Targeted expression of c-Myc in the epidermis alters normal proliferation,differentiation and UV-B induced apoptosis

c-Myc overexpression has been associated with several types of human cancer s. To study the role of c-myc in epidermal differentiation and carcinogenes is, a transgenic mouse model was created to overexpress c-myc in the epider mis, Human c-myc 2 cDNA was subcloned into a 6.5 kb mouse loricrin expressi on vector, ML.myc2. This loricrin promoter primarily directs expression in the epidermis in both proliferating and differentiated keratinocytes. On da y 4, ML.myc2 transgenic pups develop a hyperkeratotic phenotype, which prog ressively worsens until day 7. Upon histological analysis, both hyperplasia and hyperkeratosis were evident. Bromodeoxyuridine (BrdU) incorporation re vealed that transgenic mice had a threefold increase in the number of proli ferating cells as compared with a normal littermate, Proliferative cells in the ML.myc2 epidermis were also found to be suprabasal, suggesting an inhi bition of terminal differentiation in keratinocytes, Inhibition of terminal differentiation by c-Myc overexpression was further suggested by aberrant expression of differentiation markers, keratin 1, keratin 6, loricrin, and filaggrin in ML.myc2 transgenic mice, Interestingly, ML.myc2 keratinocytes exhibit a reduced sensitivity to UV-B induced apoptosis, in vivo. In vitro studies reveal the reduced sensitivity of ML.myc2 keratinocytcs to UV-B irr adiation is growth factor dependent. These findings provide evidence that o verexpression of c-Myc in the epidermis induces proliferation, inhibits ter minal differentiation and decreases the sensitivity of keratinocytes to UV- B induced apoptosis.