MDM2 and MDMX in cancer and development.

The p53 tumor suppressor pathway is active in cells that are subjected to stress and/or damaged, where it promotes cell cycle arrest or apoptosis. In contrast, in normal cells that are not exposed to stress signals and in tumor cells p53 is tightly kept in check or completely silenced. In most, if not all, tumor cells p53 is indeed inactivated by mutations in the p53 locus or by alternative, yet unclear, mechanisms that impinge directly or indirectly on p53 function. Recent biochemical and genetic data indicate that tumor cells hijack and enforce some of the mechanisms used by normal cells to restrain p53 function. This is best illustrated by the aberrant expression in tumor cells of MDM2 and MDMX (or MDM4), two structurally related proteins that play a critical role in maintaining p53 in an OFF state under normal conditions, but in particular in embryonic and stem cells. These advances and their potential implications for the development of new cancer therapeutic strategies form the focus of this chapter.