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J Biol Chem, Vol. 275, Issue 8, 5733-5738, February 25, 2000

p76^MDM2 Inhibits the Ability of p90^MDM2 to Destabilize p53^*

Mary Ellen Perry, Susan M. Mendrysa^§, Leslie J. Saucedo^§, Paul Tannous, and Marisa Holubar

From the Department of Oncology, McArdle Laboratory for Cancer Research, Madison, Wisconsin 53706

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 -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.

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^* This work was supported by developmental funds from NCI Cancer Center Support Grant CA-07175 (to the McArdle Laboratory for Cancer Research), by NCI Grant CA-14520-26 (to the University of Wisconsin Comprehensive Cancer Center Flow Cytometry Facility), and by NCI Grant CA-70718 (to M. E. P.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: 207A McArdle Laboratory for Cancer Research, 1400 University Ave., Madison, WI 53706. Tel.: 608-265-5537; Fax: 608-262-2824; E-mail: perry@oncology.wisc.edu.

^§ Supported by NCI, National Institutes of Health, Predoctoral Training Grant CA-09135.

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Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

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