Abstract
The mdm2 oncogene encodes a 90–kilodalton nuclear phosphoprotein that binds and inactivates the p53 tumor suppressor protein. Here we report the observation of five alternatively spliced mdm2 gene transcripts in a range of human cancers and their absence in normal tissues. Transfection of NIH 3T3 cells with each of these forms gave foci of morphologically transformed cells. A higher frequency of splice variants lacking p53 binding domain sequences was found in late–stage and high–grade ovarian and bladder carcinomas. Four of the splice variants show loss of p53 binding, consistent with partial deletion of sequences encoding the p53 binding domain, but retain carboxy–terminal zinc–finger domains. These observations suggest a reassessment of the transforming mechanisms of mdm2 and its relation to p53.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Oliner, J.D., Kinzler, K.W., Meltzer, P.S., George, D.L. & Vogelstein, B. Amplification of a gene encoding a p53-associated protein in human sarcomas. Nature 358, 80–83 (1992).
Fakharzadeh, S.S., Trusko, S.P. & George, D.L. Tumorigenic potential associated with enhanced expression of a gene that is amplified in a mouse tumour cell line. EMBO J. 10, 1565–1569 (1991).
Momand, J., Zambetti, G.P., Olson, D.C. & Levine, A.J. The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell 69, 1237–1245 (1992).
Oliner, J.D. et al. Oncoprotein MDM2 conceals the activation domain of tumour suppressor p53. Nature 362, 857–860 (1993).
Leach, F.S. et al. P53 mutation and MDM2 amplification in human soft tissue sarcomas. Cancer Res. 53, 2231–2234 (1993).
Reifenberger, G., Liu, L., Ichimura, K., Schmidt, E.E. & Collins, V.P. Amplification and overexpression of the MDM2 gene in a subset of human malignant gliomas without p53 mutations. Cancer Res. 53, 2736–2739 (1993).
Waber, P., Chen, J. & Nisen, P. Infrequency of MDM2 gene amplification in pediatric solid tumours and lack of association with p53 mutations in adult squamous cell carcinomas. Cancer Res. 53, 6028–6030 (1993).
Quesnel, B., Preudhomme, C., Fournier, J., Fenaux, P. & Peyrat, J.P. MDM2 gene amplification in human breast cancer. Eur. J. Cancer 30, 982–984 (1994).
Barak, Y., Juven, T., Haffne, R. & Oren, M. mdm2 expression is induced by wild type p53 activity. EMBO J. 12, 461–468 (1993).
Wu, X., Bayle, J.H., Olso, D. & Levine, A.J. The p53-mdm-2 autoregulatory feedback loop. Genes Dev. 7, 1126–1132 (1993).
Chen, J., Marechal, V. & Levine, A.J. Mapping of the p53 and mdm-2 interaction domains. Mol. Cell. Biol. 13, 4107–4114 (1993).
Boddy, M.N., Freemont, P.S. & Borden, K.L.B. The p53-associated protein MDM2 contains a newly characterized zinc-finger domain called the RING finger. Trends Biochem. Sci. 19, 188–189 (1994).
Xiao, Z-X. et al. Interaction between the retinoblastoma protein and the onco-protein MDM2. Nature 375, 694–698 (1995).
Martin, K. et al. Stimulation of E2F1/DP1 transcriptional activity by MDM2 oncoprotein. Nature 375, 691–694 (1995).
Olson, D.C. et al. Identification and characterization of multiple mdm-2 proteins and mdm-2-p53 protein complexes. Oncogene 8, 2353–2360 (1993).
Barak, Y., Gottlieb, E., Juven-Gershon, T. & Oren, M. Regulation of mdm2 expression by p53: Alternative promoters produce transcripts with nonidentical translation potential. Genes Dev. 8, 1739–1749 (1994).
Haines, D.S., Landers, J.E., Engel, L.J. & George, D.L. Physical and functional interactions between wild-type p53 and mdm2 proteins. Mol. Cell. Biol. 14, 1171–1178 (1994).
Gudas, J.M. et al. Differential expression of multiple MDM2 messenger RNAs and proteins in normal and tumorigenic breast epithelial cells. Clin. Cancer Res. 1, 71–80 (1995).
Roberts, B. Nuclear location signal-mediated protein transport. Biochim. Biophys. Acta 1008, 263–280 (1989)
Nakatsu, Y., Hattori, K., Hayakawa, H., Shimizu, K. & Sekiguchi, M. Organisation of the human gene for O6-methylguanine-DNA methyltransferase. Mutat. Res. DNA Repair Rep. 293, 119–132 (1993).
Dubs-Poterszman, M-C., Tocque, B. & Wasylyk, B. MDM2 transformation in the absence of p53 and abrogation of the p107 G1 cell-cycle arrest. Oncogene 11, 2445–2449 (1995).
Clifford, S.J., Thomas, D.J., Neal, D.E. & Lunec, J. Increased mdrl gene transcript levels in high-grade carcinoma of the bladder determined by quantitative PCR-based assay. Br. J. Cancer 69, 680–686 (1994).
Challen, C., Lunec, J., Warren, W. & Bassendine, M.F. Analysis of the p53 tumour-suppressor gene in hepatocellular carcinomas from Britain. Hepatology 16, 1362–1366 (1992).
Chen, C. & Okayama, H. High-efficiency transformation of mammalian cells by plasmid DNA. Mol. Cell. Biol. 7, 2745–2752 (1987).
Spandidos, D.A. & Wilkie, N.M. Malignant transformation of early passage rodent cells by a single mutated human oncogene. Nature 310, 469–475 (1984).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Sigalas, I., Calvert, A., Anderson, J. et al. Alternatively spliced mdm2 transcripts with loss of p53 binding domain sequences: Transforming ability and frequent detection in human cancer. Nat Med 2, 912–917 (1996). https://doi.org/10.1038/nm0896-912
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/nm0896-912