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.