The liver-specific tumor suppressor STAT5 controls expression of the reactive oxygen species–generating enzyme NOX4 and the proapoptotic proteins PUMA and BIM in mice§

Authors

  • Ji Hoon Yu,

    1. Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD
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  • Bing-Mei Zhu,

    1. Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing, China
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  • Gregory Riedlinger,

    1. Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD
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  • Keunsoo Kang,

    1. Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD
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  • Lothar Hennighausen

    Corresponding author
    1. Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD
    2. Department of Nanobiomedical Science and WCU Research Center of Nanobiomedical Science, Dankook University, Cheonan, Chungnam, Republic of Korea
    • Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 8 Center Drive, Room 101, Bethesda, MD 20892-0822, fax: 301-480-7312

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    • fax: 301-480-7312


  • Potential conflict of interest: Nothing to report.

  • Supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases and in part by the World Class University Program, Ministry of Education, Science and Technology, through the National Research Foundation of Korea (grant R31-10069).

  • §

    L. H. is an adjunct member of the Department of Nanobiomedical Science and WCU Research Center for Nanobiomedical Science.

Abstract

Loss of signal transducer and activator of transcription 5 (STAT5) from liver tissue results in steatosis and enhanced cell proliferation. This study demonstrates that liver-specific Stat5-null mice develop severe hepatic steatosis as well as hepatocellular carcinomas at 17 months of age, even in the absence of chemical insults. To understand STAT5′s role as a tumor suppressor, we identified and investigated new STAT5 target genes. Expression of Nox4, the gene encoding the reactive oxygen species (ROS)-generating enzyme NOX4, was induced by growth hormone through STAT5. In addition, the genes encoding the proapoptotic proteins PUMA and BIM were induced by growth hormone through STAT5, which bound to GAS motifs in the promoter regions of all three genes. We further show that STAT5-induced activation of Puma and Bim was dependent on NOX4. Treatment of mice with transforming growth factor-β, an inducer of apoptosis, resulted in cleaved caspase-3 in control but not in liver-specific Stat5-null mice. This study demonstrates for the first time that cytokines through STAT5 regulate the expression of the ROS-generating enzyme NOX4 and key proapoptotic proteins. Conclusion: STAT5 harnesses several distinct signaling pathways in the liver and thereby functions as a tumor suppressor. Besides suppressing the activation of STAT3, STAT5 induces the expression of proapoptotic genes and the production of ROS. (HEPATOLOGY 2012;56:2375–2386)

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