Keratinocyte Stem Cells Are Protected from Apoptosis

Carlo Pincelli *,


Human epidermis is maintained and renewed by keratinocyte stem cells (KSC). KSC are protected from programmed cell death (apoptosis) through their anchorage with the ECM, which in turn is allowed by the presence of adhesion molecules such as integrins. Indeed, KSC are identified and characterized by highest levels of beta1 integrin that is poorly expressed in transit amplifying cells and absent in post mitotic keratinocytes. Moreover, KSC are identified by the expression of survivin, a unique member of Inhibitors of Apoptosis Protein (IAP), which is able to both inhibit apoptosis and regulate cell cycle. In human KSC, survivin expression decreases following apoptosis induced by integrin signal blockade, thus indicating that the anti-apoptotic action of survivin is involved in the survival signal mediated by integrins. In addition, survivin plays a role in keratinocyte cell cycle, under homeostatic conditions. Survivin inhibition markedly decreases keratinocyte viability and proliferation, thus reducing their ability to form colonies. Moreover, deprivation of survivin in human keratinocytes induces a cell cycle arrest at earlier times, which eventually culminates in cell apoptosis. Survivin inhibition renders human keratinocytes more susceptible to UVB-induced apoptosis. Finally, survivin over-expression in these cells protects them from apoptosis induced by UVB radiations. Altogether, these results suggest that survivin protects human KSC from apoptosis and is necessary for cell cycle progression. KSC seem to be at the origin of skin cancer, which is caused mainly by UV radiations. In human skin cancer, survivin is expressed at high levels and its intra-cellular localization changes from nuclear to cytoplasmic following treatments with therapeutic agents. It is also interesting to note that human skin cancer develops following continuous UV exposures which cause p53 mutations, and that mutated p53 clones seem to be responsible for skin carcinogenesis. Because survivin expression is negatively regulated by p53 and is restricted to the KSC population, it can play a role in cutaneous carcinogenesis.