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Molecular and Cellular Biology, August 2007, p. 5479-5485, Vol. 27, No. 15
0270-7306/07/$08.00+0     doi:10.1128/MCB.00555-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Haploinsufficiency of Mdm2 and Mdm4 in Tumorigenesis and Development{triangledown}

Tamara Terzian,1 Yongxing Wang,1 Carolyn S. Van Pelt,2 Neil F. Box,3 Elisabeth L. Travis,4 and Guillermina Lozano1*

Department of Cancer Genetics,1 Department of Veterinary Medicine and Surgery,2 Department of Experimental Radiation Oncology, The University of Texas M. D. Anderson Cancer Center,4 Department of Dermatology, Baylor College of Medicine, Houston, Texas 770303

Received 29 March 2006/ Returned for modification 15 May 2006/ Accepted 10 May 2007

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 compared to Eµ-myc mice. Additionally, Mdm2+/– Mdm4+/– double-heterozygous mice are not viable and exhibit defects in hematopoiesis and cerebellar development. The defects in Mdm2+/– Mdm4+/– mice are corrected 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.

* Corresponding author. Mailing address: Department of Cancer Genetics, Box 1010, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: (713) 834-6387. Fax: (713) 834-6380. E-mail: gglozano{at}mdanderson.org

{triangledown} Published ahead of print on 25 May 2007.

Molecular and Cellular Biology, August 2007, p. 5479-5485, Vol. 27, No. 15
0270-7306/07/$08.00+0     doi:10.1128/MCB.00555-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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