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Molecular and Cellular Biology, January 2003, p. 462-472, Vol. 23, No. 2
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.2.462-473.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

mdm2 Is Critical for Inhibition of p53 during Lymphopoiesis and the Response to Ionizing Irradiation

Susan M. Mendrysa,1,{dagger} Matthew K. McElwee,1 Jennifer Michalowski,1,{ddagger} Kathleen A. O'Leary,1 Karen M. Young,2 and Mary Ellen Perry1*

Department of Oncology, School of Medicine,1 Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, Wisconsin 537062

Received 27 August 2002/ Returned for modification 23 September 2002/ Accepted 13 October 2002

The function of the p53 tumor suppressor protein must be highly regulated because p53 can cause cell death and prevent tumorigenesis. In cultured cells, the p90MDM2 protein blocks the transcriptional activation domain of p53 and also stimulates the degradation of p53. Here we provide the first conclusive demonstration that p90MDM2 constitutively regulates p53 activity in homeostatic tissues. Mice with a hypomorphic allele of mdm2 revealed a heretofore unknown role for mdm2 in lymphopoiesis and epithelial cell survival. Phenotypic analyses revealed that both the transcriptional activation and apoptotic functions of p53 were increased in these mice. However, the level of p53 protein was not coordinately increased, suggesting that p90MDM2 can inhibit the transcriptional activation and apoptotic functions of p53 in a manner independent of degradation. Cre-mediated deletion of mdm2 caused a greater accumulation of p53, demonstrating that p90MDM2 constitutively regulates both the activity and the level of p53 in homeostatic tissues. The observation that only a subset of tissues with activated p53 underwent apoptosis indicates that factors other than p90MDM2 determine the physiological consequences of p53 activation. Furthermore, reduction of mdm2 in vivo resulted in radiosensitivity, highlighting the importance of mdm2 as a potential target for adjuvant cancer therapies.

* Corresponding author. Present address: Cancer Cell Biology Branch, Division of Cancer Biology, National Cancer Institute, Suite 5000, 6130 Executive Blvd., Bethesda, MD 20892-7396. Phone: (301) 496-7028. Fax: (301) 402-1037. E-mail: perryma{at}mail.nih.gov.

{dagger} Present address: Fred Hutchinson Cancer Research Center, Seattle, Wash.

{ddagger} Present address: National Cancer Institute, Bethesda, Md.

Molecular and Cellular Biology, January 2003, p. 462-472, Vol. 23, No. 2
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.2.462-473.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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