Spontaneous Tumorigenesis in Mice Overexpressing the p53-Negative Regulator Mdm4
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Abstract
High levels of the critical p53 inhibitor Mdm4 is common in tumors that retain a wild-type p53 allele, suggesting that Mdm4 overexpression is an important mechanism for p53 inactivation during tumorigenesis. To test this hypothesis in vivo, we generated transgenic mice with widespread expression of Mdm4. Two independent lines of transgenic mice, Mdm4Tg1 and Mdm4Tg15, developed spontaneous tumors, the most prevalent of which were sarcomas. To determine whether overexpression of Mdm4 also cooperated with p53 heterozygosity to induce tumorigenesis, we generated Mdm4Tg1 p53+/− mice. These mice had significantly accelerated tumorigenesis and a distinct tumor spectrum with more carcinomas and significantly fewer lymphomas than p53+/− or Mdm4Tg1 mice. Importantly, the remaining wild-type p53 allele was retained in most Mdm4Tg1 p53+/− tumors. Mdm4 is thus a bona fide oncogene in vivo and cooperates with p53 heterozygosity to drive tumorigenesis. These Mdm4 mice will be invaluable for in vivo drug studies of Mdm4 inhibitors. Cancer Res; 70(18); 7148–54. ©2010 AACR.
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Transgenic mice overexpressing Mdmx have an increased incidence of malignancies.
“Recently, it was reported that transgenic mice overexpressing Mdmx had an increased incidence of malignancies.52”
From Mdmx promotes genomic instability independent of p53 and Mdm2 (2015) · cites this paper as [52]
In one study, transgenic mice that ubiquitously expressed MDMX developed tumours with a latency comparable to Trp53-hemizygous mice.
“In one study, transgenic mice that ubiquitously expressed MDMX developed tumours with a latency that was comparable to that of Trp53-hemizygous mice68.”
From MDM2, MDMX and p53 in oncogenesis and cancer therapy (2013) · cites this paper as [68]
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- Authors
- Xiong, S., Pant, V., Suh, Y.-A., Van Pelt, C. S., Wang, Y., Valentin-Vega, Y. A., Post, S. M., & Lozano, G.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Authors' Affiliations: Departments of 1Genetics and 2Veterinary Medicine and Surgery, The University of Texas M.D. Anderson Cancer Center Houston, Texas; and 3The University of Texas Graduate School in Biomedical Sciences and Program in Genes and Development, Houston, Texas
- Corresponding author
- Lozano, Guillermina
- Venue
- Cancer Research
- Published
- 2010-09-14
- Volume
- 70
- Issue
- 18
- Pages
- 7148-7154
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC2940952
- OpenAlex
- W2115905835
- Cited by
- 82
- References
- 40
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 1 · 2023: 3 · 2022: 3 · 2021: 2 · 2020: 4 · 2019: 5 · 2018: 3 · 2017: 5 · 2016: 12 · 2015: 7 · 2014: 10 · 2013: 6 · 2012: 11
- FWCI
- 3.63
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (CA47296, R01CA047296)
- 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 › PI3K/AKT/mTOR signaling in cancer
- Keywords
- MDM4, p53, p53 inactivation, spontaneous tumor development, transgenic mice, sarcoma, carcinoma, lymphoma, oncogene cooperation, tumor spectrum
- MeSH terms
- Actins, Animals, Cell Transformation, Neoplastic, Chickens, DNA Damage, Female, HeLa Cells, Humans, Mice, Inbred C57BL, Mice, Transgenic, Neoplasms, Experimental, Promoter Regions, Genetic, Proto-Oncogene Proteins, Tumor Suppressor Protein p53, Ubiquitin-Protein Ligases, Mice
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