ACTIVATION OF P53-P21(WAF1) PATHWAY IN RESPONSE TO DISRUPTION OF CELL-MATRIX INTERACTIONS

The proliferation of most cells is strictly dependent on cell-matrix i nteractions, a phenomenon called anchorage dependence, Because tumor c ells often are independent of this regulation, it is important to char acterize the molecular pathways that control cellular proliferation af ter detachment of cells from their matrix. In this report, we investig ated a possible role of p53 and one of its target genes, p21(waf1/cip1 ), as components of anchorage-dependent cell growth control, We found that p53 protein is rapidly activated upon the disruption of cellular attachment. This led to p21 transcriptional activation via two p53 bin ding sites in its promoter. Elevated p21 protein levels blocked transc ription and activity of the cell cycle-regulator cyclin A, and cells b ecame arrested in G(1) of the cell cycle. Under the same conditions, f ibroblasts from p53 knock out mice did not activate p21 and did not do wn-regulate cyclin A expression but rather induced another cell cycle inhibitor, p27, Thus, our results characterize a chain of events, star ting from the activation of p53 and proceeding via p21 to cyclin A, th at is activated in response to the loss of cellular adherence, This p5 3 regulated pathway may constitute one of a few redundant systems to e nsure proper cell control in multicellular organisms.