Strict control of cell growth is essential for embryonic development as well as for cancer prevention. The protein MDM2 plays a key role in cell growth by inhibiting the activity of the tumor suppressor protein p53. Many shortened versions of MDM2 have been identified in both normal and tumor tissues; however, their function in either context is unknown. One short form of MDM2 known as MDM2-A has been frequently detected in tumors, particularly in childhood rhabdomyosarcomas, which are tumors made up of cells that would normally develop into skeletal muscle. Thus, determining MDM2-A function may provide an insight into how these tumors develop and how the disease might respond to treatment.

Here, the authors generate a transgenic mouse expressing MDM2-A protein in normal tissues. Although this protein was detected in tumors, the MDM2-A mouse was not tumor prone. Rather, the most striking phenotype was that mice expressing high levels of MDM2-A did not survive beyond birth and that mice expressing lower levels of MDM2-A had a shortened life span. Further analysis of cells and tissues from MDM2-A mice demonstrated that MDM2-A expression activates the tumor suppressor protein p53 and results in increased cell senescence and earlier cell death.

These results demonstrate that shorter forms of MDM2, such as MDM2-A, can be detrimental with respect to enhancing cellular senescence and reducing life expectancy. In contrast, because MDM2-A is implicated in the activation of the p53 tumor suppressor protein, it is possible that MDM2-A expression can protect against tumor formation. Future studies using tissue-specific MDM2-A expression will further clarify the physiological effects of MDM2-A. Additionally, since activation of p53 enhances the sensitivity of cells to certain cancer drugs, MDM2-A may serve as a marker of tumor response to chemotherapeutic agents.

2009