Validation of MdmX as a therapeutic target for reactivating p53 in tumors
Open accessAbstract
MdmX, also known as Mdm4, is a critical negative regulator of p53, and its overexpression serves to block p53 tumor suppressor function in many cancers. Consequently, inhibiting MdmX has emerged as an attractive approach to restoring p53 function in those cancers that retain functional p53. However, the consequences of acute systemic MdmX inhibition in normal adult tissues remain unknown. To determine directly the effects of systemic MdmX inhibition in normal tissues and in tumors, we crossed mdmX −/− mice into the p53ER TAM knockin background. In place of wild-type p53, p53ER TAM knockin mice express a variant of p53, p53ER TAM , that is completely dependent on 4-hydroxy-tamoxifen for its activity. MdmX inhibition was then modeled by restoring p53 function in these MdmX-deficient mice. We show that MdmX is continuously required to buffer p53 activity in adult normal tissues and their stem cells. Importantly, the effects of transient p53 restoration in the absence of MdmX are nonlethal and reversible, unlike transient p53 restoration in the absence of Mdm2, which is ineluctably lethal. We also show that the therapeutic impact of restoring p53 in a tumor model is enhanced in the absence of MdmX, affording a significant extension of life span over p53 restoration in the presence of MdmX. Hence, systemic inhibition of MdmX is both a feasible therapeutic strategy for restoring p53 function in tumors that retain wild-type p53 and likely to be significantly safer than inhibition of Mdm2.
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Mouse tissues seem to tolerate the p53 activation that accompanies Mdmx deletion.
“Mouse tissues also seem to tolerate the p53 activation that accompanies Mdmx deletion85.”
From MDM2, MDMX and p53 in oncogenesis and cancer therapy (2013) · cites this paper as [85]
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- Authors
- Garcia, D., Warr, M. R., Martins, C. P., Brown Swigart, L., Passegué, E., & Evan, G. I.
- Affiliations
- University of California, San Francisco (US)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2011-08-15
- Volume
- 25
- Issue
- 16
- Pages
- 1746-1757
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC3165938
- OpenAlex
- W2168650390
- Cited by
- 83
- References
- 55
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 3 · 2023: 3 · 2022: 3 · 2021: 2 · 2020: 3 · 2019: 4 · 2018: 2 · 2017: 9 · 2016: 8 · 2015: 13 · 2014: 9 · 2013: 9 · 2012: 10
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ellison Medical Foundation
- National Cancer Institute (R01CA100193, CA100193, CA 98-018, R01CA098018)
- National Institute of General Medical Sciences (R25GM056847, GM 56847, R25-GM56847)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- MDMX, MDM4, p53, p53 reactivation, MDM2, normal tissue toxicity, stem cells, tumor suppression, drug target validation
- MeSH terms
- Animals, Bone Marrow, Embryo, Mammalian, Female, Fibroblasts, Liver, Lymphoma, Male, Mice, Transgenic, Mutation, Proto-Oncogene Proteins, Tamoxifen, Tumor Cells, Cultured, Immunoblotting, Gene Expression, Tumor Suppressor Protein p53, Proto-Oncogene Proteins c-myc, Apoptosis, Mice, Knockout, Antineoplastic Agents, Hormonal, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases, Cyclin-Dependent Kinase Inhibitor p21, Apoptosis Regulatory Proteins, Mice, Proto-Oncogene Proteins c-mdm2, Kaplan-Meier Estimate
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