Structure and function of a new STAT-induced STAT inhibitor

被引:1133
作者
Naka, T
Narazaki, M
Hirata, M
Matsumoto, T
Minamoto, S
Aono, A
Nishimoto, N
Kajita, T
Taga, T
Yoshizaki, K
Akira, S
Kishimoto, T
机构
[1] OSAKA UNIV,SCH MED,DEPT MED 3,SUITA,OSAKA 565,JAPAN
[2] INT REAGENTS CORP,CTR RES & DEV,NISHI KU,KOBE 65122,JAPAN
[3] TOKYO MED & DENT UNIV,MED RES INST,DEPT MOL CELL BIOL,CHIYODA KU,TOKYO 101,JAPAN
[4] HYOGO MED UNIV,DEPT BIOCHEM,NISHINOMIYA,HYOGO 663,JAPAN
[5] OSAKA UNIV,SCH HLTH & SPORTS SCI,SUITA,OSAKA 565,JAPAN
关键词
D O I
10.1038/43219
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 inside(1-3). 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 4-7). 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.
引用
收藏
页码:924 / 929
页数:6
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