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Molecular and Cellular Biology, July 2005, p. 6259-6266, Vol. 25, No. 14
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.14.6259-6266.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Inhibiting Myosin Light Chain Kinase Induces Apoptosis In Vitro and In Vivo

Fabeha Fazal,1 Lianzhi Gu,1 Ivanna Ihnatovych,1 YooJeong Han,1 WenYang Hu,1 Nenad Antic,1 Fernando Carreira,1 James F. Blomquist,2 Thomas J. Hope,2 David S. Ucker,2 and Primal de Lanerolle1*

Departments of Physiology and Biophysics,1 Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, Chicago, Illinois 606122

Received 6 February 2004/ Returned for modification 19 March 2004/ Accepted 13 April 2005

Previous short-term studies have correlated an increase in the phosphorylation of the 20-kDa light chain of myosin II (MLC20) with blebbing in apoptotic cells. We have found that this increase in MLC20 phosphorylation is rapidly followed by MLC20 dephosphorylation when cells are stimulated with various apoptotic agents. MLC20 dephosphorylation is not a consequence of apoptosis because MLC20 dephosphorylation precedes caspase activation when cells are stimulated with a proapoptotic agent or when myosin light chain kinase (MLCK) is inhibited pharmacologically or by microinjecting an inhibitory antibody to MLCK. Moreover, blocking caspase activation increased cell survival when MLCK is inhibited or when cells are treated with tumor necrosis factor alpha. Depolymerizing actin filaments or detaching cells, processes that destabilize the cytoskeleton, or inhibiting myosin ATPase activity also resulted in MLC20 dephosphorylation and cell death. In vivo experiments showed that inhibiting MLCK increased the number of apoptotic cells and retarded the growth of mammary cancer cells in mice. Thus, MLC20 dephosphorylation occurs during physiological cell death and prolonged MLC20 dephosphorylation can trigger apoptosis.

* Corresponding author. Mailing address: Department of Physiology and Biophysics, University of Illinois at Chicago, 835 South Wolcott Avenue, Chicago, IL 60612. Phone: (312) 996-6430. Fax: (312) 996-1414. E-mail: Primal{at}UIC.edu.

Molecular and Cellular Biology, July 2005, p. 6259-6266, Vol. 25, No. 14
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.14.6259-6266.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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