A novel c-Jun-dependent signal transduction pathway necessary for the transcriptional activation of interferon γ response genes
A novel c-Jun-dependent signal transduction pathway necessary for the transcriptional activation of interferon γ response genes
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DOI：
10.1074/jbc.m607674200
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发表时间：
2007-01-12
影响因子：
4.8
通讯作者：
Johnstone, Ricky W.
中科院分区：
文献类型：
--
作者：
Gough, Daniel J.;Sabapathy, Kanaga;Johnstone, Ricky W.
干扰素γ（IFN γ）的生物学效应由干扰素刺激基因（ISG）介导，其中许多基因在Janus激酶（JAK）/信号转导子和转录激活子1（STAT 1）信号传导的下游被激活。在此，我们已经表明，IFN γ快速激活AP-1 DNA结合，这需要c-Jun，但不依赖于JAK 1和STAT 1。IFN γ诱导的c-Jun磷酸化和AP-1 DNA结合需要MEK 1/2和ERK 1/2信号通路，而JNK 1/2和p38丝裂原活化蛋白激酶通路则不需要。在IFN γ处理的c-Jun（-/-）细胞中，包括ifi-205和iNOS在内的几种ISG的诱导受损，但其他ISG，如IP-10和SOCS 3，不受影响，染色质免疫沉淀证明，在IFN γ处理后，c-Jun与iNOS启动子结合。因此，IFN γ诱导ERK促分裂原活化蛋白激酶途径的JAK 1和STAT 1非依赖性活化、c-Jun的磷酸化和AP-1 DNA结合的活化，这对于诱导ISG的子集是重要的。这代表了由IFN γ诱导的新的信号转导途径，其与常规JAK/STAT信号传导平行进行以激活ISG。
The biological effects of interferon gamma(IFN gamma) are mediated by interferon-stimulated genes (ISGs), many of which are activated downstream of Janus kinase (JAK)/signal transducer and activator of transcription 1 (STAT1) signaling. Herein we have shown that IFN gamma rapidly activated AP-1 DNA binding that required c-Jun but was independent of JAK1 and STAT1. IFN gamma-induced c-Jun phosphorylation and AP-1 DNA binding required the MEK1/2 and ERK1/2 signaling pathways, whereas the JNK1/2 and p38 mitogen-activated protein kinase pathways were dispensable. The induction of several ISGs, including ifi-205 and iNOS, was impaired in IFN gamma-treated c-Jun(-/-) cells, but others, such as IP-10 and SOCS3, were unaffected, and chromatin immunoprecipitation demonstrated that c-Jun binds to the iNOS promoter following treatment with IFN gamma. Thus, IFN gamma induced JAK1- and STAT1-independent activation of the ERK mitogen-activated protein kinase pathway, phosphorylation of c-Jun, and activation of AP-1 DNA binding, which are important for the induction of a subset of ISGs. This represents a novel signal transduction pathway induced by IFN gamma that proceeds in parallel with conventional JAK/STAT signaling to activate ISGs.