Protecting the genome from mdm2 and mdmx
Open accessAbstract
The contribution of Mdm2, and its recently identified family member Mdmx (Mdm4), to tumorigenesis has primarily focused on their negative regulation of the p53 tumor suppressor. Although Mdm2 and Mdmx clearly inhibit p53, which can lead to tumor development, both have also been shown to affect tumorigenesis independent of p53. Given that Mdm2 and/or Mdmx overexpression is common and likely underestimated in human cancers, understanding the functions of these proteins beyond p53 control is critical. In recent years, new functions of Mdm2 and Mdmx that lead to genome instability, a hallmark of malignancy, have emerged. Specifically, roles in the DNA damage response that are distinct from their regulation of p53 have been identified. Inhibition of p53 as well as other components of the DNA damage response by Mdm2 and Mdmx can result in delayed DNA repair and increased genome instability, making Mdm2 and Mdmx a danger to the genome when aberrantly expressed. However, the genome instability caused by altered levels of Mdm2 and Mdmx could be used therapeutically for the treatment of cancer. Specifically, drugs/small molecules that target the interaction between Mdm2 and p53 can stabilize Mdm2, resulting in negative consequences on the genome that could be exploited for cancer treatment, particularly malignancies lacking functional p53.
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Mdm2 has functions independent of p53 that negatively affect genome stability.
“While Mdm2 negatively regulates p53, Mdm2 also has p53-independent functions that negatively impact genome stability (9).”
From Pharmacologically increasing Mdm2 Inhibits DNA repair and cooperates with genotoxic agents to kill p53-inactivated ovarian cancer cells (2015) · cites this paper as [9]
Mdm2 associates with Nbs1 of the MRN complex in a p53-independent manner.
“We, specifically, discovered a novel p53-independent association between Mdm2 and Nbs1 of the Mre11-Rad50-Nbs1 (MRN) DNA repair complex.5,6,8”
From Mdmx promotes genomic instability independent of p53 and Mdm2 (2015) · cites this paper as [8]
Mdm2 overexpression results in increased genome instability independently of its regulation of p53.
“Ultimately, Mdm2 overexpression results in increased genome instability that can occur independent of its regulation of p53.6,8”
From Mdmx promotes genomic instability independent of p53 and Mdm2 (2015) · cites this paper as [8]
Mdm2 and Mdm4 have p53-independent functions that contribute to tumorigenesis.
“data generated over the past 20 years that indicate Mdm2 and Mdm4 have p53-independent functions that contribute to tumorigenesis (Melo and Eischen, 2012).”
From The Mdm network and its regulation of p53 activities: a rheostat of cancer risk (2014) · cites this paper as Melo and Eischen, 2012
Mdm2 inhibits the early DNA damage signal that phosphorylates multiple targets and marks broken DNA for repair.
“multiple lines of evidence indicate that Mdm2 inhibits the early DNA damage signal that results in phosphorylation of multiple protein targets and marks broken DNA for repair”
From The Mdm network and its regulation of p53 activities: a rheostat of cancer risk (2014) · cites this paper as Melo and Eischen, 2012
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Self-citationBiderman, L., Poyurovsky, M. V., Assia, Y., Manley, J. L., & Prives, C. L. (2012) · Molecular and Cellular Biology · doi:10.1128/mcb.06150-11 · Cited by 26 · see citing works
Overproduction of MDM2 in vivo disrupts S phase independent of E2F1.
Reinke, V., Bortner, D. M., Amelse, L. L., Lundgren, K., Rosenberg, M. P., Finlay, C. A., & Lozano, G. (1999) · PubMed · Cited by 25 · see citing works
Kass, E. M., Poyurovsky, M. V., Zhu, Y. Y., et al. (2009) · Cell Cycle · doi:10.4161/cc.8.3.7624 · Cited by 24 · see citing works
The phenotype of MDM2 auto-degradation after DNA damage is due to epitope masking by phosphorylation
Cheng, Q., & Chen, J. (2011) · Cell Cycle · doi:10.4161/cc.10.7.15249 · Cited by 21 · see citing works
Inoue, K., Nakanjishi, M., Kikuchi, H., Yamamoto, H., Todo, S., Nakagawara, A., & Ozaki, T. (2008) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2008.04.155 · Cited by 7 · see citing works
Decreased Mdm2 levels after DNA damage: Antibody masking or protein degradation?
Eischen, C. M. (2011) · Cell Cycle · doi:10.4161/cc.10.9.15437 · Cited by 7 · see citing works
Self-citation
Flagged first, then by citations
Cited by
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Zhu, H., Gao, H., Ji, Y., Zhou, Q., Du, Z., Tian, L., Jiang, Y., Yao, K., & Zhou, Z. (2022) · Journal of Hematology & Oncology · doi:10.1186/s13045-022-01314-3 · Cited by 223 · see citing works
Eischen, C. M. (2016) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a026096 · Cited by 161 · see citing works
Self-citationThe Mdm network and its regulation of p53 activities: a rheostat of cancer risk
Eischen, C. M., & Lozano, G. (2014) · Human Mutation · doi:10.1002/humu.22524 · Cited by 79 · see citing works
Self-citationMdmx promotes genomic instability independent of p53 and Mdm2
Carrillo, A. M., Bouska, A., Arrate, M. P., & Eischen, C. M. (2015) · Oncogene · doi:10.1038/onc.2014.27 · Cited by 69 · see citing works
Self-citationCarrillo, A. M., Hicks, M., Khabele, D., & Eischen, C. M. (2015) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-15-0089 · Cited by 31 · see citing works
Self-citationResistance acquisition to MDM2 inhibitors
Cinatl, J., Speidel, D., Hardcastle, I., & Michaelis, M. (2014) · Biochemical Society Transactions · doi:10.1042/bst20140035 · Cited by 30 · see citing works
- Authors
- Melo, A. N., & Eischen, C. M.
- Affiliations
- Vanderbilt University Medical Center (US)
- Corresponding author
- Eischen, C. M.
- ORCID
- Eischen, C. M.
- Venue
- Genes & Cancer
- Publisher
- SAGE Publications
- Published
- 2012-03-01
- Volume
- 3
- Issue
- 3-4
- Pages
- 283-290
- ISSN
- 1947-6019 (ISSN-L)
- 1947-6027
- PMC
- PMC3494371
- OpenAlex
- W2118224973
- Semantic Scholar
- 8efad7dee5b927cf6818dcacd35273144564bf3c
- Cited by
- 20
- References
- 97
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 1 · 2022: 1 · 2021: 1 · 2020: 1 · 2017: 1 · 2016: 5 · 2015: 2 · 2014: 5 · 2013: 1
- FWCI
- 1.27
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Cancer (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (R01CA117935, R01CA160432, F31CA150546, T32CA009582, P30CA068485)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- MDM2, MDMX, MDM4, p53, genomic instability, DNA damage response, DNA repair, carcinogenesis, p53-independent function, p53-MDM2 interaction, cancer therapy, small molecule inhibitors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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