The family of fibroblast growth factors (FGFs) and cognate receptors (FGFR) plays an important role in a large number of developmental processes, including sketal development. Activating mutations in FGFR1-3 cause a number of human bone morphogenetic disorders, including dwarfism and craniosynostosis syndromes, by affecting the proliferation and differentiation of chondrocytes and osteoblasts, the two major cell types responsible for bone formation. The main focus of this project is to investigate the mechanisms and identify the key events which detrmine the response of chondrocytes to FGF signaling. Elucidating these mechansims should shed light on the physiological and pathological role of FGF signaling in bone development. Our previous studies have shown that proliferating chondrocytes respond to FGF with growth- inhibition and that this inhibition requires STAT1 function, both in vitro and in vivo. FGF also induces some aspects of hypertrophic differentiation, including apoptosis. In addition to STAT1, we have shown that FGF- mediated growth inhibition also requires the retinoblastoma proteins p107 and p130, and that p107 dephosphorylation is an early critical event in the FGF response of choncrocytes. We have also recently uncovered a novel role for STAT3 in endochondral ossification. The goals of this project are: 1) To study the role and the mechanism of p107 dephosphorylation in the FGF response of chondrocytes, and whether a specific activation of the PP2A phosphatase by FGF is responsible for p107 dephosphorylation. 2) To study further FGF signaling in chondrocytes to understand the role that STAT1 plays in the FGF response. We will determine whether STAT1 regulates the growth-inhibitory response to FGF by a transcriptional or non- transcriptional mechanism and identify the genes whose activation or downregulation of expression by FGF requires STAT1 function. 3) To investigate the role of STATS in bone development and the response of chondrocytes to FGF. We have found that a conditional knockout of STATS in chondrocytes reduces proliferation, and accelerates differentiation and apoptosis in the growth plate. We will study the mechanisms of this effect and the hypothesis that STAT1 and STATS play opposite roles in chondrocyte proliferatin and differentiation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE013745-09
Application #
7810518
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Scholnick, Steven
Project Start
2007-05-01
Project End
2011-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
9
Fiscal Year
2010
Total Cost
$290,428
Indirect Cost
Name
New York University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Kolupaeva, Victoria; Daempfling, Lea; Basilico, Claudio (2013) The B55* regulatory subunit of protein phosphatase 2A mediates fibroblast growth factor-induced p107 dephosphorylation and growth arrest in chondrocytes. Mol Cell Biol 33:2865-78
Basu-Roy, Upal; Basilico, Claudio; Mansukhani, Alka (2013) Perspectives on cancer stem cells in osteosarcoma. Cancer Lett 338:158-67
Kolupaeva, Victoria; Basilico, Claudio (2012) Overexpression of cyclin E/CDK2 complexes overcomes FGF-induced cell cycle arrest in the presence of hypophosphorylated Rb proteins. Cell Cycle 11:2557-66
Basu-Roy, U; Seo, E; Ramanathapuram, L et al. (2012) Sox2 maintains self renewal of tumor-initiating cells in osteosarcomas. Oncogene 31:2270-82
Tran, Tri; Kolupaeva, Victoria; Basilico, Claudio (2010) FGF inhibits the activity of the cyclin B1/CDK1 kinase to induce a transient G?arrest in RCS chondrocytes. Cell Cycle 9:4379-86
Kolupaeva, Victoria; Laplantine, Emmanuel; Basilico, Claudio (2008) PP2A-mediated dephosphorylation of p107 plays a critical role in chondrocyte cell cycle arrest by FGF. PLoS One 3:e3447
Yaragatti, Mahesh; Basilico, Claudio; Dailey, Lisa (2008) Identification of active transcriptional regulatory modules by the functional assay of DNA from nucleosome-free regions. Genome Res 18:930-8
Priore, Riccardo; Dailey, Lisa; Basilico, Claudio (2006) Downregulation of Akt activity contributes to the growth arrest induced by FGF in chondrocytes. J Cell Physiol 207:800-8
Mansukhani, Alka; Ambrosetti, Davide; Holmes, Greg et al. (2005) Sox2 induction by FGF and FGFR2 activating mutations inhibits Wnt signaling and osteoblast differentiation. J Cell Biol 168:1065-76
Olsen, Shaun K; Ibrahimi, Omar A; Raucci, Angela et al. (2004) Insights into the molecular basis for fibroblast growth factor receptor autoinhibition and ligand-binding promiscuity. Proc Natl Acad Sci U S A 101:935-40

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