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J. Biol. Chem., Vol. 279, Issue 14, 14039-14048, April 2, 2004

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N Terminus Is Essential for Tropomyosin Functions

N-TERMINAL MODIFICATION DISRUPTS STRESS FIBER ORGANIZATION AND ABOLISHES ANTI-ONCOGENIC EFFECTS OF TROPOMYOSIN-1^*

Shantaram Bharadwaj, Sarah Hitchcock-DeGregori, Andrew Thorburn¶, and G. L. Prasad, Recipient of Career Development Award DAMD-98-1-8162) from the United States Army Breast Cancer Research Program¶||

From the Departments of General Surgery and ^¶Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157 and the Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854

Down-regulation of several key actin-binding proteins, such as -actinin, vinculin, gelsolin, and tropomyosins (TMs), is considered to contribute to the disorganized cytoskeleton present in many neoplastic cells. TMs stabilize actin filaments against the gel severing actions of proteins such as cofilin. Among multiple TMs expressed in non-muscle cells, tropomyosin-1 (TM1) isoform induces stress fibers and functions as a suppressor of malignant transformation. However, the molecular mechanisms of TM1-mediated cytoskeletal effects and tumor suppression remain poorly understood. We have hypothesized that the ability of TM1 to stabilize microfilaments is crucial for tumor suppression. In this study, by employing a variant TM1, which contains an N-terminal hemagglutinin epitope tag, we demonstrate that the N terminus is a key determinant of tropomyosin-1 function. Unlike the wild type TM1, the modified protein fails to restore stress fibers and inhibit anchorage-independent growth in transformed cells. Furthermore, the N-terminal modification of TM1 disorganizes the cytoskeleton and delays cytokinesis in normal cells, abolishes binding to F-actin, and disrupts the dimeric associations in vivo. The functionally defective TM1 allows the association of cofilin to stress fibers and disorganizes the microfilaments, whereas wild type TM1 appears to restrict the binding of cofilin to stress fibers. TM1-induced cytoskeletal reorganization appears to be mediated through preventing cofilin interaction with microfilaments. Our studies provide in vivo functional evidence that the N terminus is a critical determinant of TM1 functions, which in turn determines the organization of stress fibers.

Received for publication, October 3, 2003 , and in revised form, January 3, 2004.

^* This work was supported in part by the Research and Development funds from the Department of General Surgery, a Cancer Center Pilot grant, and National Institutes of Health Grant GM 63257 (to S. H-D.). 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.

^|| To whom correspondence should be addressed. Tel.: 336-716-2788; Fax: 336-716-2528; E-mail: gprasad{at}wfubmc.edu.

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