p27(Kip1) is an inducer of intestinal epithelial cell differentiation

Constant renewal of the intestinal epithelium is a highly coordinated proce ss that has been subject to intense investigation, but its regulatory mecha nisms are still essentially unknown. In this study, we have demonstrated th at forced expression of the cyclin-dependent kinase inhibitors (CKIs) p27(K ip1) and p21(Cip1/WAF1) in human intestinal epithelial cells led to express ion of differentiation markers at both the mRNA and protein levels. Cell di fferentiation was temporally dissociated from inhibition of retinoblastoma protein phosphorylation and growth arrest, already established 1 day after infection with recombinant adenoviruses. p27(Kip1) proved significantly mor e efficient than p21(Cip1/WAF1) in induction of cell differentiation. In co ntrast, forced expression of p16(INK4a) resulted in growth arrest without i nduction of differentiation markers. These results implicate both p27(Kip1) and p21(Cip1/WAF1) in the differentiation-timing process, but p21(Cip1/WAF 1) may act indirectly by increasing p27(Kip1) levels. These results also su ggest that induction of intestinal epithelial cell differentiation by CKIs is not related to their effects on the cell cycle and may involve interacti ons with cellular components other than cyclins and cyclin-dependent kinase s.