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(Circulation Research. 2006;98:1273.)
© 2006 American Heart Association, Inc.

Molecular Medicine

A Calmodulin-Binding Site on Cyclin E Mediates Ca²⁺-Sensitive G₁/S Transitions in Vascular Smooth Muscle Cells

Jaehyun Choi, Andrew Chiang, Nicolas Taulier, Robert Gros, Asif Pirani, Mansoor Husain

From the Heart & Stroke Richard Lewar Centre of Excellence in Cardiovascular Research and the Faculty of Medicine (J.C., A.C., A.P., M.H.); Departments of Medicine, Physiology, and Laboratory Medicine and Pathobiology (J.C., R.G., M.H.); Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy (N.T.); and McLaughlin Centre for Molecular Medicine (M.H.), University of Toronto, Ontario; and Division of Cell and Molecular Biology (M.H.), Toronto General Hospital Research Institute, Ontario, Canada.

Correspondence to Mansoor Husain, MD, Toronto General Hospital, 200 Elizabeth St, EN12-221, Toronto, Ontario, Canada M5G 2C4. E-mail mansoor.husain{at}utoronto.ca

Calcium transients are known to control several transition points in the eukaryotic cell cycle. For example, we have previously shown that a coordinate elevation in the intracellular free calcium ion concentration is required for G₁- to S-phase cell cycle progression in vascular smooth muscle cells (VSMC). However, the molecular basis for this Ca²⁺ sensitivity was not known. Using buffers with differing [Ca²⁺], we found that the kinase activity of mouse and human cyclin E/CDK2, but not other G₁/S-associated cell cycle complexes, was responsive to physiological changes in [Ca²⁺]. We next determined that this Ca²⁺-responsive kinase activity was dependent on a direct interaction between calmodulin (CaM), one of the major Ca²⁺-signal transducers of eukaryotic cells, and cyclin E. Pharmacological inhibition of CaM abrogated the Ca²⁺ sensitivity of cyclin E/CDK2 and retarded mouse VSMC proliferation by causing G₁ arrest. We next defined the presence of a highly conserved 22 amino acid N-terminal CaM-binding motif in mammalian cyclin E genes (dissociation constant, 1.5±0.1 µmol/L) and showed its essential role in mediating Ca²⁺-sensitive kinase activity of cyclin E/CDK2. Mutant human cyclin E protein, lacking this CaM-binding motif, was incapable of binding CaM or responding to [Ca²⁺]. Taken together, these findings reveal CaM-dependent cyclin E/CDK2 activity as a mediator of the known Ca²⁺ sensitivity of the G₁/S transition of VSMC.

Key Words: calcium • calmodulin • cell cycle • cell cycle progression • CDK2 • cyclin E • vascular smooth muscle cells

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Vera V. Koledova and Raouf A. Khalil
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