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J. Biol. Chem., Vol. 281, Issue 11, 7118-7128, March 17, 2006

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Cell Cycle-dependent Phosphorylation of the RUNX2 Transcription Factor by cdc2 Regulates Endothelial Cell Proliferation^*

Meng Qiao, Paul Shapiro, Matthew Fosbrink, Horea Rus, Rakesh Kumar^¶, and Antonino Passaniti^||1

From the Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Department of Neurology, University of Maryland School of Medicine, Baltimore, Maryland 21201, ^¶Department of Cellular and Molecular Oncology, M. D. Anderson Cancer Center, Houston, Texas 77030, and ^||Departments of Pathology and Biochemistry & Molecular Biology, Marlene and Stewart Greenebaum Cancer Center Program in Oncology, University of Maryland School of Medicine, Baltimore, Maryland 21201

RUNX2 is a member of the runt family of DNA-binding transcription factors. RUNX2 mediates endothelial cell migration and invasion during tumor angiogenesis and is expressed in metastatic breast and prostate tumors. Our published studies showed that RUNX2 DNA-binding activity is low during growth arrest, but elevated in proliferating endothelial cells. To investigate its role in cell proliferation and cell cycle regulation, RUNX2 was depleted in human bone marrow endothelial cells using RNA interference. Specific RUNX2 depletion inhibited DNA-binding activity as measured by electrophoretic mobility shift assay resulting in inhibition of cell proliferation. Cells were synchronized at the G₁/S boundary with excess thymidine or in mitosis (M phase) with nocodazole. Endogenous or ectopic RUNX2 activity was maximal at late G₂ and during M phase. Inhibition of RUNX2 expression by RNA interference delayed entry into and exit out of the G₂/M phases of the cell cycle. RUNX2 was coimmunoprecipitated with cyclin B1 in mitotic cells, which further supported a role for RUNX2 in cell cycle progression. Moreover, in vitro kinase assays using recombinant cdc2 kinase showed that RUNX2 was phosphorylated at Ser⁴⁵¹. The cdc2 inhibitor roscovitine dose dependently inhibited in vivo RUNX2 DNA-binding activity during mitosis and the RUNX2 mutant S451A exhibited lower DNA-binding activity and reduced stimulation of anchorage-independent growth relative to wild type RUNX2. These results suggest for the first time that RUNX2 phosphorylation by cdc2 may facilitate cell cycle progression possibly through regulation of G₂ and M phases, thus promoting endothelial cell proliferation required for tumor angiogenesis.

Received for publication, July 26, 2005 , and in revised form, December 14, 2005.

^* This work was supported in part by American Heart Association Grant-in-aid AHA 0151434U (to A. P.) and National Institutes of Health Grant R21 CA95350-01 (to A. P.). 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.

¹ Supported in part by a University of Maryland Marlene and Stewart Greenebaum Cancer Center Pilot Project Grant. To whom correspondence should be addressed: 655 W Baltimore St., Baltimore, MD 21201. Tel.: 410-328-5470; Fax: 410-328-6559; E-mail: apass001{at}umaryland.edu.

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