T. Juven

The p53 tumor suppressor gene product can complex with polypeptides encoded by the mdm2 putative protoncogene. In addition, mdm2 mRNA levels have been shown to increase following the activation of wild type (wt) p53. To determine the basis for the effect of wt p53 on mdm2 mRNA, we studied the interaction of the mdm2 gene with p53. We report that wt p53 can bind sequence-specifically to a DNA region residing downstream to exon 1 of the mdm2 gene. This is correlated with a pronounced p53-dependent transcriptional activation. Efficient p53-dependent transactivation can be obtained with an mdm2 genomic DNA fragment lacking the putative mdm2 promoter. These findings suggest that p53 can induce transcription from an internal promoter located within the mdm2 gene. These findings raise the possibility that, in addition to increasing the overall levels of mdm2 mRNA, wt p53 may also modulate the repertoire of mdm2 transcripts present within the cell.

The p53 protein is the product of a tumor suppressor gene which is subject to an extremely high frequency of structural alterations in human cancer (for review, see Hollstein et al. 1991; Levine et al. 1991; Oren 1992; Donehower and Bradley 1993; Harris and Hollstein 1993; Berns 1994). The main selective advantage of such alterations is probably the elimination of the tumor suppressor functions of the wild-type (wt) p53 protein. However, at least some of the p53 point mutations commonly encountered in tumor cells may also entail an oncogenic gain of function (Wolf et al. 1984; Chen et al. 1990; Michalovitz et al. 1991; Dittmer et al. 1993).