Role of Rac1 and Oxygen Radicals in Collagenase-1 Expression Induced by Cell Shape Change
Author:
Kheradmand Farrah123, Werner Erica123, Tremble Patrice123, Symons Marc123, Werb Zena123
Affiliation:
1. F. Kheradmand, Department of Medicine, University of California, San Francisco, CA, USA. 2. E. Werner, P. Tremble, Z. Werb, Department of Anatomy, University of California, San Francisco, CA 94143-0750, USA. 3. M. Symons, Onyx Pharmaceuticals, Richmond, CA 94806, USA.
Abstract
Integrin-mediated reorganization of cell shape leads to an altered cellular phenotype. Disruption of the actin cytoskeleton, initiated by binding of soluble antibody to α5β1 integrin, led to increased expression of the collagenase-1 gene in rabbit synovial fibroblasts. Activation of the guanosine triphosphate–binding protein Rac1, which was downstream of the integrin, was necessary for this process, and expression of activated Rac1 was sufficient to increase expression of collagenase-1. Rac1 activation generated reactive oxygen species that were essential for nuclear factor kappa B–dependent transcriptional regulation of interleukin-1α, which, in an autocrine manner, induced collagenase-1 gene expression. Remodeling of the extracellular matrix and consequent alterations of integrin-mediated adhesion and cytoarchitecture are central to development, wound healing, inflammation, and malignant disease. The resulting activation of Rac1 may lead to altered gene regulation and alterations in cellular morphogenesis, migration, and invasion.
Publisher
American Association for the Advancement of Science (AAAS)
Subject
Multidisciplinary
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