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Genomic instability in Gadd45a-deficient mice

Nature Genetics volume 23, pages 176–184 (1999)Cite this article

Abstract

Gadd45a-null mice generated by gene targeting exhibited several of the phenotypes characteristic of p53-deficient mice, including genomic instability, increased radiation carcinogenesis and a low frequency of exencephaly. Genomic instability was exemplified by aneuploidy, chromosome aberrations, gene amplification and centrosome amplification, and was accompanied by abnormalities in mitosis, cytokinesis and growth control. Unequal segregation of chromosomes due to multiple spindle poles during mitosis occurred in several Gadd45a–/– cell lineages and may contribute to the aneuploidy. Our results indicate that Gadd45a is one component of the p53 pathway that contributes to the maintenance of genomic stability.

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Figure 1: Targeting of Gadd45a.
Figure 2: Increased growth rate and ras transformation of Gadd45a–/– MEFs.
Figure 3: Gadd45a–/– MEFs exhibit aneuploidy and gene amplification.
Figure 4: Amplification of centrosomes in Gadd45a–/– cells.
Figure 5: Enhanced radiation-induced carcinogenesis and normal radiation-induced apoptosis in Gadd45a–/– mice.
Figure 6: Checkpoint activation in Gadd45a–/– cells.
Figure 7: Hyperploidy and centrosome amplification in E7/ras-transformed Gadd45a–/– MEFs.

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Acknowledgements

We thank J.M. Ward, M. Anver, F. Gonzalez, D.R. Lowy, M.L. Smith, H. Petrie, J. Sanchez, C. Vargas and P.M. O'Connor for advice and support.

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Authors and Affiliations

  1. Gene Response Section, DBS, National Cancer Institute, , Bethesda, 20892-4255, Maryland, USA

    M. Christine Hollander, M. Saeed Sheikh, Dmitry V. Bulavin, Laura Augeri-Henmueller, Thomas A. Molinaro, Kate E. Kim, Qimin Zhan & Albert J. Fornace Jr

  2. Glaxo Wellcome Research and Development, Inc., Research Triangle Park,, 27709, North Carolina, USA

    Karen Lundgren, Ronald Shehee & Michael P. Rosenberg

  3. Laboratory of Immune Cell Biology, DBS, National Cancer Institute,, Bethesda, 20892, Maryland, USA

    Eva Tolosa & Jonathan D. Ashwell

  4. Laboratory of Metabolism, DBS, National Cancer Institute, , Bethesda, 20892, Maryland, USA

    Pedro M. Fernández-Salguero

  5. Department of Radiation Oncology, University of California, San Francisco, 94143-0750, California, USA

    William F. Morgan

  6. Life Sciences Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Road MS 934, Berkeley , 94720, California, USA

    William F. Morgan

  7. Genetics of Development and Disease Branch, NIDDKD, , Bethesda, 20892, Maryland, USA

    Chu-Xia Deng

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Correspondence to Albert J. Fornace Jr.

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Hollander, M., Sheikh, M., Bulavin, D. et al. Genomic instability in Gadd45a-deficient mice. Nat Genet 23, 176–184 (1999). https://doi.org/10.1038/13802

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