MdmX Promotes Bipolar Mitosis To Suppress Transformation and Tumorigenesis in p53-Deficient Cells and Mice
Open accessAbstract
Mdm2 and MdmX are structurally related p53-binding proteins that function as critical negative regulators of p53 activity in embryonic and adult tissue. The overexpression of Mdm2 or MdmX inhibits p53 tumor suppressor functions in vitro, and the amplification of Mdm2 or MdmX is observed in human cancers retaining wild-type p53. We now demonstrate a surprising role for MdmX in suppressing tumorigenesis that is distinct from its oncogenic ability to inhibit p53. The deletion of MdmX induces multipolar mitotic spindle formation and the loss of chromosomes from hyperploid p53-null cells. This reduction in chromosome number, not observed in p53-null cells with Mdm2 deleted, correlates with increased cell proliferation and the spontaneous transformation of MdmX/p53-null mouse embryonic fibroblasts in vitro and with an increased rate of spontaneous tumorigenesis in MdmX/p53-null mice in vivo. These results indicate that MdmX has a p53-independent role in suppressing oncogenic cell transformation, proliferation, and tumorigenesis by promoting centrosome clustering and bipolar mitosis.
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Recent studies determined that Mdmx influences genome stability independently of p53.
“Recent studies determined that Mdmx influences genome stability independent of p53.32,33”
From Mdmx promotes genomic instability independent of p53 and Mdm2 (2015) · cites this paper as [32]
Mdmx has p53-independent functions.
“the identification of Mdmx overexpression in tumors with mutated or deleted p53 and effects of Mdmx on genome instability in cells lacking p53 indicate p53-independent functions of Mdmx.3,19,30–33”
From Mdmx promotes genomic instability independent of p53 and Mdm2 (2015) · cites this paper as [32]
Loss of Mdmx leads to genome instability in MEFs lacking p53.
“Loss of Mdmx also led to genome instability in MEFs lacking p53.”
From Mdmx promotes genomic instability independent of p53 and Mdm2 (2015) · cites this paper as [32]
Mdmx−/−p53−/− MEFs have multipolar spindle formation and altered chromosome number.
“Specifically, Mdmx−/−p53−/− MEFs had multipolar spindle formation and altered chromosome number.32,33”
From Mdmx promotes genomic instability independent of p53 and Mdm2 (2015) · cites this paper as [32]
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- Authors
- Matijasevic, Z., Steinman, H. A., Hoover, K., & Jones, S. N.
- Affiliations
- Departments of Cell Biology and Cancer Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, Massachusetts 01655
- University of Massachusetts Chan Medical School (US)
- Corresponding author
- Jones, Stephen N.
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2008-02-01
- Volume
- 28
- Issue
- 4
- Pages
- 1265-1273
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC2258754
- OpenAlex
- W2163604447
- Cited by
- 58
- References
- 47
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 5 · 2022: 1 · 2021: 2 · 2020: 4 · 2019: 1 · 2018: 1 · 2017: 3 · 2016: 8 · 2015: 3 · 2014: 5 · 2013: 4 · 2012: 5
- FWCI
- 2.02
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (R01CA077735, R01CA77735)
- National Institute of Diabetes and Digestive and Kidney Diseases (5 P30 DK 32520, P30DK032520)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- MDMX, MDM2, p53, centrosome clustering, multipolar mitosis, chromosome loss, hyperploidy, spontaneous tumor development, cell transformation, cell proliferation, mouse embryonic fibroblasts, spindle assembly
- MeSH terms
- Animals, Cell Transformation, Neoplastic, Embryo, Mammalian, Fibroblasts, Mitosis, Spindle Apparatus, Neoplasms, Ploidies, Tumor Suppressor Protein p53, Cell Polarity, Chromosomes, Mammalian, Cell Proliferation, Mice, Proto-Oncogene Proteins c-mdm2
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