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p76(MDM2) inhibits the ability of p90(MDM2) to destabilize p53
M E Perry1, S M Mendrysa, L J Saucedo
1Department of Oncology, McArdle Laboratory for Cancer Research, Madison, Wisconsin 53706, USA. perry@oncology.wisc.edu
Abstract:
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 gamma-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.
Insights
The MDM2 oncogene produces two proteins, p90(MDM2) and p76(MDM2). p76(MDM2) can counteract p90(MDM2)
Area of Science:
- Molecular Biology
- Oncology
- Genetics
Background:
- The MDM2 oncogene encodes p90(MDM2), a protein that binds and inactivates the p53 tumor suppressor.
- p90(MDM2) inhibits p53 by blocking its transcriptional activation and promoting degradation.
- A shorter form, p76(MDM2), lacks the N-terminal domain of p90(MDM2) and cannot bind p53.
Purpose of the Study:
- To investigate the expression and function of p76(MDM2) in relation to p90(MDM2) and p53.
- To determine the tissue-specific expression patterns of both MDM2 isoforms.
- To explore the potential role of the p90(MDM2)/p76(MDM2) ratio in regulating cellular responses to DNA damage.
Main Methods:
- Analysis of MDM2 protein expression in various murine tissues.
- Investigating the subcellular localization of p76(MDM2).
- Assessing the impact of p76(MDM2) overexpression on p53 levels and activity.
Main Results:
- p76(MDM2) is expressed in both nuclear and cytoplasmic compartments.
- Overexpression of p76(MDM2) inhibits p90(MDM2)'s degradation of p53, increasing p53 levels and activity.
- Seven murine tissues express alternatively spliced mdm2 mRNA encoding p76(MDM2), and both MDM2 proteins are present in all tested tissues.
- The relative abundance of p90(MDM2) and p76(MDM2) varies by tissue, with roughly equivalent levels in tissues undergoing p53-mediated apoptosis.
Conclusions:
- p76(MDM2) acts as a functional antagonist to p90(MDM2), modulating p53 stability and activity.
- The ratio of p90(MDM2) to p76(MDM2) may be a critical factor in determining tissue sensitivity to DNA damage and p53-mediated apoptosis.