Simian virus 40 transformation alters the actin cytoskeleton, expression of matrix metalloproteinases and inhibitors of metalloproteinases, and invasive behavior of normal and ataxia-telangiectasia human skin fibroblasts

Abstract

Alterations in the actin cytoskeleton of normal cells result in changes in cell shape and adhesiveness and induce expression of matrix-degrading matrix metalloproteinases. We examined the effect of simian virus 40 transformation of normal and ataxia-telangiectasia human skin fibroblasts, a process that produces actin reorganization, altered cell morphology, and altered cell behavior, on expression of genes of the matrix metalloproteinase and tissue inhibitor of metalloproteinases gene families. Simian virus 40 transformation induced collagenase-1 gene expression; in contrast, stromelysin-1, 72-kDa gelatinase (gelatinase A), tissue inhibitor of metalloproteinases-1, and tissue inhibitor of metalloproteinases-2 genes were repressed. Transformation also altered the response of the fibroblasts to 12-O-tetradecanoylphorbol-13-acetate. Collagenase mRNA was induced in 12-O-tetradecanoylphorbol-13-acetate treated transformed cells up to 50-fold more than in untreated transformed cells or in 12-O-tetradecanoylphorbol-13-acetate treated untransformed parent cells. In contrast, 12-O-tetradecanoylphorbol-13-acetate did not overcome the attenuated expression of stromelysin-1 in the simian virus 40 transformants. In addition, 92-kDa gelatinase (gelatinase B) was induced by 12-O-tetradecanoylphorbol-13-acetate only in the simian virus 40 transformants. The responses of gelatinase A and tissue inhibitor of metalloproteinases-1 to 12-O-tetradecanoylphorbol-13-acetate were unchanged. The pattern of altered proteinase expression after transformation was accompanied by a phenotypic alteration in cell invasion. The simian virus 40 transformants exhibited enhanced invasiveness through a basement-membrane-like matrix. These data demonstrate that enhanced invasiveness in simian virus 40 transformed cells is accompanied by changes in actin organization and expression of proteinases and inhibitors, as well as in the balance between proteinases and inhibitors in favor of proteinases.Key words: actin cytoskeleton, collagenase, metalloproteinase, tissue inhibitor of metalloproteinases, SV40 transformation, ataxia-telangiectasia.