Functional involvement of Daxx in gp130-mediated cell growth and survival in BaF3 cells

Authors

  • Ryuta Muromoto,

    1. Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12 Nishi-6, Kita-Ku, Sapporo, Japan
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  • Makoto Kuroda,

    1. Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12 Nishi-6, Kita-Ku, Sapporo, Japan
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  • Sumihito Togi,

    1. Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12 Nishi-6, Kita-Ku, Sapporo, Japan
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  • Yuichi Sekine,

    1. Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12 Nishi-6, Kita-Ku, Sapporo, Japan
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  • Asuka Nanbo,

    1. Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12 Nishi-6, Kita-Ku, Sapporo, Japan
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  • Kazuya Shimoda,

    1. Department of Internal Medicine II, Faculty of Medicine, University of Miyazaki, Kihara, Kiyotake, Miyazaki, Japan
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  • Kenji Oritani,

    1. Department of Hematology and Oncology, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka, Japan
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  • Tadashi Matsuda

    Corresponding author
    1. Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12 Nishi-6, Kita-Ku, Sapporo, Japan
    • Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12 Nishi-6, Kita-Ku, Sapporo, 060-0812, Japan Fax: +81-11-706-4990
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Abstract

Death domain-associated protein (Daxx) is a multifunctional protein that modulates both cell death and transcription. Several recent studies have indicated that Daxx is a mediator of lymphocyte death and/or growth suppression, although the detailed mechanism is unclear. Previously, we reported that Daxx suppresses IL-6 family cytokine-induced gene expression by interacting with STAT3. STAT3 is important for the growth and survival of lymphocytes; therefore, we here examined the role of Daxx in the gp130/STAT3-dependent cell growth/survival signals. We found that Daxx suppresses the gp130/STAT3-dependent cell growth and that Daxx endogenously interacts with STAT3 and inhibits the DNA-binding activity of STAT3. Moreover, small-interfering RNA-mediated knockdown of Daxx enhanced the expression of STAT3-target genes and accelerated the STAT3-mediated cell cycle progression. In addition, knockdown of Daxx-attenuated lactate dehydrogenase leakage from cells, indicating that Daxx positively regulates cell death during gp130/STAT3-mediated cell proliferation. Notably, Daxx specifically suppressed the levels of Bcl2 mRNA and protein, even in cytokine-unstimulated cells, indicating that Daxx regulates Bcl2 expression independently of activated STAT3. These results suggest that Daxx suppresses gp130-mediated cell growth and survival by two independent mechanisms: inhibition of STAT3-induced transcription and down-regulation of Bcl2 expression.

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