THE ABSENCE OF P21(CIP1 WAF1) ALTERS KERATINOCYTE GROWTH AND DIFFERENTIATION AND PROMOTES RAS-TUMOR PROGRESSION/

p21(Cip1/WAF1) was the first cyclin-dependent kinase (CDK) inhibitor t o be identified, as a mediator of p53 in DNA damage-induced growth arr est, cell senescence, and direct CDK regulation. p21 may also play an important role in differentiation-associated growth arrest, as its exp ression is augmented in many terminally differentiating cells. A gener al involvement of p21 in growth/differentiation control and tumor supp ression has been questioned, as mice lacking p21 undergo a normal deve lopment, harbor no gross alterations in any of their organs, and exhib it no increase in spontaneous tumor development. However, a significan t imbalance between growth and differentiation could be unmasked under conditions where normal homeostatic mechanisms are impaired. We repor t here that primary keratinocytes derived from p21 knockout mice, tran sformed with a ras oncogene, and injected subcutaneously into nude mic e exhibit a very aggressive tumorigenic behavior, which is not observe d with wild-type control keratinocytes nor with keratinocytes with a d isruption of the closely related p27 gene. p21 knockout keratinocytes tested under well-defined in vitro conditions show a significantly inc reased proliferative potential, which is also observed but to a lesser extent with p27 knockout cells. More profound differences were found in the differentiation behavior of p21 versus p27 knockout keratinocyt es, with p21 (but not p27) deficiency causing a drastic down-modulatio n of differentiation markers linked with the late stages of the kerati nocyte terminal differentiation program. Thus, our results reveal a so far undetected role of p21 in tumor suppression, demonstrate that thi s function is specific as it cannot be attributed to the closely relat ed p27 molecule, and point to an essential involvement of p21 in termi nal differentiation control, which may account for its role in tumor s uppression.