Loss of Mdm4 Results in p53 -Dependent Dilated Cardiomyopathy
Abstract
BACKGROUND: Although several loci for familial dilated cardiomyopathy (DCM) have been mapped, the origin of a large percentage of DCM remains unclear. Mdm2, a p53-negative regulator, protects cardiomyocytes from ischemic and reperfusion-induced cell death. Mdm4, a homolog of Mdm2, inhibits p53 activity in numerous cell types. It is unknown whether Mdm4 plays a role in the inhibition of p53 in fully differentiated tissues such as adult cardiomyocytes and whether this role is associated with DCM. METHODS AND RESULTS: The conditional knockout of Mdm4 in the heart by use of cardiomyocyte-specific Cre (alphaMyHC-Cre) allele does not result in any developmental defects. With time, however, mice with deletion of Mdm4 in the adult heart developed DCM and had a median survival of 234 days. More interestingly, the onset of DCM occurs significantly earlier in male mice than in female mice, which mimics human DCM disease. DCM in Mdm4 mutant mice was caused by loss of cardiomyocytes by apoptosis, and it was p53-dose dependent. CONCLUSION: Activity of p53 was inhibited by Mdm4 even in the fully differentiated cardiomyocyte. Elevated apoptosis mediated by the p53 pathway in cardiomyocytes may be a mechanism for DCM.
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Mdm2 and Mdmx contribute to p53 regulation to different extents in different tissues in vivo.
“Mdm2 and Mdmx seem to contribute to p53 regulation to different extents in different tissues in vivo (Table 1; [32–40]).”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [39]
In smooth muscle cells, loss of Mdmx has no phenotype.
“However, in other cases, such as smooth muscle cells, loss of Mdmx has no phenotype.”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [39]
In some tissues and cell types, such as the central nervous system and proliferative intestinal cells, there is a requirement for both Mdm2 and Mdmx.
“Clearly in some tissues and cell types [such as the central nervous system (CNS) and proliferative intestinal cells], there is a requirement for both Mdm2 and Mdmx.”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [39]
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- Authors
- Xiong, S., Van Pelt, C. S., Elizondo-Fraire, A. C., Fernandez-Garcia, B., & Lozano, G.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- From the Department of Cancer Genetics (S.X., A.C.E.-F., G.L.), and Department of Veterinary Medicine & Surgery (C.S.V.P.), The University of Texas, M.D. Anderson Cancer Center, Houston, and Instituto de Biomedicina (B.F.-G.), Universidad de Leon, Campus de Vegazana, Leon, Spain.
- Venue
- Circulation
- Published
- 2007-06-12
- Volume
- 115
- Issue
- 23
- Pages
- 2925-2930
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- OpenAlex
- W2160723659
- Cited by
- 71
- References
- 46
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 2 · 2023: 3 · 2022: 2 · 2020: 5 · 2019: 4 · 2018: 2 · 2017: 6 · 2016: 5 · 2015: 5 · 2014: 2 · 2013: 5 · 2012: 5
- FWCI
- 3.52
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (CA-16672, CA47296, P30CA016672)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Keywords
- MDM4, p53, dilated cardiomyopathy, cardiomyocyte apoptosis, p53-dependent apoptosis, MDM2, conditional knockout, sex differences
- MeSH terms
- Animals, Cardiomyopathy, Dilated, Female, Male, Proto-Oncogene Proteins, Sex Factors, Survival Rate, Tumor Suppressor Protein p53, Apoptosis, Mice, Knockout, Myocytes, Cardiac, Ubiquitin-Protein Ligases, Mice
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