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Structure and function of a new STAT-induced STAT inhibitor

Author

Listed:
  • Tetsuji Naka

    (Yamada-Oka)

  • Masashi Narazaki

    (Yamada-Oka)

  • Moritoshi Hirata

    (Yamada-Oka)

  • Tomoshige Matsumoto

    (Yamada-Oka)

  • Seijiro Minamoto

    (Yamada-Oka)

  • Atsufumi Aono

    (Yamada-Oka)

  • Norihiro Nishimoto

    (Medical Science I, School of Health and Sports Sciences, Yamada-Oka)

  • Tadahiro Kajita

    (‡Research and Development Center, International Reagents Corporation, 1-2, 1-Chome, Murotani
    Correspondence and requests for materials should be addressed to T.K.)

  • Tetsuya Taga

    (Medical Research Institute, Tokyo Medical and Dental University. 2-3-10, Kanda-Surugadai)

  • Kazuyuki Yoshizaki

    (Medical Science I, School of Health and Sports Sciences, Yamada-Oka)

  • Shizuo Akira

    (1-1, Mukogawa)

  • Tadamitsu Kishimoto

    (Yamada-Oka)

Abstract

The signalling pathway that comprises JAK kinases and STAT proteins (for signal transducer and activator of transcription) is important for relaying signals from various cytokines outside the cell to the inside1,2,3. The feedback mechanism responsible for switching off the cytokine signal has not been elucidated. We now report the cloning and characterization of an inhibitor of STAT activation which we name SSI-1 (for STAT-induced STAT inhibitor-1). We found that SSI-1 messenger RNA was induced by the cytokines interleukins 4 and 6 (IL-4, IL-6), leukaemia-inhibitory factor (LIF), and granulocyte colony-stimulating factor (G-CSF). Stimulation by IL-6 or LIF of murine myeloid leukaemia cells (M1 cells) induced SSI-1 mRNA expression which was blocked by transfection of a dominant-negative mutant of Stat3, indicating that the SSI-1 gene is a target of Stat3 (refs 4, 5, 6, 7). Forced overexpression of SSI-1 complementary DNA interfered with IL-6- and LIF-mediated apoptosis and macrophage differentiation of M1 cells, as well as IL-6 induced tyrosine-phosphorylation of a receptor glycoprotein component, gp130, and of Stat3. When SSI-1 is overexpressed in COS7 cells, it can associate with the kinases Jak2 and Tyk2. These findings indicate that SSI-1 is responsible for negative-feedback regulation of the JAK–STAT pathway induced by cytokine stimulation.

Suggested Citation

  • Tetsuji Naka & Masashi Narazaki & Moritoshi Hirata & Tomoshige Matsumoto & Seijiro Minamoto & Atsufumi Aono & Norihiro Nishimoto & Tadahiro Kajita & Tetsuya Taga & Kazuyuki Yoshizaki & Shizuo Akira & , 1997. "Structure and function of a new STAT-induced STAT inhibitor," Nature, Nature, vol. 387(6636), pages 924-929, June.
    • Handle: RePEc:nat:nature:v:387:y:1997:i:6636:d:10.1038_43219
    DOI: 10.1038/43219
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    Cited by:

    1. Haoxi Chai & Harianto Tjong & Peng Li & Wei Liao & Ping Wang & Chee Hong Wong & Chew Yee Ngan & Warren J. Leonard & Chia-Lin Wei & Yijun Ruan, 2023. "ChIATAC is an efficient strategy for multi-omics mapping of 3D epigenomes from low-cell inputs," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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