THE HUMAN ONCOPROTEIN MDM2 ARRESTS THE CELL-CYCLE - ELIMINATION OF ITS CELL-CYCLE-INHIBITORY FUNCTION INDUCES TUMORIGENESIS

The human oncoprotein MDM2 (hMDM2) overexpresses in various human tumo rs. If amplified, the mdm2 gene can enhance the tumorigenic potential of murine cells. Here, we present evidence to show that the full-lengt h human or mouse MDM2 expressed from their respective cDNA can inhibit the G(0)/G(1)-S phase transition of NIH 3T3 and normal human diploid cells. The protein harbors more than one cell-cycle-inhibitory domain that does not overlap with the p53-interaction domain. Deletion mutant s of hMDM2 that lack the cell-cycle-inhibitory domains can be stably e xpressed in NIH 3T3 cells, enhancing their tumorigenic potential, The tumorigenic domain of hMDM2 overlaps with the p53-interaction domain. Some tumor-derived cells, such as Saos-2, H1299 or U-2OS, are relative ly insensitive to the growth-inhibitory effects of hMDM2. These observ ations suggest that hMDM2 overexpression in response to oncogenic stim uli would induce growth arrest in normal cells. Elimination or inactiv ation of the hMDM2-induced G(0)/G(1) arrest may contribute to one of t he steps of tumorigenesis.