MDM-2 is one of the target genes of the p53 tumor suppressor protein. Its best characterized function is found in the inhibition of p53's ability to modulate transcription. Deregulated expression of MDM-2 could thus at least partially substitute for p53 mutation in the process of tumorigenesis. We show here that MDM-2 is highly expressed in biopsies of normal human skin or in vitro reconstituted human skin. The protein is detected in the nucleus of keratinocytes throughout the different layers of the epidermis and in reconstituted skin as early as the two to three cell layer stage. The 90 kiloDalton (kD) protein is one of the major forms detected in Western blot experiments. MDM-2 is detected in skin reconstituted from keratinocytes in which p53 is inactivated by mutation or degradation by E6 protein, providing evidence that MDM-2 expression in the skin can occur in the absence of wild type p53. Moreover, we found no correlation between the p53 status and MDM-2 expression levels in a series of basal and squamous cell carcinomas or Bowen diseases. Our data provide first evidence for the expression of MDM-2 in a differentiated adult tissue.