MDM2 overexpression generates a skin phenotype in both wild type and p53 null mice

The MDM2 proto-oncogene is overexpressed in human tumours and regulates the activities of the tumour suppressors p53 and pRB We created mice that over express MDM2 under the control of the CMV promoter. These mice did not disp lay an increased tumour incidence, but rather a specific skin phenotype, ch aracterized by desquamation and hyperkeratosis. Transgenic MDM2 was found t o be overexpressed in the epidermis, a tissue that normally expresses high levels of MDM2. The phenotype appeared during the first week after birth an d then lessened with age, closely following the level of expression of the transgene. MDM2 overexpression was associated with an increase in prolifera tion in the basal layer, thickening of the epidermis, altered expression of the differentiation markers cytokeratin CK14, CK10 and CK1, and a decrease in the size and the number of granules that contain products of differenti ation. Transgenic mice on a p53 null background displayed similar although not identical changes, showing that the effects of MDM2 are to a certain de gree p53 independent. The skin is a major site of MDM2 expression in mice, raising the possibility that MDM2 overexpression perturbs the normal patter n of MDM2 expression and inhibits differentiation of the epidermis.