Abstract
THE gene p53 encodes a transcriptional activator1,2 of genes involved in growth arrest3,4, DNA repair5 and apoptosis6–8. Loss of p53 function contributes to tumour development in vivo 9–11. The transcriptional activation function of p53 is inactivated by interaction with the mdnil gene product12–14. Amplification of mdm2 has been observed in 36% of human sarcomas, indicating that it may represent an alternative mechanism of preventing p53 function in tumour development15. To study mdm2 function in vivo, we generated an mdm2 null allele by homologous recombination. Mdm2 null mice are not viable, and further analysis revealed embryonic lethality around implantation. To examine the importance of the interaction of MDM2 with p53 in vivo, we crossed mice heterozygous for mdm2 and p53 and obtained progeny homozygous for both p53 and mdm2 null alleles. Rescue of the mdm2−/− lethality in a p53 null background suggests that a critical in vivo function of MDM2 is the negative regulation of p53 activity.
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References
Fields, S. & Jang, S. K. Science 249, 1046–1049 (1990).
Raycroft, L., Wu, H. & Lozano, G. Science 249, 1049–1051 (1990).
El-diery, W. S. et al. Cell 75, 817–825 (1993).
Harper, W. J., Adami, G. R., Wei, N., Keyomarsi, K. & Elledge, S. J. Cell 75, 805–816 (1993).
Kastan, M. B. et al. Cell 71, 587–597 (1992).
Lowe, S. W., Schmitt, E. M., Smith, S. W., Osborne, B. A. & Jacks, T. Nature 362, 847–849 (1993).
Clarke, A. R. et al. Nature 362, 849–852 (1993).
Miyashita, T. & Reed, J. C. Cell 80, 293–299 (1995).
Greenblatt, M. S., Bennett, W. P., Hollstein, M. & Harris C. C. Cancer Res. 54, 4855–4878 (1994).
Donehower, L. A. et al. Nature 356, 215–221 (1992).
Jacks, T. et al. Curr. Biol. 4, 1–7 (1994).
Momand, J., Zambetti, G. P., Olson, D. C., George, D. & Levine, A. J. Cell 69, 1237–1245 (1992).
Chen, J., Marechal, V. & Levine, A. J. Molec. cell. Biol. 13, 4107–4114 (1993).
Oliner, J. D. et al. Nature 362, 857–860 (1993).
Oliner, J. D., Kinzler, K. W., Meltzer, P. S., George, D. L. & Vogelstein, B. Nature 358, 80–83 (1992).
Fakharzadeh, S. S., Trusko, S. P. & George, D. L. EMBO J. 10, 1565–1569 (1991).
Finlay, C. A. Molec. cell. Biol. 13, 301–306 (1993).
Maltzman, W. & Czyzyk, L. Molec. cell. Biol. 4, 1689–1694 (1984).
Kuerbitz, S. J., Plunkett, B. S., Walsh, W. V. & Kastan, M. B. Proc. natn. Acad. Sci. U.S.A. 89, 7491–7495 (1992).
Lu, X. & Lane, D. P. Cell 75, 765–778 (1993).
Lowe, S. W., Ruley, H. E., Jacks, T. & Housman, D. E. Cell 74, 957–967 (1993).
Di Leonardo, A., Linke, S. P., Clarkin, K. & Wahl, G. M. Genes Dev. 8, 2540–2551 (1994).
Xiao, Z.-X. et al. Nature 375, 694–698 (1995).
Martin, K. et al. Nature 375, 691–694 (1995).
Soriano, P., Montgomery, C., Geske, R. & Bradley, A. Cell 64, 693–702 (1991).
Mansour, S. L., Thomas, K. R. & Capecchi, M. R. Nature 336, 348–352 (1988).
McMahon, A. P. & Bradley, A. Cell 62, 1073–1085 (1990).
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de Oca Luna, R., Wagner, D. & Lozano, G. Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53. Nature 378, 203–206 (1995). https://doi.org/10.1038/378203a0
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DOI: https://doi.org/10.1038/378203a0
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