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Kinetics of myc-max-mad gene expression during hepatocyte proliferation in vivo: Differential regulation of mad family and stress-mediated induction of c-myc

Authors

  • Itsaso Mauleon,

    1. Grupo de Biología Molecular del Cáncer, Departamento de Biología Molecular y Unidad de Biomedicina del CSIC, Facultad de Medicina, Universidad de Cantabria, Santander, Spain
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  • Marie-Noëlle Lombard,

    1. Biologie Parasitaire, Muséum National d'Histoire Naturelle, Paris, France
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  • Maria J. Muñoz-Alonso,

    1. Grupo de Biología Molecular del Cáncer, Departamento de Biología Molecular y Unidad de Biomedicina del CSIC, Facultad de Medicina, Universidad de Cantabria, Santander, Spain
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  • Matilde Cañelles,

    1. Grupo de Biología Molecular del Cáncer, Departamento de Biología Molecular y Unidad de Biomedicina del CSIC, Facultad de Medicina, Universidad de Cantabria, Santander, Spain
    Current affiliation:
    1. Laboratory of Molecular and Cellular Immunology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892.
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  • Javier Leon

    Corresponding author
    1. Grupo de Biología Molecular del Cáncer, Departamento de Biología Molecular y Unidad de Biomedicina del CSIC, Facultad de Medicina, Universidad de Cantabria, Santander, Spain
    • Departamento de Biología Molecular y Unidad de Biomedicina del CSIC, Facultad de Medicina, 39011 Santander, Spain.
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Abstract

Mad proteins (Mad1, Mxi1, Mad3, Mad4, Mnt/Rox) are biochemical and biological antagonists of c-Myc oncoprotein. Mad-Max dimers repress the transcription of the same target genes activated by Myc-Max dimers. Despite the critical role of Max and Mad proteins as modulators of c-Myc functions, there are no comparative data on their regulation in vivo. We carried out a systematic analysis of c-myc, max, and mad family expression in a model of synchronized cell proliferation in vivo in adult tissues, that is, rat hepatocytes after partial hepatectomy. We confirmed the previously reported early peak of c-myc expression after hepatectomy but we show that it did not correlate with hepatocyte proliferation as it also occurred in sham-operated animals as a result of surgical stresses. A second peak of c-myc expression was observed later, at the time of the wave of DNA synthesis. No such expression was detected in sham-operated rat quiescent hepatocytes. max expression increased around 4–16 h after hepatectomy, before the peaks of c-myc and DNA synthesis. mxi1 and mad4 were slightly downregulated during liver regeneration. mnt/rox expression did not change. These expression patterns suggest a role of Myc-Max for efficient mitogenic response of hepatocytes. We also analyzed the effects of Myc and Max ectopic expression on the clonogenic growth of the rat hepatoma cells. Expression of c-Myc and Max increased clonogenic growth, whereas the reduction of c-Myc levels by an antisense vector decreased growth. The results suggest nonredundant roles for mad genes in hepatocyte proliferation and point to c-Myc as a putative target for anticancer therapy of liver cancer. © 2004 Wiley-Liss, Inc.

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