p76(MDM2) inhibits the ability of p90(MDM2) to destabilize p53

The mdm2 oncogene encodes p90(MDM2), which binds to and inactivates the p53 tumor suppressor protein. p90(MDM2) inhibits p53 by blocking the transcriptional activation domain of p53 as well as by stimulating its degradation. Recently, we showed that another product of the wild-type mdm2 gene, p76(MDM2), lacks the first 49 amino acids of p90(MDM2) and cannot bind p53. Here, we report that, like p90(MDM2), p76(MDM2) is expressed in both the nuclear and cytoplasmic compartments. Overexpression of p76(MDM2) antagonizes the ability of p90(MDM2) to stimulate the degradation of p53 and leads to an increase in the levels and activity of p53. Seven murine tissues express an alternatively spliced mdm2 mRNA that can encode p76(MDM2) but not p90(MDM2), as well as the normally spliced mdm2 mRNA that encodes both MDM2 proteins. All seven tissues express both MDM2 proteins. p90(MDM2) is much more abundant than p76(MDM2) in the testis, brain, heart, and kidney. However, in those tissues known to undergo p53-mediated apoptosis in response to γ- irradiation, the thymus, spleen, and intestine, the levels of the MDM2 proteins are roughly equivalent. Our results indicate that the ratio of the two MDM2 proteins may regulate the response of tissues to DNA damage.