Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 29, Pages 11995-12000Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1102241108
Keywords
Mdmx; mouse models; p53 stability; ubiquitination
Categories
Funding
- National Institutes of Health [CA47296]
- Molecular Genetics of Cancer Training Grant [CA009299]
- Dodie P. Hawn Foundation
- Lupe C. Garcia Foundation
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Mdm2 and Mdm4 are homologous RING domain-containing proteins that negatively regulate the tumor suppressor p53 under physiological and stress conditions. The RING domain of Mdm2 encodes an E3-ubiquitin ligase that promotes p53 degradation. In addition, Mdm2 and Mdm4 interact through their respective RING domains. The in vivo significance of Mdm2-Mdm4 heterodimerization in regulation of p53 function is unknown. In this study, we generated an Mdm4 conditional allele lacking the RING domain to investigate its role in Mdm2 and p53 regulation. Our results demonstrate that homozygous deletion of the Mdm4 RING domain results in prenatal lethality. Mechanistically, Mdm2-Mdm4 heterodimerization is critical for inhibiting lethal p53 activation during early embryogenesis. However, Mdm2-Mdm4 interaction is dispensable for regulating p53 activity as well as the stability of Mdm2 and p53 at later stages of development. We propose that Mdm4 is a key cofactor of Mdm2 that inhibits p53 activity primarily during early embryogenesis but is dispensable for regulating p53 and Mdm2 stability in the adult mouse.
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