ACTIVATION OF THE P21 PATHWAY OF GROWTH ARREST AND APOPTOSIS BY THE BETA(4) INTEGRIN CYTOPLASMIC DOMAIN

The integrin alpha(6) beta(4), a receptor for members of the laminin f amily of basement membrane components, contributes to the function of epithelial cells and their oncogenically transformed derivatives, In o ur efforts to study alpha(6) beta(4)-mediated functions in more detail and to assess the contribution of the beta(4) cytoplasmic domain in s uch functions, we identified a rectal carcinoma cell line that lacks e xpression of the beta(4) integrin subunit, This cell line, termed RKO, expresses alpha(6) beta(4), but not alpha(6) beta(4), and it interact s with laminin-1 less avidly than similar cell lines that express alph a(6) beta(4). We expressed a full-length beta(4) cDNA, as well as a mu tant cDNA that lacks the beta(4) cytoplasmic domain, in RKO cells and isolated stable subclones of these transfectants. In this study, we re port that subclones that expressed the full-length beta(4) cDNA in ass ociation with endogenous alpha 6 exhibited partial G(1) arrest and apo ptosis, properties that were not evident in RKO cells transfected with either the cytoplasmic domain mutant or the expression vector alone, In an effort to define a mechanism for these observed changes in growt h, we observed that expression of the alpha(6) beta(4) integrin induce d expression of the p21 (WAF1; CiP1) protein, an inhibitor of cyclin-d ependent kinases. These data suggest that the beta(4) integrin cytopla smic domain is linked to a signaling pathway involved in cell cycle re gulation in the beta(4) transfected RKO cells.