SIMIAN-VIRUS-40 TRANSFORMATION ALTERS THE ACTIN CYTOSKELETON, EXPRESSION OF MATRIX METALLOPROTEINASES AND INHIBITORS OF METALLOPROTEINASES,AND INVASIVE BEHAVIOR OF NORMAL AND ATAXIAL TELANGIECTASIA HUMAN SKINFIBROBLASTS

Alterations in the actin cytoskeleton of normal cells result in change s in cell shape and adhesiveness and induce expression of matrix-degra ding matrix metalloproteinases. We examined the effect of simian virus 40 transformation of normal and ataxia-telangiectasia human skin fibr oblasts, a process that produces actin reorganization, altered cell mo rphology, and altered cell behavior, on expression of genes of the mat rix metalloproteinase and tissue inhibitor of metalloproteinases gene families. Simian virus 40 transformation induced collagenase-1 gene ex pression; in contrast, stromelysin-1, 72-kDa gelatinase (gelatinase A) , tissue inhibitor of metalloproteinases-1, and tissue inhibitor of me talloproteinases-2 genes were repressed. Transformation also altered t he 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 transf ormed cells or in 12-O-tetradecanoylphorbol-13-acetate treated untrans formed parent cells. In contrast, 12-O-tetradecanoylphorbol-13-acetate did not overcome the attenuated expression of stromelysin-l in the si mian virus 40 transformants. In addition, 92-kDa gelatinase (gelatinas e B) was induced by 12-O-tetradecanoylphorbol-13-acetate only in the s imian virus 40 transformants. The responses of gelatinase A and tissue inhibitor of metalloproteinases-1 to 12-O-tetradecanoylphorbol-13-ace tate were unchanged. The pattern of altered proteinase expression afte r transformation was accompanied by a phenotypic alteration in cell in vasion. The simian virus 40 transformants exhibited enhanced invasiven ess through a basement-membrane-like matrix. These data demonstrate th at enhanced invasiveness in simian virus 40 transformed cells is accom panied by changes in actin organization and expression of proteinases and inhibitors, as well as in the balance between proteinases and inhi bitors in favor of proteinases.