.K. Plouet J. Gospodarowicz D. Endocrinology. 1988; 124: 1539-1547Crossref Scopus (266) Google Scholar, 2Long M.W. Robin J.A. Ashcraft E.A. Mann K.G. J. Clin. Invest. 1995; 95: 881-887Crossref PubMed Google Scholar, 3Pitaru S. Kotev-Emeth S. Noff D. Kaffuler S. Savion N. J. Bone Miner. Res. 1993; 8: 919-929Crossref PubMed Scopus (183) Google Scholar, 4Rodan S.B. Wesolowski G. Thomas K.A. Yoon K. Rodan G.A. Conn. Tissue Res. 1989; 20: 283-288Crossref PubMed Scopus (118) Google Scholar, 5Cannalis E. Centrella M. MacCarthy T.L. J. Clin. Invest. 1988; 81: 1572-1577Crossref PubMed Scopus (327) Google Scholar). Disruption of theFGF2 gene results in decreased bone formation (6Montero A. Okada Y. Tomita M. Ito M. Tsurukami H. Nakamura T. Doetschman T. Coffin J.D. Hurley M.M. J. Clin. Invest. 2000; 105: 1085-1093Crossref PubMed Scopus (400) Google Scholar), whereas overexpression of FGF2 in transgenic mice causes achondroplasia, the premature transformation of cartilage to bone (7Coffin J.D. Florkiewicz R.Z. Neumann J. Mort-Hopkins T. Dorn 2nd, G.W. Lightfoot P. German R. Howles P.N. Kier A. O'Toole B.A. Mol. Biol. Cell. 1995; 6: 1861-1873Crossref PubMed Scopus (259) Google Scholar). Constitutive active mutations of FGF receptors (FGFR) 1, 2, and 3 caused a congenital abnormality, craniosynostosis, which is characterized by premature osseous obliteration of cranial suture (8Muenke M. Schell U. Hehr A. Robin N.H. Losken H.W. Schinzed A. Pulleyn L.J. Nat. Genet. 1994; 8: 269-273Crossref PubMed Scopus (537) Google Scholar, 9Reardon W. Winter R.M. Rutland P. Pulleyn L.J. Jones B.M. Malcolm S. Nat. Genet. 1994; 8: 98-103Crossref PubMed Scopus (608) Google Scholar). In osteoblasts, the interaction of FGFs like FGF2 with their FGFRs induces receptor dimerization and autophosphorylation of receptors, which in turn activates multiple signal transduction pathways, including those involving mitogen-activated protein kinases (MAPKs) and protein kinase C (PKC) (10Chaudhary L.R. Avioli L.V. Biochem. Biophys. Res. Commun. 1997; 238: 134-139Crossref PubMed Scopus (70) Google Scholar, 11Kozawa O. Tokuda H. Matsuno H. Uematsu T. J. Cell. Biochem. 1999; 74: 479-485Crossref PubMed Scopus (48) Google Scholar, 12Suzuki A. Palmer G. Bonjour J.P. Caverzasio J. J. Bone Miner. Res. 2000; 15: 95-102Crossref PubMed Scopus (62) Google Scholar, 13Debiais F. Lemonnier J. Hay E. Delannoy P. Caverzasio J. Marie P.J. J. Cell. Biochem. 2001; 81: 68-81Crossref PubMed Scopus (71) Google Scholar). However, the signaling pathways that mediate the biological actions of FGF/FGFR in osteoblasts remain unclear. Runt-related transcription factor 2 (Runx2), previously known asCbfa1/Pebp2αA/AML3, plays an essential role in osteoblast differentiation (14Ducy P. Zhang R. Geoffroy V. Ridall A.L. Karsenty G. Cell. 1997; 89: 747-754Abstract Full Text Full Text PDF PubMed Scopus (3607) Google Scholar, 15Komori T. Yagi H. Nomura S. Yamaguchi A. Sasaki K. Deguchi K. Shimizu Y. Bronson R.T. Gao Y.H. Inada M. Sato M. Okamoto R. Kitamura Y. Yoshiki S. Kishimoto T. Cell. 1997; 89: 755-764Abstract Full Text Full Text PDF PubMed Scopus (3599) Google Scholar, 16Otto F. Thornell A.P. Crompton T. Denzel A. Gilmour K.C. Rosewell I.R. Stamp G.W. Beddington R.S. Mundlos S. Olsen B. Selby P.B. Owen M.J. Cell. 1997; 89: 765-771Abstract Full Text Full Text PDF PubMed Scopus (2378) Google Scholar).Runx2-knockout animals display complete bone loss because of arrested osteoblast maturation (15Komori T. Yagi H. Nomura S. Yamaguchi A. Sasaki K. Deguchi K. Shimizu Y. Bronson R.T. Gao Y.H. Inada M. Sato M. Okamoto R. Kitamura Y. Yoshiki S. Kishimoto T. Cell. 1997; 89: 755-764Abstract Full Text Full Text PDF PubMed Scopus (3599) Google Scholar) while heterozygotes develop cleidocranial dysplasia, which is characterized by delayed ossification (16Otto F. Thornell A.P. Crompton T. Denzel A. Gilmour K.C. Rosewell I.R. Stamp G.W. Beddington R.S. Mundlos S. Olsen B. Selby P.B. Owen M.J. Cell. 1997; 89: 765-771Abstract Full Text Full Text PDF PubMed Scopus (2378) Google Scholar, 17Mundlos S. Otto F. Mundlos C. Mulliken J.B. Aylsworth A.S. Albright S. Lindhout D. Cole W.G. Henn W. Knoll J.H.M. Owen M.J. Mertelsmann R. Zabel B.U. Olsen B.R. Cell. 1997; 89: 773-779Abstract Full Text Full Text PDF PubMed Scopus (1264) Google Scholar). Several reports show that Runx2 regulates the expression of bone marker genes during osteoblast differentiation (14Ducy P. Zhang R. Geoffroy V. Ridall A.L. Karsenty G. Cell. 1997; 89: 747-754Abstract Full Text Full Text PDF PubMed Scopus (3607) Google Scholar, 18Banerjee G. McCabe L.R. Choi J.Y. Hiebert S.W. Stein J.L. Stein G.S. Lian J.B. J. Cell. Biochem. 1997; 66: 1-8Crossref PubMed Scopus (396) Google Scholar, 19Ji C. Casinghino S. Chang D.J. Chen Y. Javed A. Ito Y. Hiebert S.W. Lian J.B. Stein G.S. McCarthy T.L. Centrella M. J. Cell. Biochem. 1998; 69: 353-363Crossref PubMed Scopus (87) Google Scholar). In our previous report, we investigated the expression pattern of Runx2 during intramembranous bone formation and found that Runx2 expression is needed for all steps of osteoblast differentiation, namely, from the commitment to differentiate through to the final differentiation event (20Park M.H. Shin H.I. Choi J.Y. Nam S.H. Kim Y.J. Kim H.J. Ryoo H.M. J. Bone Mineral. Res. 2001; 16: 885-892Crossref PubMed Scopus (73) Google Scholar). Taken together, these observations clearly indicate that Runx2 plays a key role in osteoblast differentiation. In humans, a mutation in FGFR1 that causes its constitutive activation is associated with Pfeiffer syndrome, one of the syndromes that comprise craniosynostosis as a phenotype. In mice, gene replacement with a constitutively active FGFR1 mutant results in increased expression of Runx2 and premature suture closure that is the representative phenotype of human craniosynostosis (21Zhou Y.X., Xu, X. Chen L., Li, C. Brodie S.G. Deng C.X. Hum. Mol. Genet. 2000; 9: 2001-2008Crossref PubMed Scopus (199) Google Scholar). This suggests that Runx2 may be a downstream target gene in FGF/FGFR signaling during bone formation. However, the mechanisms by which activated FGFRs increase Runx2 expression are not yet understood. In this report, we demonstrate for the first time that FGF/FGFR stimulation of Runx2 expression, which leads to the transactivation of downstream genes, is mediated by the PKC pathway. The FGFR mutant found in patients with Crouzon syndrome was generously provided by Dr. Daniel Donoghue, Department of Chemistry and Biochemistry, University of California, San Diego, CA. OC208-CAT and OC208-CAT Runx mut reporter constructs and Runx2-type II expression vector were provided by Drs. Gary S. Stein and Jane B. Lian, Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA. Dominant negative PKCδ expression vector (PKCδ-KR) was generously provided by Dr. Jae-Won Soh, Department of Biochemistry & Molecular Biophysics and Herbert Irving Comprehensive Cancer Center, Columbia University, NY." @default.
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• W2089016492 date "2003-01-01" @default.
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• W2089016492 title "The Protein Kinase C Pathway Plays a Central Role in the Fibroblast Growth Factor-stimulated Expression and Transactivation Activity of Runx2" @default.
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• W2089016492 doi "https://doi.org/10.1074/jbc.m203750200" @default.
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