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J. Biol. Chem., Vol. 282, Issue 44, 32112-32120, November 2, 2007

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Cell Shape-dependent Control of Ca²⁺ Influx and Cell Cycle Progression in Swiss 3T3 Fibroblasts^*

Stephen R. Pennington¹, Brian J. Foster², Shaun R. Hawley³, Rosalind E. Jenkins⁴, Olga Zolle, Michael R. H. White, Christine J. McNamee, Peter Sheterline, and Alec W. M. Simpson⁵

From the Department of Human Anatomy and Cell Biology, School of Biomedical Sciences, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool L69 3GE, United Kingdom and the Centre for Cell Imaging, School of Biological Sciences, University of Liverpool, Crown Street, Liverpool L69 7ZB, United Kingdom

The ability of adherent cells such as fibroblasts to enter the cell cycle and progress to S phase is strictly dependent on the extent to which individual cells can attach to and spread on a substratum. Here we have used microengineered adhesive islands of 22 and 45 µm diameter surrounded by a nonadhesive substratum of polyhydroxyl methacrylate to accurately control the extent to which individual Swiss 3T3 fibroblasts may spread. The effect of cell shape on mitogen-evoked Ca²⁺ signaling events that accompany entry into the cell cycle was investigated. In unrestricted cells, the mitogens bombesin and fetal calf serum evoked a typical biphasic change in the cytoplasmic free Ca²⁺ concentration. However, when the spreading of individual cells was restricted, such that progression to S phase was substantially reduced, both bombesin and fetal calf serum caused a rapid transient rise in the cytoplasmic free Ca²⁺ concentration but failed to elicit the normal sustained influx of Ca²⁺ that follows Ca²⁺ release. As expected, restricting cell spreading led to the loss of actin stress fibers and the formation of a ring of cortical actin. Restricting cell shape did not appear to influence mitogen-receptor interactions, nor did it influence the presence of focal adhesions. Because Ca²⁺ signaling is an essential component of mitogen responses, these findings implicate Ca²⁺ influx as a necessary component of cell shape-dependent control of the cell cycle.

Received for publication, June 20, 2007 , and in revised form, August 21, 2007.

^* This work was supported by the funds from the BBSRC (to A. W. M. S. and M. R. H. W.), the North West Cancer Research Fund (to S. R. P.), and the Wellcome Trust (to S. R. P., A. W. M. S., and M. R. H. W.). 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 Present address: The Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.

² Recipient of a University of Liverpool Studentship.

³ Present address: AstraZeneca, Discovery BioScience, Bakewell Rd., Lough-borough, Leics. LE11 5RH, UK.

⁴ Present address: University of Liverpool, School of Biomedical Sciences, Pharmacology & Therapeutics, Sherrington Buildings, Ashton St., Liverpool L69 3GE, UK.

⁵ To whom correspondence should be addressed. Tel.: 151-794-5510; Fax: 151-794-5517; E-mail: awms{at}liv.ac.uk.

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