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Published 6 December 2004. doi:10.1083/jcb.200409187
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 167, Number 5, 925-934
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Article

 Terminal osteoblast differentiation, mediated by runx2 and p27KIP1, is disrupted in osteosarcoma

David M. Thomas1, Sandra A. Johnson4, Natalie A. Sims4, Melanie K. Trivett1, John L. Slavin1, Brian P. Rubin6, Paul Waring1, Grant A. McArthur1, Carl R. Walkley1, Andrew J. Holloway1, Dileepa Diyagama1, Jonathon E. Grim5, Bruce E. Clurman5, David D.L. Bowtell1, Jong-Seo Lee2, Gabriel M. Gutierrez2, Denise M. Piscopo2, Shannon A. Carty3, and Philip W. Hinds2

1 Ian Potter Foundation Centre for Cancer Genomics and Predictive Medicine, Sir Donald and Lady Trescowthick Laboratories, Peter MacCallum Cancer Center, Victoria 3002, Melbourne, Australia
2 Department of Pathology, Harvard Medical School, Boston, MA 02115
3 Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461
4 Department of Medicine, The University of Melbourne, St. Vincent's Hospital, Victoria 3065, Melbourne, Australia
5 Divisions of Clinical Research and Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109
6 Department of Pathology, University of Washington, Seattle, WA 98195

Correspondence to David Thomas: david.thomas{at}petermac.org

The molecular basis for the inverse relationship between differentiation and tumorigenesis is unknown. The function of runx2, a master regulator of osteoblast differentiation belonging to the runt family of tumor suppressor genes, is consistently disrupted in osteosarcoma cell lines. Ectopic expression of runx2 induces p27KIP1, thereby inhibiting the activity of S-phase cyclin complexes and leading to the dephosphorylation of the retinoblastoma tumor suppressor protein (pRb) and a G1 cell cycle arrest. Runx2 physically interacts with the hypophosphorylated form of pRb, a known coactivator of runx2, thereby completing a feed-forward loop in which progressive cell cycle exit promotes increased expression of the osteoblast phenotype. Loss of p27KIP1 perturbs transient and terminal cell cycle exit in osteoblasts. Consistent with the incompatibility of malignant transformation and permanent cell cycle exit, loss of p27KIP1 expression correlates with dedifferentiation in high-grade human osteosarcomas. Physiologic coupling of osteoblast differentiation to cell cycle withdrawal is mediated through runx2 and p27KIP1, and these processes are disrupted in osteosarcoma.

G. Gutierrez's and P.W. Hinds's present address is Dept. of Radiation Oncology and Molecular Oncology Research Institute, Tufts-New England Medical Center, Boston, MA 02111.

Abbreviations used in this paper: BMP, bone morphogenetic protein; MEF, murine embryonic fibroblast; PCNA, proliferating cell nuclear antigen.


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