Cited by 1,949Cancer-related Molecular PathwaysSarcoma Diagnosis and TreatmentHeat shock proteins research

Amplification of a gene encoding a p53-associated protein in human sarcomas

Oliner, J. D., Kinzler, K. W., Meltzer, P. S., George, D. L., Vogelstein, B.·1992·Nature

Abstract

Despite extensive data linking mutations in the p53 gene to human tumorigenesis, little is known about the cellular regulators and mediators of p53 function. MDM2 is a strong candidate for one such cellular protein; the MDM2 gene was originally identified by virtue of its amplification in a spontaneously transformed derivative of mouse BALB/c cells and the MDM2 protein subsequently shown to bind to p53 in rat cells transfected with p53 genes. To determine whether MDM2 plays a role in human cancer, we have cloned the human MDM2 gene. Here we show that recombinant-derived human MDM2 protein binds human p53 in vitro, and we use MDM2 clones to localize the human MDM2 gene to chromosome 12q13-14. Because this chromosomal position appears to be altered in many sarcomas, we looked for changes in human MDM2 in such cancers. The gene was amplified in over a third of 47 sarcomas, including common bone and soft tissue forms. These results are consistent with the hypothesis that MDM2 binds to p53, and that amplification of MDM2 in sarcomas leads to escape from p53-regulated growth control. This mechanism of tumorigenesis parallels that for virally-induced tumours, in which viral oncogene products bind to and functionally inactivate p53.

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Crossref · 10.1038/358080a0

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Authors
Oliner, J. D., Kinzler, K. W., Meltzer, P. S., George, D. L., & Vogelstein, B.
Affiliations
  • University of Michigan (US)
  • Johns Hopkins University (US)
  • University of Pennsylvania (US)
Venue
Nature
Published
1992-07
Volume
358
Issue
6381
Pages
80-83
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
OpenAlex
W2091151265
Cited by
1,949
References
32
Citations by year
2026: 14 · 2025: 22 · 2024: 23 · 2023: 27 · 2022: 25 · 2021: 36 · 2020: 37 · 2019: 32 · 2018: 20 · 2017: 37 · 2016: 52 · 2015: 46 · 2014: 63 · 2013: 46 · 2012: 58
FWCI
52.87
Type
journal article
Language
en
Open access
closed
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • Deep Blue (University of Michigan) (submittedVersion)
Topics
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Sarcoma Diagnosis and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
Keywords
MDM2, p53, gene amplification, sarcoma, p53 binding, tumor suppressor inactivation, bone sarcoma, soft tissue sarcoma, viral oncogenes, carcinogenesis
MeSH terms
Amino Acid Sequence, Base Sequence, Chromosomes, Human, Pair 12, Cloning, Molecular, DNA, Gene Amplification, Humans, Molecular Sequence Data, Neoplasm Proteins, Neoplasms, Nuclear Proteins, Proto-Oncogene Proteins, RNA, Messenger, RNA, Neoplasm, Sequence Homology, Nucleic Acid, Gene Expression, Tumor Suppressor Protein p53, Sequence Alignment, Proto-Oncogene Proteins c-mdm2

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