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J. Biol. Chem., Vol. 282, Issue 6, 3940-3950, February 9, 2007

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Evidence for Actin Cytoskeleton-dependent and -independent Pathways for RelA/p65 Nuclear Translocation in Endothelial Cells^*

Fabeha Fazal, Mohd Minhajuddin, Kaiser M. Bijli, James L. McGrath, and Arshad Rahman¹

From the Departments of Pediatrics and Biomedical Engineering, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642

Activation of the transcription factor NF-B involves its release from the inhibitory protein IB in the cytoplasm and subsequently, its translocation to the nucleus. Whereas the events responsible for its release have been elucidated, mechanisms regulating the nuclear transport of NF-B remain elusive. We now provide evidence for actin cytoskeleton-dependent and -independent mechanisms of RelA/p65 nuclear transport using the proinflammatory mediators, thrombin and tumor necrosis factor , respectively. We demonstrate that thrombin alters the actin cytoskeleton in endothelial cells and interfering with these alterations, whether by stabilizing or destabilizing the actin filaments, prevents thrombin-induced NF-B activation and consequently, expression of its target gene, ICAM-1. The blockade of NF-B activation occurs downstream of IB degradation and is associated with impaired RelA/p65 nuclear translocation. Importantly, thrombin induces association of RelA/p65 with actin and this interaction is sensitive to stabilization/destabilization of the actin filaments. In parallel studies, stabilizing or destabilizing the actin filaments fails to inhibit RelA/p65 nuclear accumulation and ICAM-1 expression by tumor necrosis factor , consistent with its inability to induce actin filament formation comparable with thrombin. Thus, these studies reveal the existence of actin cytoskeleton-dependent and -independent pathways that may be engaged in a stimulus-specific manner to facilitate RelA/p65 nuclear import and thereby ICAM-1 expression in endothelial cells.

Received for publication, August 22, 2006 , and in revised form, November 16, 2006.

^* This work was supported by National Institutes of Health NHLBI Grant HL67424. 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 To whom correspondence should be addressed: Dept. of Pediatrics, Box 850, 601 Elmwood Ave., Rochester, NY 14642. Tel.: 585-275-5948; Fax: 585-756-7780; E-mail: Arshad_Rahman{at}urmc.rochester.edu.

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