Cell proliferation is regulated in part by cell-cell interactions mediated by cadherin and connexin. Here we present evidence that these two molecules act synergistically to suppress HEK293 cell proliferation by prolonging the G2/M phase. This event was accompanied by expression of p21, a potent Cdc2 kinase inhibitor. Not surprisingly, there was a concomitant decline in Cdc2 kinase activity. beta-Catenin/TCF signaling, which was downregulated by overexpression of N-cadherin, was found to inhibit transactivation of p21 gene expression. The effect of N-cadherin on cell proliferation and p21 expression was augmented by co-expression of connexin-43. Moreover, the magnitude of the connexin's effect was dependent on its ability to mediate intercellular communication. We conclude, therefore, that two major components of cell-cell interaction synergistically regulate cell cycle progression in HEK293 cells by regulating p21 expression in a beta-catenin/TCF-dependent manner.