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PMID: 21730132 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Heterodimerization of Mdm2 and Mdm4 is critical for regulating p53 activity during embryogenesis but dispensable for p53 and Mdm2 stability.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 108 ·No. 29 ·2011-07-19 ·Pages 11995-2000

Pant V, Xiong S, Iwakuma T, Quintás-Cardama A, Lozano G

Abstract

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.

MeSH Terms
Animals Blotting, Southern Cesium Radioisotopes DNA Primers/genetics Embryonic Development/genetics,physiology Gene Expression Regulation, Developmental/genetics Genotype Mice Mice, Transgenic Protein Multimerization/genetics Proto-Oncogene Proteins/genetics,metabolism Proto-Oncogene Proteins c-mdm2/genetics,metabolism Reverse Transcriptase Polymerase Chain Reaction Tumor Suppressor Protein p53/metabolism Ubiquitin-Protein Ligases/genetics,metabolism Ubiquitination
Chemicals
Cesium Radioisotopes DNA Primers Mdm4 protein, mouse Proto-Oncogene Proteins Tumor Suppressor Protein p53 Mdm2 protein, mouse Proto-Oncogene Proteins c-mdm2 Ubiquitin-Protein Ligases
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Pant Vinod
Department of Genetics, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Xiong Shunbin
Iwakuma Tomoo
Quintás-Cardama Alfonso
Lozano Guillermina
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.1102241108
Published
2011-07-19
Epub
2011-00-05
Pages
11995-2000
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC3141986
Subset
IM
Grants
NCI NIH HHS · CA47296 · United States
NCI NIH HHS · P30 CA016672 · United States
NCI NIH HHS · CA009299 · United States
NCI NIH HHS · R01 CA047296 · United States
NCI NIH HHS · T32 CA009299 · United States
External Links
PubMed source DOI: 10.1073/pnas.1102241108 PMC Full Text View journal details
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