Elevated Mdm2 expression induces chromosomal instability and confers a survival and growth advantage to B cells
Abstract
Mdm2, a regulator of the p53 tumor suppressor, is frequently overexpressed in lymphomas, including lymphomas that have inactivated p53. However, the biological consequences of Mdm2 overexpression in lymphocytes are not fully resolved. Here, we report that increased expression of Mdm2 in B cells augmented proliferation and reduced susceptibility to p53-dependent apoptosis, which was due to inhibition of p53 and suppression of p21 expression. Notably, developing and mature B cells from Mdm2 transgenic mice had an increased frequency of chromosomal/chromatid breaks and/or aneuploidy. This Mdm2-mediated genome instability occurred at a similar frequency as that in B cells overexpressing the oncogene c-Myc, but the chromosomal instability was not further enhanced when Mdm2 and c-Myc were overexpressed together. Elevated Mdm2 expression alone increased the occurrence of B-cell transformation in vivo and cooperated with c-Myc overexpression, resulting in an acceleration of B-cell lymphomagenesis. In addition, the frequency of p53 mutations was reduced, but not eliminated, in lymphomas arising in Mdm2/Emu-myc double transgenic mice. Therefore, increased Mdm2 expression facilitated B-cell lymphomagenesis, in part, through regulation of p53 by altering B-cell proliferation and susceptibility to apoptosis, and by inducing chromosomal instability.
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Studies have shown that Mdm2 overexpression can promote certain forms of genome instability, such as aneuploidy and centrosome duplication.
“Studies have shown that Mdm2 overexpression can promote certain forms of genome instability, such as aneuploidy and centrosome duplication (9, 50).”
From Mdm2 Promotes Genetic Instability and Transformation Independent of p53 (2008) · cites this paper as [50]
Deleting Arf or overexpressing Mdm2 accelerated Myc-driven B cell lymphoma at a rate similar to that caused by Myc overexpression plus p53 deficiency.
“Specifically, deletion of Arf or overexpression of Mdm2 accelerated Myc (MIM#190080) oncogene-induced B cell lymphoma development at a rate similar to that caused by Myc overexpression and p53 deficiency.”
From The Mdm network and its regulation of p53 activities: a rheostat of cancer risk (2014) · cites this paper as Wang, et al., 2008
Loss of Arf or overexpression of Mdm2 significantly reduced the selection for p53 mutations that normally occurs during Myc-induced B cell lymphomagenesis.
“Moreover, loss of Arf or overexpression of Mdm2 significantly reduced the selection for p53 mutations that normally arise during Myc-induced B cell lymphomagenesis (Eischen, et al., 1999; Wang, et al., 2008).”
From The Mdm network and its regulation of p53 activities: a rheostat of cancer risk (2014) · cites this paper as Wang, et al., 2008
Lymphoma caused by c-Myc appears sooner in transgenic mice that overexpress Mdm2.
“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 [76]
In primary B cells from young mice, Mdm2 overexpression leads to an increase in DNA breaks and aneuploidy.
“We previously showed that in primary B cells in young mice, Mdm2 overexpression leads to an increase in DNA breaks and aneuploidy (Wang et al., 2008).”
From Aging mice have increased chromosome instability that is exacerbated by elevated Mdm2 expression (2011) · cites this paper as Wang et al., 2008
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References 29 · Cited by 86
- Authors
- Wang, P., Lushnikova, T., Odvody, J., Greiner, T. C., Jones, S. N., & Eischen, C. M.
- Affiliations
- Vanderbilt University (US)
- University of Nebraska Medical Center (US)
- University of Massachusetts Chan Medical School (US)
- Corresponding author
- Eischen, C M
- Venue
- Oncogene
- Published
- 2007-09-10
- Volume
- 27
- Issue
- 11
- Pages
- 1590-1598
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W2066910712
- Semantic Scholar
- ecce6c17cb651ecc360480b21b986eacb125cb9f
- Cited by
- 86
- References
- 29
- Citations by year
- 2024: 3 · 2023: 3 · 2022: 1 · 2021: 8 · 2020: 2 · 2019: 2 · 2018: 6 · 2017: 7 · 2016: 8 · 2015: 6 · 2014: 8 · 2013: 5 · 2012: 6
- FWCI
- 3.21
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion)
- Funders
- Lymphoma Research Foundation
- Leukemia and Lymphoma Society
- National Cancer Institute (R01CA117935, CA098139, CA117935, R01CA098139)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- MDM2, p53, B cells, chromosomal instability, B-cell lymphomagenesis, p21, apoptosis resistance, B cell proliferation, aneuploidy, c-Myc, TP53 mutation, genomic instability
- MeSH terms
- Animals, Cell Survival, Female, Humans, Male, Mice, Transgenic, Blotting, Southern, Blotting, Western, Survival Rate, Tumor Suppressor Protein p53, Proto-Oncogene Proteins c-myc, Mutagenesis, Site-Directed, Lymphoma, B-Cell, Apoptosis, Chromosomal Instability, Mice, Proto-Oncogene Proteins c-mdm2, Precursor Cells, B-Lymphoid
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