INHIBITORY FUNCTION OF P21(CIP1 WAF1) IN DIFFERENTIATION OF PRIMARY MOUSE KERATINOCYTES INDEPENDENT OF CELL-CYCLE CONTROL/

The cyclin-dependent kinase inhibitor p21(Cip1/WAF1) has been implicat ed as an inducer of differentiation. However, although expression of p 21 is increased in postmitotic cells immediately adjacent to the proli ferative compartment, its expression is decreased in cells further alo ng the differentiation program. Expression of the p21 protein was decr eased in terminally differentiated primary keratinocytes of mice, and this occurred by a proteasome-dependent pathway. Forced expression of p21 in these cells inhibited the expression of markers of terminal dif ferentiation at both the protein and messenger RNA levels. These inhib itory effects on differentiation were not observed with a carboxyl-ter minal truncation mutant or with the unrelated cyclin-dependent kinase inhibitor p16(INK4a), although all these molecules exerted similar inh ibition of cell growth. These findings reveal an inhibitory role of p2 1 in the late stages of differentiation that does not result from the effects of p21 on the cell cycle.