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Mol. Cell. Biol. doi:10.1128/MCB.00555-06
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Haploinsufficiency of Mdm2 and Mdm4 in Tumorigenesis and Development

Department of Cancer Genetics, and Department of Veterinary Medicine and Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA, Department of Dermatology, Baylor College of Medicine, Houston, Texas 77030, USA, Department of Experimental Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA

^* To whom correspondence should be addressed. Email: gglozano{at}mdanderson.org.

	Abstract

The tumor suppressor p53 is inactivated by multiple mechanisms that include mutations of the p53 gene itself and increased levels of the p53 inhibitors MDM2 and MDM4. Mice lacking Mdm2 or Mdm4 exhibit embryo lethal phenotypes that are completely rescued by concomitant deletion of p53. Here, we show that Mdm2 and Mdm4 haploinsufficiency leads to increased p53 activity exhibited as increased sensitivity to DNA damage and decreased transformation potential. Moreover, in in vivo tumor development Eµ-myc:Mdm4^+/- mice show a delayed onset of B cell lymphomas as compared to Eµ-myc mice. Additionally, Mdm2^+/- Mdm4^+/- double heterozygous mice are not viable and exhibit defects in hematopoiesis and cerebellar development. The defects are corrected in Mdm2^+/- Mdm4^+/- mice by deletion of a single p53 allele. These findings highlight the exquisite sensitivity of p53 to Mdm2 and Mdm4 levels, and suggest that some cell types may be more sensitive to therapeutic drugs that inhibit the Mdm/p53 interaction.

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