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J. Biol. Chem., Vol. 279, Issue 11, 9882-9891, March 12, 2004

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Accelerated Cell Cycle Progression in Osteoblasts Overexpressing the c-fos Proto-oncogene

INDUCTION OF CYCLIN A AND ENHANCED CDK2 ACTIVITY^*

Andrew Sunters, David P. Thomas, W. Andrew Yeudall¶, and Agamemnon E. Grigoriadis||**

From the Departments of Craniofacial Development and ^||Orthodontics, King's College London, Guy's Hospital, Guy's Tower, Floor 28, London Bridge, London SE1 9RT, United Kingdom and ^¶The Philips Institute of Oral & Craniofacial Molecular Biology, Virginia Commonwealth University, Richmond, Virginia 23298-0566

Transgenic mice overexpressing the c-Fos oncoprotein develop osteosarcomas that are associated with deregulated expression of cell cycle genes. Here we have generated osteoblast cell lines expressing c-fos under the control of a tetracycline-regulatable promoter to investigate the role of c-Fos in osteoblast cell cycle control in vitro. Three stable subclones, AT9.2, AT9.3, and AT9.7, derived from MC3T3-E1 mouse osteoblasts, expressed high levels of exogenous c-fos mRNA and protein in the absence of tetracycline. Functional contribution of ectopic c-Fos to AP-1 complexes was confirmed by electromobility shift assays and transactivation of AP-1 reporter constructs. Induction of exogenous c-Fos in quiescent AT9.2 cells caused accelerated S-phase entry following serum stimulation, resulting in enhanced growth rate. Ectopic c-Fos resulted in increased expression of cyclins A and E protein levels, and premature activation of cyclin A-, cyclin E-, and cyclin-dependent kinase (CDK) 2-associated kinase activities, although cyclin D levels and CDK4 activity were not affected significantly in these cell lines. The enhanced CDK2 kinase activity was associated with a rapid, concomitant dissociation of p27 from CDK2-containing complexes. Deregulated cyclin A expression and CDK2 activity was also observed in primary mouse osteoblasts overexpressing c-Fos, but not in fibroblasts, and c-Fos transgenic tumorderived osteosarcoma cells constitutively expressed high levels of cyclin A protein. These data suggest that overexpression of c-Fos in osteoblasts results in accelerated S phase entry as a result of deregulated cyclin A/E-CDK2 activity. This represents a novel role for c-Fos in osteoblast growth control and may provide c-Fos-overexpressing osteoblasts with a growth advantage during tumorigenesis.

Received for publication, September 12, 2003 , and in revised form, December 10, 2003.

^* This work was supported by the Arthritis Research Campaign (G0538). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: Dept. Cancer Cell Biology, Imperial College London, 6th Floor, Medical Research Council, Cyclotron Bldg., Hammersmith Hospital, DuCane Rd., London W12 0NN, United Kingdom.

^** To whom correspondence should be addressed. Tel.: 44-(0)20-7955-4588; Fax: 44-(0)20-7955-2704; E-mail: agrigori{at}hgmp.mrc.ac.uk.

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