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

Nature 1992 Jul;358(6381):80-3

Department of Pediatrics, University of Michigan Cancer Center, Ann Arbor 48109.

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.

Download full-text PDF

Source
http://dx.doi.org/10.1038/358080a0DOI Listing
July 1992

Publication Analysis

Top Keywords

human mdm2
16
mdm2 gene
12
mdm2
11
mdm2 protein
8
human
8
p53
7
gene
5
localize human
4
gene chromosome
4
clones localize
4
mdm2 clones
4
chromosome 12q13-14
4
chromosomal position
4
altered sarcomas
4
sarcomas looked
4
looked changes
4
appears altered
4
position appears
4
changes human
4
vitro mdm2
4

References

(Supplied by CrossRef)

M Hollstein et al.
Science 1991

S Fakharzadeh et al.
EMBO J. 1991

PW Hinds et al.
Cell Growth Differ. 1990

N Mandahl et al.
Genes Chrom. Cancer 1989

C Turc-Carel et al.
Cancer genet. Cytogenet. 1986

PS Meltzer et al.
Cell Growth Differ. 1991

DP Lane et al.
Genes Dev. 1990

BA Werness et al.
Science 1990

H Ochman et al.
1985

K Tanaka et al.
FEBS Lett. 1990

Similar Publications