Activating mutations in FGF receptor 3 (FGFR3) cause several human dwarfism syndromes by affecting both chondrocyte proliferation and differentiation. Using microarray and biochemical analyses of FGF-treated rat chondrosarcoma chondrocytes, we show that FGF inhibits chondrocyte proliferation by initiating multiple pathways that result in the induction of antiproliferative functions and the down-regulation of growth-promoting molecules. The initiation of growth arrest is characterized by the rapid dephosphorylation of the retinoblastoma protein (pRb) p107 and repression of a subset of E2F target genes by a mechanism that is independent of cyclin E–Cdk inhibition. In contrast, hypophosphorylation of pRb and p130 occur after growth arrest is first detected, and may contribute to its maintenance. Importantly, we also find a number of gene expression changes indicating that FGF promotes many aspects of hypertrophic differentiation, a notion supported by in situ analysis of developing growth plates from mice expressing an activated form of FGFR3. Thus, FGF may coordinate the onset of differentiation with chondrocyte growth arrest in the developing growth plate.
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23 June 2003
Article|
June 23 2003
A network of transcriptional and signaling events is activated by FGF to induce chondrocyte growth arrest and differentiation
Lisa Dailey,
Lisa Dailey
Department of Microbiology, New York University School of Medicine, New York, NY 10016
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Emmanuel Laplantine,
Emmanuel Laplantine
Department of Microbiology, New York University School of Medicine, New York, NY 10016
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Riccardo Priore,
Riccardo Priore
Department of Microbiology, New York University School of Medicine, New York, NY 10016
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Claudio Basilico
Claudio Basilico
Department of Microbiology, New York University School of Medicine, New York, NY 10016
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Lisa Dailey
Department of Microbiology, New York University School of Medicine, New York, NY 10016
Emmanuel Laplantine
Department of Microbiology, New York University School of Medicine, New York, NY 10016
Riccardo Priore
Department of Microbiology, New York University School of Medicine, New York, NY 10016
Claudio Basilico
Department of Microbiology, New York University School of Medicine, New York, NY 10016
Address correspondence to C. Basilico, Dept. of Microbiology, NYU School of Medicine, 550 First Avenue, New York, NY 10016. Tel.: (212) 263-5341. Fax: (212) 263-8714. E-mail: [email protected]; or L. Dailey, Dept. of Microbiology, NYU School of Medicine, 550 First Avenue, New York, NY 10016. Tel.: (212) 263-5341. Fax: (212) 263-8714. E-mail: [email protected]
The online version of this article includes supplemental material.
*
Abbreviations used in this paper: CDKI, Cdk inhibitor; FGFR3, FGF receptor 3; Ihh, Indian hedgehog; MMP13, matrix metalloproteinase 13; OPG, osteoprotegerin; OPN, osteopontin; pRb, retinoblastoma protein; RCS, rat chondrosarcoma.
Received:
February 12 2003
Revision Received:
May 14 2003
Accepted:
May 14 2003
Online ISSN: 1540-8140
Print ISSN: 0021-9525
The Rockefeller University Press
2003
J Cell Biol (2003) 161 (6): 1053–1066.
Article history
Received:
February 12 2003
Revision Received:
May 14 2003
Accepted:
May 14 2003
Citation
Lisa Dailey, Emmanuel Laplantine, Riccardo Priore, Claudio Basilico; A network of transcriptional and signaling events is activated by FGF to induce chondrocyte growth arrest and differentiation . J Cell Biol 23 June 2003; 161 (6): 1053–1066. doi: https://doi.org/10.1083/jcb.200302075
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