ArticleMolecular cancer research : MCR2008
Mdm2 and Mdm4 loss regulates distinct p53 activities.
Article in Molecular cancer research : MCR, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 56 papers.
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Who cites it
56 citing papers in PubMed, 90 citations in OpenAlex.
- The Enigmatic Tumor Suppressor p53 Biomolecule: Its Role and Prognostic and Predictive Values in Cancer Therapy and Precision Medicine.Biomolecules · 2026Review
- Targeting the MDM2-MDM4 interaction interface reveals an otherwise therapeutically active wild-type p53 in colorectal cancer.Molecular oncology · 2025Article
- Dependence on Mdm2 for Mdm4 inhibition of p53 activity.Cancer letters · 2025Article
- SETBP1 activation upon MDM4-enhanced ubiquitination of NR3C1 triggers dissemination of colorectal cancer cells.Clinical & experimental metastasis · 2024Article
- Review
- LASS2 enhances p53 protein stability and nuclear import to suppress liver cancer progression through interaction with MDM2/MDMX.Cell death discovery · 2023Article
- Article
- FAM193A is a positive regulator of p53 activity.Cell reports · 2023Article
- MDM2 E3 ligase activity is essential for p53 regulation and cell cycle integrity.PLoS genetics · 2022Article
- MDM2-Driven Ubiquitination Rapidly Removes p53 from Its Cognate Promoters.Biomolecules · 2021Article
- Targeting mechanosensitive MDM4 promotes lung fibrosis resolution in aged mice.The Journal of experimental medicine · 2021Article
- The roles and regulation of MDM2 and MDMX: it is not just about p53.Genes & development · 2021Review
- MDMX Recruits UbcH5c to Facilitate MDM2 E3 Ligase Activity and Subsequent p53 DegradationCancer research · 2021Article
- Mdm4 controls ureteric bud branching via regulation of p53 activity.Mechanisms of development · 2020Article
- USP47 Promotes Tumorigenesis by Negative Regulation of p53 through Deubiquitinating Ribosomal Protein S2.Cancers · 2020Article
- Inferring Leading Interactions in the p53/Mdm2/Mdmx Circuit through Live-Cell Imaging and Modeling.Cell systems · 2019Article
- A genetic variant within MDM4 3'UTR miRNA binding site is associated with HPV16-positive tumors and survival of oropharyngeal cancer.Molecular carcinogenesis · 2019Article
- Dual inhibition of MDMX and MDM2 as a therapeutic strategy in leukemia.Science translational medicine · 2018Article
- miR-100 antagonism triggers apoptosis by inhibiting ubiquitination-mediated p53 degradation.Oncogene · 2017Article
- SHARPIN Facilitates p53 Degradation in Breast Cancer Cells.Neoplasia (New York, N.Y.) · 2017Article
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
Abstract
Mutational inactivation of p53 is a hallmark of most human tumors. Loss of p53 function also occurs by overexpression of negative regulators such as MDM2 and MDM4. Deletion of Mdm2 or Mdm4 in mice results in p53-dependent embryo lethality due to constitutive p53 activity. However, Mdm2(-/-) and Mdm4(-/-) embryos display divergent phenotypes, suggesting that Mdm2 and Mdm4 exert distinct control over p53. To explore the interaction between Mdm2 and Mdm4 in p53 regulation, we first generated mice and cells that are triple null for p53, Mdm2, and Mdm4. These mice had identical survival curves and tumor spectrum as p53(-/-) mice, substantiating the principal role of Mdm2 and Mdm4 as negative p53 regulators. We next generated mouse embryo fibroblasts null for p53 with deletions of Mdm2, Mdm4, or both; introduced a retrovirus expressing a temperature-sensitive p53 mutant, p53A135V; and examined p53 stability and activity. In this system, p53 activated distinct target genes, leading to apoptosis in cells lacking Mdm2 and a cell cycle arrest in cells lacking Mdm4. Cells lacking both Mdm2 and Mdm4 had a stable p53 that initiated apoptosis similar to Mdm2-null cells. Additionally, stabilization of p53 in cells lacking Mdm4 with the Mdm2 antagonist nutlin-3 was sufficient to induce a cell death response. These data further differentiate the roles of Mdm2 and Mdm4 in the regulation of p53 activities.
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