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Published online 12 August 2002. doi:10.1083/jcb.200205025
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© The Rockefeller University Press, 0021-9525/2002/8/741 $5.00
The Journal of Cell Biology, Volume 158, Number 4, August 19, 2002 741-750

Article

 FGF signaling targets the pRb-related p107 and p130 proteins to induce chondrocyte growth arrest

Emmanuel Laplantine1, Ferdinand Rossi2, Malika Sahni3,4, Claudio Basilico1 and David Cobrinik2

1 Department of Microbiology, New York University School of Medicine, New York, NY 10016
2 Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032
3 Department of Orthopaedics, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ 07103
4 Department of Microbiology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ 07103

Address correspondence to Claudio Basilico, Department of Microbiology, New York University School of Medicine, 550 First Avenue, New York, NY 10016. Tel.: (212) 263-5341. Fax: (212) 263-8714. E-mail: basilc01{at}med.nyu.edu

Unregulated FGF signaling affects endochondral ossification and long bone growth, causing several genetic forms of human dwarfism. One major mechanism by which FGFs regulate endochondral bone growth is through their inhibitory effect on chondrocyte proliferation. Because mice with targeted mutations of the retinoblastoma (Rb)-related proteins p107 and p130 present severe endochondral bone defects with excessive chondrocyte proliferation, we have investigated the role of the Rb family of cell cycle regulators in the FGF response. Using a chondrocyte cell line, we found that FGF induced a rapid dephosphorylation of all three proteins of the Rb family (pRb, p107, and p130) and a blockade of the cells in the G1 phase of the cell cycle. This cell cycle block was reversed by inactivation of Rb proteins with viral oncoproteins such as polyoma large T (PyLT) antigen and Adenovirus E1A. Expression of a PyLT mutant that efficiently binds pRb, but not p107 and p130, allowed the cells to be growth inhibited by FGF, suggesting that pRb itself is not involved in the FGF response. To investigate more precisely the role of the individual Rb family proteins in FGF-mediated growth inhibition, we used chondrocyte micromass culture of limb bud cells isolated from mice lacking Rb proteins individually or in combination. Although wild-type as well as Rb-/- chondrocytes were similarly growth inhibited by FGF, chondrocytes null for p107 and p130 did not respond to FGF. Furthermore, FGF treatment of metatarsal bone rudiments obtained from p107-/-;p130-/- embryos failed to inhibit proliferation of growth plate chondrocytes, whereas rudiments from p107-null or p130-null embryos showed only a slight inhibition of growth. Our findings indicate that p107 and p130, but not pRb, are critical effectors of FGF-mediated growth inhibition in chondrocytes.

Key Words: cell cycle; growth factors; pocket proteins; knockout mice; bone development


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