The ink4/arf tumor suppressors cooperate with p21(cip1/waf) in the processes of mouse epidermal differentiation, senescence, and carcinogenesis

In mammalian cells, cell cycle withdrawal is a prerequisite for terminal di fferentiation. Accordingly, in most tissues, including epidermis, the expre ssion of the cyclin-dependent kinase inhibitors increases during differenti ation. However, the actual role of cyclin-dependent kinase inhibitors is un clear. Different aspects of epidermal growth and differentiation in ink4a(D elta2,3)-null, p21-null, and ink4a(Delta2,3)/p21-doubly deficient mice were studied. Altered differentiation and decreased age-related senescence were found in the epidermis of ink4a(Delta2,3)/p21-null mice and, to a lesser e xtent, in ink4a(Delta2,3)- and p21-null mice. inh4a(Delta2,3)/p21-null prim ary keratinocytes underwent cell cycle arrest upon calcium or transforming growth factor-P treatment, but failed to differentiate. This differentiatio n deficiency was not observed in p21-or ink4a(Delta2,3) -deficient keratino cytes. Upon infection with a v-Ha-ras-coding retrovirus, wild-type keratino cytes displayed features indicative of premature cell senescence. In p21- o r ink4a(Delta2,3)-deficient keratinocytes, only a partial response was obse rved. ink4a(Delta2,3)/p21-deficient keratinocytes did not display senescent features, but showed increased tumorigenic potential upon injection into n ude mice. These results indicate that ink4a/ arf and cip1/waf genes coopera te to allow normal keratinocyte differentiation and that the absence of bot h favors malignant transformation.