p53 regulates a mitotic transcription program and determines ploidy in normal mouse liver

Authors

  • Svitlana Kurinna,

    1. Department of Biochemistry and Molecular BiologyThe University of Texas MD Anderson Cancer Center, Houston, TX
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  • Sabrina A. Stratton,

    1. Department of Biochemistry and Molecular BiologyThe University of Texas MD Anderson Cancer Center, Houston, TX
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  • Zeynep Coban,

    1. Department of Biochemistry and Molecular BiologyThe University of Texas MD Anderson Cancer Center, Houston, TX
    2. Center for Cancer EpigeneticsThe University of Texas MD Anderson Cancer Center, Houston, TX
    3. Graduate Program in Genes and Development, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX
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  • Jill M. Schumacher,

    1. Center for Cancer EpigeneticsThe University of Texas MD Anderson Cancer Center, Houston, TX
    2. Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX
    3. Graduate Program in Genes and Development, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX
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  • Markus Grompe,

    1. Oregon Stem Cell Center, Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, OR
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  • Andrew W. Duncan,

    Corresponding author
    1. Oregon Stem Cell Center, Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, OR
    2. Department of Pathology, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA
    • Department of Pathology, McGowan Institute for Regenerative Medicine, University of Pittsburgh, 450 Technology Drive, Suite 300, Pittsburgh, PA 15219
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    • fax: 412-624-5363

  • Michelle Craig Barton

    Corresponding author
    1. Department of Biochemistry and Molecular BiologyThe University of Texas MD Anderson Cancer Center, Houston, TX
    2. Center for Stem Cell and Developmental BiologyThe University of Texas MD Anderson Cancer Center, Houston, TX
    3. Center for Cancer EpigeneticsThe University of Texas MD Anderson Cancer Center, Houston, TX
    4. Graduate Program in Genes and Development, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX
    • Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Box 1000, Houston, TX 77030
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    • fax: 713-834-6273


  • Potential conflict of interest: Nothing to report.

  • Supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases (grant R01-DK078024 to M. C. B.), the William Randolph Hearst Foundation (Z. C.), and the National Cancer Institute Cancer Center Support Grant (to The University of Texas MD Anderson Cancer Center).

Abstract

Functions of p53 during mitosis reportedly include prevention of polyploidy and transmission of aberrant chromosomes. However, whether p53 plays these roles during genomic surveillance in vivo and, if so, whether this is done via direct or indirect means remain unknown. The ability of normal, mature hepatocytes to respond to stimuli, reenter the cell cycle, and regenerate liver mass offers an ideal setting to assess mitosis in vivo. In quiescent liver, normally high ploidy levels in adult mice increased with loss of p53. Following partial hepatectomy, p53−/− hepatocytes exhibited early entry into the cell cycle and prolonged proliferation with an increased number of polyploid mitoses. Ploidy levels increased during regeneration of both wild-type (WT) and p53−/− hepatocytes, but only WT hepatocytes were able to dynamically resolve ploidy levels and return to normal by the end of regeneration. We identified multiple cell cycle and mitotic regulators, including Foxm1, Aurka, Lats2, Plk2, and Plk4, as directly regulated by chromatin interactions of p53 in vivo. Over a time course of regeneration, direct and indirect regulation of expression by p53 is mediated in a gene-specific manner. Conclusion: Our results show that p53 plays a role in mitotic fidelity and ploidy resolution in hepatocytes of normal and regenerative liver. (HEPATOLOGY 2013)

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