Haploinsufficiency of Mdm2 and Mdm4 in Tumorigenesis and Development
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The tumor suppressor p53 is inactivated by multiple mechanisms that include mutations of the p53 gene itself and increased levels of the p53 inhibitors MDM2 and MDM4. Mice lacking Mdm2 or Mdm4 exhibit embryo-lethal phenotypes that are completely rescued by concomitant deletion of p53. Here we show that Mdm2 and Mdm4 haploinsufficiency leads to increased p53 activity, exhibited as increased sensitivity to DNA damage and decreased transformation potential. Moreover, in in vivo tumor development, Emu-myc Mdm4+/- mice show a delayed onset of B-cell lymphomas compared to Emu-myc mice. Additionally, Mdm2+/- Mdm4+/- double-heterozygous mice are not viable and exhibit defects in hematopoiesis and cerebellar development. The defects in Mdm2+/- Mdm4+/- mice are corrected by deletion of a single p53 allele. These findings highlight the exquisite sensitivity of p53 to Mdm2 and Mdm4 levels and suggest that some cell types may be more sensitive to therapeutic drugs that inhibit the Mdm-p53 interaction.
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Mdm4 heterozygous mice with Mdm4 haploinsufficiency have increased sensitivity to gamma radiation.
“Similar results have been observed for Mdm4 heterozygous mice with Mdm4 haploinsufficiency resulting in increased sensitivity to gamma radiation (Terzian, et al., 2007).”
From The Mdm network and its regulation of p53 activities: a rheostat of cancer risk (2014) · cites this paper as Terzian, et al., 2007
Heterozygosity of both Mdm2 and Mdm4 causes lethality, with 30% of mice dying in utero and the rest dying of hematopoietic failure within 21 days after birth.
“Notably, heterozygosity of both Mdm2 and Mdm4 results in lethality, with 30% of mice dying in utero and the rest of hematopoietic failure within 21 days after birth.”
From The Mdm network and its regulation of p53 activities: a rheostat of cancer risk (2014) · cites this paper as Terzian, et al., 2007
Gamma radiation or Myc overexpression causes cell death when cells are haploinsufficient for Mdm2.
“Consequently, gamma radiation or overexpression of the Myc oncogene leads to cell death when cells are haploinsufficient for Mdm2 (Alt, et al., 2003; O’Leary, et al., 2004; Terzian, et al., 2007).”
From The Mdm network and its regulation of p53 activities: a rheostat of cancer risk (2014) · cites this paper as Terzian, et al., 2007
Lymphoma caused by c-Myc appears later in mice that are heterozygous for Mdm2 or Mdmx.
“Previous studies have shown that c-Myc-induced lymphoma was accelerated in transgenic mice overexpressing Mdm2 [76], but was delayed in Mdm2 or Mdmx heterozygous mice [77].”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [77]
Haploinsufficiency of MDM2 delays onset of MYC-induced lymphoma in vivo.
“Conversely, haploinsufficiency of MDM2 delays the onset of MYC-induced lymphoma in vivo27.”
From MDM2, MDMX and p53 in oncogenesis and cancer therapy (2013) · cites this paper as [27]
In Mdm2+/− and Mdmx+/− heterozygous mice, the threshold for p53 activation in response to MYC is lowered, resulting in lower rates of MYC-induced lymphoma.
“In Mdm2+/−- and Mdmx+/−-heterozygous mice, the threshold for p53 activation in response to MYC is lowered, resulting in lower rates of MYC-induced lymphoma26,27.”
From MDM2, MDMX and p53 in oncogenesis and cancer therapy (2013) · cites this paper as [27]
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Self-citation
- Authors
- Terzian, T., Wang, Y., Van Pelt, C. S., Box, N. F., Travis, E. L., & Lozano, G.
- Affiliations
- Department of Cancer Genetics
- Department of Veterinary Medicine and Surgery
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Lozano, Guillermina
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2007-08-01
- Volume
- 27
- Issue
- 15
- Pages
- 5479-5485
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC1952101
- OpenAlex
- W2156521746
- Cited by
- 116
- References
- 23
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 4 · 2023: 3 · 2022: 5 · 2021: 3 · 2020: 4 · 2019: 3 · 2018: 6 · 2017: 4 · 2016: 8 · 2015: 4 · 2014: 8 · 2013: 6 · 2012: 15
- FWCI
- 4.37
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- MDM2, MDM4, p53, haploinsufficiency, p53 inhibitors, tumor suppressor, DNA damage sensitivity, transformation potential, B-cell lymphoma, hematopoiesis, cerebellar development, embryonic lethality, MDM2 inhibitors
- MeSH terms
- Animals, Animals, Newborn, Bone Marrow, Cell Transformation, Neoplastic, Cerebellum, Embryo, Mammalian, Haploidy, Hematopoiesis, Lymphoma, Phenotype, Proto-Oncogene Proteins, Radiation Tolerance, Tumor Suppressor Protein p53, Apoptosis, Ubiquitin-Protein Ligases, Mice, Proto-Oncogene Proteins c-mdm2
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