p21(WAF1/Cip1) functions as a suppressor of malignant skin tumor formationand a determinant of keratinocyte stem-cell potential

p21(WAF1/Cip1) is one of the best characterized downstream targets of p53 a nd the growth suppressing function of this cyclin-dependent kinase inhibito r is well established. However, whether p21 exerts a tumor-suppressing func tion of its own remains to be established, We report here that, similarly t o loss of p53 disruption of the p21(WAF1/Cip1) gene results in a markedly i ncreased susceptibility to chemically induced skin carcinoma formation, whe reas the number of papillomas is reduced. previous evidence indicates that malignant versus benign keratinocyte tumor formation is likely to involve d istinct target-cell populations with a different commitment to differentiat ion. In parallel with the increased susceptibility to carcinoma formation, loss of p21(WAF/Cip1) was found to promote keratinocyte subpopulations with increased growth/differentiation potential, including clonal grow th capab ility, reversible commitment to differentiation, and capability to generate all types of terminally differentiated keratinocytes present irt vivo, not only in the interfollicular epidermis but also in hair follicles. Thus, th ese findings have revealed a function of p21 as a suppressor of malignant b ut not benign skin-tumor formation and a determinant of the growth/differen tiation potential of keratinocyte subpopulations.