P21(WAF1 CIP1) AND TERMINAL DIFFERENTIATION CONTROL OF NORMAL EPITHELIA/

Induction of the cell cycle inhibitor p21(WAF1/CIP1) occurs as an earl y and specific event in most, if not all, terminally differentiating c ells tested so far. In the present review, we will focus on the role a nd control of p21(WAF1/CIP1) function in terminal differentiation of n ormal epithelial cells, and keratinocytes in particular. As in other c ells, increased p21 expression can explain, at least in part, the obse rved inhibition of CDK activity in terminally differentiating keratino cytes. However, p21 function in differentiation is not indispensable, and may be compensated by a number of additional cell cycle regulatory events, some of which are common to most cells, and others which are cell type specific. One of the main consequences of CDK inhibition is an increase in the growth suppressing activity of p105-Rb and related proteins. However, these proteins may not be the major determinants of growth arrest in terminally differentiating epithelial cells, and a m ore important role may be played by other, as yet unidentified CDK sub strates. The specific modifications of the transcriptional apparatus w hich are associated with cell cycle arrest in terminal differentiation are poorly understood. Studies of the p21 promoter already indicate t hat induction of its activity is controlled by transcription factors o f the myoD family in myoblasts but not in keratinocytes, while in thes e latter cells the function of a novel transcriptional coactivator, p3 00, is required. Future studies of epithelial as well as other termina lly differentiating cells will likely focus on the complex interplay b etween specific differentiation signals and the modifications of the t ranscriptional and cell cycle apparatus which lead to growth arrest.