Abstract
THE Mdm2 proto-oncogene was originally identified as one of several genes contained on a mouse double minute chromosome present in a transformed derivative of 3T3 cells1. Over expression of Mdm2 can immortalize primary cultures of rodent fibroblasts2. Human MDM2 is amplified in 30–40% of sarcomas, and is overex-pressed in leukaemic cells3,4. The Mdm2 oncoprotein forms a complex with the p53 tumour-suppressor protein and inhibits p53-mediated transregulation of gene expression5,6. Because Mdm2 expression increases in response to p53, Mdm2–p53 binding may autoregulate Mdm2 expression and modulate the activity of p53 in the cell7,8. We have created Mdm2-null and Mdm2/p53-null mice to determine whether Mdm2 possesses developmental functions in addition to the ability to complex with p53, and to investigate the biological role of Mdm2–p53 complex formation in development. Mice deficient for Mdm2 die early in development. In contrast, mice deficient for both Mdm2 and p53 develop normally and are viable. These results suggest that a critical role of Mdm2 in development is the regulation of p53 function.
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References
Cahilly-Snyder, L., Yang-Feng, T., Franke, U. & George, D. Somatic Cell molec. Genet. 13, 235–244 (1987).
Finlay, C. A. Molec. cell. Biol. 13, 301–306 (1993).
Oliner, J. D., Kinzler, K. W., Meltzer, P. S., George, D. & Vogelstein, B. Nature 358, 80–83 (1992).
Bueso-Ramos, C. et al. Blood 82, 2617–2623 (1993).
Momand, J., Zambetti, G. P., Olson, D. C., George, D. & Levine, A. J. Cell 69, 1237–1245 (1992).
Chen, J., Lin, J. & Levine, A. J. Molec. Med. 1, 142–152 (1995).
Juven, T., Barak, Y., Zauberman, A., George, D. & Oren, M. Oncogene 8, 3411–3416 (1993).
Wu, X., Bayle, H., Olson, D. & Levine, A. J. Genes Dev. 7, 1126–1132 (1993).
Snow, M. H. L. J. Embryol. exp. Morph. 42, 293–303 (1977).
Schmid, P., Lorenz, A., Hameister, H. & Montenarh, M. Development 113, 857–865 (1991).
Donehower, L. A. et al. Nature 356, 215–221 (1992).
Chen, J., Marechal, V. & Levine, A. J. Molec. cell. Biol. 13, 4107–4114 (1993).
Baker, S. J., Markowitz, S., Fearon, E. R., Willson, J. K. V. & Vogelstein, B. Science 253, 49–53 (1990).
Diller, L. et al. Molec. cell. Biol. 10, 5772–5781 (1990).
Mercer, W. E. et al. Proc. natn. Acad. Sci. U.S.A. 87, 6166–6170 (1990).
Kastan, M. B., Onyekwere, O., Sidransky, D., Vogelstein, B. & Craig, R. W. Cancer Res. 51, 6304–6311 (1991).
Martinez, J., Georgoff, I. & Levine, A. J. Genes Dev. 5, 151–159 (1991).
Olson, D. C. et al. Oncogene 8, 2353–2360 (1993).
Chen, C.-Y. et al. Proc. natn. Acad. Sci. U.S.A. 91, 2684–2688 (1994).
Matzuk, M. M., Finegold, M. J., Su, J.-G. J., Hsueh, A. J. W. & Bradley, A. Nature 360, 313–319 (1992).
Mansour, S. L., Thomas, K. R. & Capecchi, M. R. Nature 336, 348–352 (1988).
Ramirez-Solis,, R., Davis, A. C. & Bradley, A. in Guide to Techniques in Mouse development (eds Wassarman, P. M. & DePamphilis, M. L.) 855–878 (Academic, New York, 1993).
Kaufman, M. H. in The Atlas of Mouse Development 2–5 (Academic, San Diego, CA, 1992).
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Jones, S., Roe, A., Donehower, L. et al. Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53. Nature 378, 206–208 (1995). https://doi.org/10.1038/378206a0
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DOI: https://doi.org/10.1038/378206a0
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