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A transactivation-deficient mouse model provides insights into Trp53 regulation and function

Nature Genetics volume 26, pages 37–43 (2000)Cite this article

A Corrigendum to this article was published on 01 February 2005

Abstract

The gene Trp53 is among the most frequently mutated and studied genes in human cancer, but the mechanisms by which it suppresses tumour formation remain unclear. We generated mice with an allele encoding changes at Leu25 and Trp26, known to be essential for transcriptional transactivation and Mdm2 binding, to enable analyses of Trp53 structure and function in vivo. The mutant Trp53 was abundant, its level was not affected by DNA damage and it bound DNA constitutively; however, it showed defects in cell-cycle regulation and apoptosis. Both mutant and Trp53-null mouse embryonic fibroblasts (MEFs) were readily transformed by oncogenes, and the corresponding mice were prone to tumours. We conclude that the determining pathway for Trp53 tumour-suppressor function in mice requires the transactivation domain.

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Figure 1: Targeting of the Trp53QS mutation to the Trp53 genomic locus.
Figure 2: The Trp53QS protein does not bind Mdm2 and is expressed at high levels.
Figure 3: Trp53QS binds DNA constitutively and its subcellular localization is not affected by DNA damage.
Figure 4: Trp53QS exhibits defective transactivation and cell-cycle checkpoints.
Figure 5: The thymocytes in mice containing Trp53QS is defective in apoptosis, and Trp53QS/QS MEFs are transformed by cooperating oncogenes.

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Acknowledgements

We thank C. Barlow for help with isolation of mouse thymocytes and advice on measuring apoptosis and tumorigenicity; and M. Vogt and M. Haas for helpful discussions regarding transformation assays. This work was supported by a postdoctoral fellowship from the NIH (G.S.J.), an NSF Graduate Fellowship (J.M.S.) and an ACS International Cancer Research Fellowship from the UICC (M.N.), and by grants from the NIH (G.M.W. and S.O.) and the G. Harold and Leila Y. Mathers Charitable Foundation (G.M.W.).

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  1. Gretchen S. Jimenez

    Present address: Vical Inc., San Diego, California, USA

Authors and Affiliations

  1. Gene Expression Laboratory, The Salk Institute, La Jolla, California, USA

    Gretchen S. Jimenez, Jayne M. Stommel, Michelle Beeche, Erin A. Barcarse, Stephen O'Gorman & Geoffrey M. Wahl

  2. Department of Genetics and Pathology, Tumor Biology Laboratory, Rudbeck Laboratory, University of Uppsala, Uppsala, Sweden

    Monica Nister & Xiao-Qun Zhang

  3. Department of Biology, University of California at San Diego, La Jolla, California, USA

    Jayne M. Stommel

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Correspondence to Geoffrey M. Wahl.

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Jimenez, G., Nister, M., Stommel, J. et al. A transactivation-deficient mouse model provides insights into Trp53 regulation and function. Nat Genet 26, 37–43 (2000). https://doi.org/10.1038/79152

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