ROLE OF RAC1 AND OXYGEN RADICALS IN COLLAGENASE-1 EXPRESSION INDUCED BY CELL-SHAPE CHANGE

Integrin-mediated reorganization of cell shape leads to an altered cel lular phenotype. Disruption of the actin cytoskeleton, initiated by bi nding of soluble antibody to alpha 5 beta 1 integrin, led to increased expression of the collagenase-1 gene in rabbit synovial fibroblasts. Activation of the guanosine triphosphate-binding protein Rac1, which w as downstream of the integrin, was necessary for this process, and exp ression of activated Rac1 was sufficient to increase expression of col lagenase-1. Rac1 activation generated reactive oxygen species that wer e essential for nuclear factor kappa B-dependent transcriptional regul ation of interleukin-1 alpha, which, in an autocrine manner, induced c ollagenase-1 gene expression. Remodeling of the extracellular matrix a nd consequent alterations of integrin-mediated adhesion and cytoarchit ecture are central to development, wound healing, inflammation, and ma lignant disease, The resulting activation of Rac1 may lead to altered gene regulation and alterations in cellular morphogenesis, migration, and invasion.