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Molecular and Cellular Biology, January 2006, p. 192-198, Vol. 26, No. 1
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.1.192-198.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Tissue-Specific Differences of p53 Inhibition by Mdm2 and Mdm4{ddagger}

Jason D. Grier,{dagger} Shunbin Xiong,{dagger} Ana C. Elizondo-Fraire, John M. Parant, and Guillermina Lozano*

The University of Texas Graduate School of Biomedical Sciences and Department of Molecular Genetics, Section of Cancer Genetics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

Received 20 June 2005/ Returned for modification 31 July 2005/ Accepted 12 October 2005

The function of the p53 tumor suppressor to inhibit proliferation or initiate apoptosis is often abrogated in tumor cells. Mdm2 and its homolog, Mdm4, are critical inhibitors of p53 that are often overexpressed in human tumors. In mice, loss of Mdm2 or Mdm4 leads to embryonic lethal phenotypes that are completely rescued by concomitant loss of p53. To examine the role of Mdm2 and Mdm4 in a temporal and tissue-specific manner and to determine the relationships of these inhibitors to each other, we generated conditional alleles. We deleted Mdm2 and Mdm4 in cardiomyocytes, since proliferation and apoptosis are important processes in heart development. Mice lacking Mdm2 in the heart were embryonic lethal and showed defects at the time recombination occurred. A critical number of cardiomyocytes were lost by embryonic day 13.5, resulting in heart failure. This phenotype was completely rescued by deletion of p53. Mice lacking Mdm4 in the heart were born at the correct ratio and appeared to be normal. Our studies provide the first direct evidence that Mdm2 can function in the absence of Mdm4 to regulate p53 activity in a tissue-specific manner. Moreover, Mdm4 cannot compensate for the loss of Mdm2 in heart development.

* Corresponding author. Mailing address: Department of Molecular Genetics, Section of Cancer Genetics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030. Phone: (713) 834-6386. Fax: (713) 834-6380. E-mail: gglozano{at}mdanderson.org.

{ddagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{dagger} These authors contributed equally to this work.

Molecular and Cellular Biology, January 2006, p. 192-198, Vol. 26, No. 1
0022-538X/06/$08.00+0     doi:10.1128/MCB.26.1.192-198.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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