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Molecular and Cellular Biology, June 2006, p. 4240-4256, Vol. 26, No. 11
0270-7306/06/$08.00+0     doi:10.1128/MCB.02124-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Cyclin D1 Regulates Cellular Migration through the Inhibition of Thrombospondin 1 and ROCK Signaling

Zhiping Li,1 Chenguang Wang,1 Xuanmao Jiao,1 Yinan Lu,1 Maofu Fu,1 Andrew A. Quong,1 Chip Dye,2 Jianguo Yang,1 Maozheng Dai,2 Xiaoming Ju,1 Xueping Zhang,1 Anping Li,1 Peter Burbelo,2 E. Richard Stanley,3 and Richard G. Pestell1*

Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107,1 Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, 3970 Reservoir Road, NW, Box 571468, Washington, D.C. 20057-1468,2 Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Yeshiva University, Bronx, New York 104613

Received 2 November 2005/ Returned for modification 13 December 2005/ Accepted 13 March 2006

Cyclin D1 is overexpressed in human tumors, correlating with cellular metastasis, and is induced by activating Rho GTPases. Herein, cyclin D1-deficient mouse embryo fibroblasts (MEFs) exhibited increased adhesion and decreased motility compared with wild-type MEFs. Retroviral transduction of cyclin D1 reversed these phenotypes. Mutational analysis of cyclin D1 demonstrated that its effects on cellular adhesion and migration were independent of the pRb and p160 coactivator binding domains. Genomewide expression arrays identified a subset of genes regulated by cyclin D1, including Rho-activated kinase II (ROCKII) and thrombospondin 1 (TSP-1). cyclin D1–/– cells showed increased Rho GTP and ROCKII activity and signaling, with increased phosphorylation of LIM kinase, cofilin (Ser3), and myosin light chain 2 (Thr18/Ser19). Cyclin D1 repressed ROCKII and TSP-1 expression, and the migratory defect of cyclin D1–/– cells was reversed by ROCK inhibition or TSP-1 immunoneutralizing antibodies. cyclin E knockin to the cyclin D1–/– MEFs rescued the DNA synthesis defect of cyclin D1–/– MEFs but did not rescue either the migration defect or the abundance of ROCKII. Cyclin D1 promotes cellular motility through inhibiting ROCK signaling and repressing the metastasis suppressor TSP-1.

* Corresponding author. Mailing address: Thomas Jefferson University, Department of Cancer Biology, Kimmel Cancer Center, Bluemle Building, Rm 1050, 233 South 10th St, Philadelphia, PA 19107. Phone: (215) 503-5649. Fax: (215) 503-9334. E-mail: richard.pestell{at}jefferson.edu.

Molecular and Cellular Biology, June 2006, p. 4240-4256, Vol. 26, No. 11
0270-7306/06/$08.00+0     doi:10.1128/MCB.02124-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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