p76MDM2 Inhibits the Ability of p90MDM2to Destabilize p53*

The mdm2 oncogene encodes p90MDM2, which binds to and inactivates the p53 tumor suppressor protein. p90MDM2 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-typemdm2 gene, p76MDM2, lacks the first 49 amino acids of p90MDM2 and cannot bind p53. Here, we report that, like p90MDM2, p76MDM2 is expressed in both the nuclear and cytoplasmic compartments. Overexpression of p76MDM2 antagonizes the ability of p90MDM2 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 p76MDM2but not p90MDM2, as well as the normally splicedmdm2 mRNA that encodes both MDM2 proteins. All seven tissues express both MDM2 proteins. p90MDM2 is much more abundant than p76MDM2 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.