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The human oncoprotein MDM2 arrests the cell cycle: elimination of its cell-cycle-inhibitory function induces tumorigenesis
Open accessAbstract
The human oncoprotein MDM2 (hMDM2) overexpresses in various human tumors. If amplified, the mdm2 gene can enhance the tumorigenic potential of murine cells. Here, we present evidence to show that the full-length human or mouse MDM2 expressed from their respective cDNA can inhibit the G0/G1-S phase transition of NIH 3T3 and normal human diploid cells. The protein harbors more than one cell-cycle-inhibitory domain that does not overlap with the p53-interaction domain. Deletion mutants of hMDM2 that lack the cell-cycle-inhibitory domains can be stably expressed in NIH 3T3 cells, enhancing their tumorigenic potential. The tumorigenic domain of hMDM2 overlaps with the p53-interaction domain. Some tumor-derived cells, such as Saos-2, H1299 or U-2OS, are relatively insensitive to the growth-inhibitory effects of hMDM2. These observations suggest that hMDM2 overexpression in response to oncogenic stimuli would induce growth arrest in normal cells. Elimination or inactivation of the hMDM2-induced G0/G1 arrest may contribute to one of the steps of tumorigenesis.
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“Small increases in Mdm2 levels in normal cells are tolerated”
From The Mdm network and its regulation of p53 activities: a rheostat of cancer risk (2014) · cites this paper as Brown, et al., 1998
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“higher levels are incompatible with life in vivo and in vitro, except in some cases when p53 is also inactivated”
From The Mdm network and its regulation of p53 activities: a rheostat of cancer risk (2014) · cites this paper as Brown, et al., 1998
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Metadata
- Authors
- Brown, D. R., Thomas, C. A., & Palit Deb, S.
- Affiliations
- The University of Texas at San Antonio Health Science Center (US)
- ORCID
- Brown, Doris R.
- Venue
- The EMBO Journal
- Published
- 1998-05-01
- Volume
- 17
- Issue
- 9
- Pages
- 2513-2525
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC1170593
- OpenAlex
- W2014749419
- Cited by
- 148
- References
- 78
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 2 · 2022: 3 · 2021: 3 · 2020: 1 · 2019: 3 · 2018: 3 · 2017: 4 · 2016: 3 · 2015: 4 · 2014: 6 · 2013: 4 · 2012: 14
- FWCI
- 4.24
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (R01CA070712, CA70712)
- 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 › PI3K/AKT/mTOR signaling in cancer
- Keywords
- MDM2, oncoprotein, cell cycle arrest, G0/G1 arrest, carcinogenesis, deletion mutants, NIH3T3 cells, cancer cell lines, oncogene overexpression, growth inhibition
- MeSH terms
- Animals, Cell Cycle, Cell Division, Cell Line, Cell Transformation, Neoplastic, Flow Cytometry, Gene Amplification, Humans, Neoplasm Proteins, Nuclear Proteins, Proto-Oncogene Proteins, Recombinant Proteins, Transfection, Resting Phase, Cell Cycle, G1 Phase, S Phase, Mutagenesis, Site-Directed, 3T3 Cells, Sequence Deletion, Mice, Proto-Oncogene Proteins c-mdm2
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