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Molecular and Cellular Biology, June 2006, p. 4612-4627, Vol. 26, No. 12
0270-7306/06/$08.00+0     doi:10.1128/MCB.02061-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

The Rho GTPase Effector ROCK Regulates Cyclin A, Cyclin D1, and p27Kip1 Levels by Distinct Mechanisms

Daniel R. Croft and Michael F. Olson*

The Beatson Institute for Cancer Research, Glasgow G61 1BD, United Kingdom

Received 24 October 2005/ Returned for modification 28 November 2005/ Accepted 6 April 2006

The members of the Rho GTPase family are well known for their regulation of actin cytoskeletal structures. In addition, they influence progression through the cell cycle. The RhoA and RhoC proteins regulate numerous effector proteins, with a central and vital signaling role mediated by the ROCK I and ROCK II serine/threonine kinases. The requirement for ROCK function in the proliferation of numerous cell types has been revealed by studies utilizing ROCK-selective inhibitors such as Y-27632. However, the mechanisms by which ROCK signaling promotes cell cycle progression have not been thoroughly characterized. Using a conditionally activated ROCK-estrogen receptor fusion protein, we found that ROCK activation is sufficient to stimulate G1/S cell cycle progression in NIH 3T3 mouse fibroblasts. Further analysis revealed that ROCK acts via independent pathways to alter the levels of cell cycle regulatory proteins: cyclin D1 and p21Cip1 elevation via Ras and the mitogen-activated protein kinase pathway, increased cyclin A via LIM kinase 2, and reduction of p27Kip1 protein levels. Therefore, the influence of ROCK on cell cycle regulatory proteins occurs by multiple independent mechanisms.

* Corresponding author. Mailing address: The Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Glasgow G61 1BD, United Kingdom. Phone: 44 (0)141 330 3654. Fax: 44 (0)141 942 6521. E-mail: m.olson{at}beatson.gla.ac.uk.

Molecular and Cellular Biology, June 2006, p. 4612-4627, Vol. 26, No. 12
0270-7306/06/$08.00+0     doi:10.1128/MCB.02061-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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