Alternative activation of STAT1 and STAT3 in response to interferon-γ
Alternative activation of STAT1 and STAT3 in response to interferon-γ
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DOI：
10.1074/jbc.m406413200
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发表时间：
2004-10-01
影响因子：
4.8
通讯作者：
Stark, GR
中科院分区：
文献类型：
--
作者：
Qing, YL;Stark, GR
干扰素-γ(IFNGamma)是一种多能细胞因子，其主要生物学效应是通过信号转导途径介导的，其中STAT1是主要和必需的转录因子。STAT3也可以被干扰素γ微弱地激活，但作为干扰素反应一部分的STAT3的激活机制和功能尚不清楚。在这里，我们发现在STAT1缺失的小鼠胚胎成纤维细胞中，STAT3的激活比在野生型细胞中要强得多，而且持续的时间更长。作为对IFNGamma的响应，SRC家族的激酶需要通过酪氨酸磷酸化来激活STAT3(而不是STAT1)，而受体结合的激酶JAK1和JAK2则需要激活这两个STATs。激活这两个STATs需要IFNGamma受体亚单位1(IFNGR1)的酪氨酸419，这表明STAT1和STAT3相互竞争相同的受体磷酸酪氨酸基序。在STAT1缺失的细胞中，激活的STAT3可以取代STAT1来驱动某些基因的转录，例如SOCS-3和c/ebpDelta，它们的启动子中都有伽马激活的序列基序。Ian Kerr实验室的工作表明，通常主要激活STAT3的gp130连接的白细胞介素6受体，当STAT3缺失时有效地激活STAT1(Costa-Pereira，A.P.，Tininini，S.，Strobl，B.，Alonzi，T.，Schlaak，J.F.，is‘harc，H.，Gesualdo，I.，Newman，S.J.，Kerr，I.M.，和Poli，V.(2002)proc。娜塔莉。阿卡德。SCI。美国99,8043-8047)。由于STAT1和STAT3具有相反的生物学效应(STAT3是癌基因，STAT1是肿瘤抑制因子)，这两个转录因子对IFNGamma或IL-6的相互激活表明，它们的相对丰度在不同的正常细胞类型、不同的条件下或在肿瘤中可能会对细胞对不同细胞因子的反应产生重大影响。
Interferon-gamma (IFNgamma) is a pluripotent cytokine whose major biological effects are mediated through a pathway in which STAT1 is the predominant and essential transcription factor. STAT3 can also be activated weakly by IFNgamma, but the mechanism of activation and function of STAT3 as a part of the interferon response are not known. Here we show that STAT3 activation is much stronger and more prolonged in STAT1-null mouse embryo fibroblasts than in wild-type cells. In response to IFNgamma, SRC-family kinases are required to activate STAT3 (but not STAT1) through tyrosine phosphorylation, whereas the receptor-bound kinases JAK1 and JAK2 are required to activate both STATs. Tyrosine 419 of the IFNgamma receptor subunit 1 (IFNGR1) is required to activate both STATs, suggesting that STAT1 and STAT3 compete with each other for the same receptor phosphotyrosine motif. Activated STAT3 can replace STAT1 in STAT1-null cells to drive the transcription of certain genes, for example, socs-3 and c/ebpdelta, which have gamma-activated sequence motifs in their promoters. Work from Ian Kerr's laboratory reveals that the gp130-linked interleukin-6 receptor, which usually activates STAT3 predominantly, activates STAT1 efficiently when STAT3 is absent (Costa-Pereira, A. P., Tininini, S., Strobl, B., Alonzi, T., Schlaak, J. F., Is'harc, H., Gesualdo, I., Newman, S. J., Kerr, I. M., and Poli, V. (2002) Proc. Natl. Acad. Sci. U.S.A. 99, 8043-8047). Because STAT1 and STAT3 have opposing biological effects (STAT3 is an oncogene, and STAT1 is a tumor suppressor), the reciprocal activation of these two transcription factors in response to IFNgamma or interleukin-6 suggests that their relative abundance, which may vary substantially in different normal cell types, under different conditions or in tumors is likely to have a major impact on how cells behave in response to different cytokines.