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J. Biol. Chem., Vol. 282, Issue 23, 17061-17068, June 8, 2007

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Nucleoplasmic Calcium Is Required for Cell Proliferation^*

Michele A. Rodrigues, Dawidson A. Gomes, M. Fatima Leite, Wayne Grant^¶, Lei Zhang^¶, Wing Lam^¶, Yung-Chi Cheng^¶, Anton M. Bennett^¶, and Michael H. Nathanson¹

From the Departments of Medicine and ^¶Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520-8019 and the Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil 31270-901

Ca²⁺ signals regulate cell proliferation, but the spatial and temporal specificity of these signals is unknown. Here we use selective buffers of nucleoplasmic or cytoplasmic Ca²⁺ to determine that cell proliferation depends upon Ca²⁺ signals within the nucleus rather than in the cytoplasm. Nuclear Ca²⁺ signals stimulate cell growth rather than inhibit apoptosis and specifically permit cells to advance through early prophase. Selective buffering of nuclear but not cytoplasmic Ca²⁺ signals also impairs growth of tumors in vivo. These findings reveal a major physiological and potential pathophysiological role for nucleoplasmic Ca²⁺ signals and suggest that this information can be used to design novel therapeutic strategies to regulate conditions of abnormal cell growth.

Received for publication, January 17, 2007 , and in revised form, April 6, 2007.

^* This work was supported by National Institutes of Health Grants DK57751, DK34989, and DK45710 and by grants from Howard Hughes Medical Institute, Conselho Nacional de Desenvolvimento Cientifico e Tecnologico; and Fundacao de Amparo a Pesquisa do Estado de Minas Gerais. 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 To whom correspondence should be addressed: Digestive Diseases, Rm. TAC S241D, Yale University School of Medicine, New Haven, CT 06520-8019. Tel.: 203-785-7312; Fax: 203-785-4306; E-mail: michael.nathanson{at}yale.edu.

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