Disruption of the c-JUN-JNK complex by a cell-permeable peptide containing the c-JUN δ domain induces apoptosis and affects a distinct set of interleukin-1-induced inflammatory genes
Disruption of the c-JUN-JNK complex by a cell-permeable peptide containing the c-JUN δ domain induces apoptosis and affects a distinct set of interleukin-1-induced inflammatory genes
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DOI：
10.1074/jbc.m304058200
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发表时间：
2003-10-10
影响因子：
4.8
通讯作者：
Kracht, M
中科院分区：
文献类型：
--
作者：
Holzberg, D;Knight, CG;Kracht, M
转录因子激活蛋白(AP)-1在增殖、细胞死亡和免疫应答中起着至关重要的作用。c-JUN是AP-1的重要组成部分，但迄今为止只有很少的c-JUN应答基因被鉴定出来。c-JUN的活性由jun - nh2末端蛋白激酶（JNK）家族的nh2末端磷酸化（JNP）控制。JNK在体外和体内与c-JUN形成稳定的复合物。我们通过含有人类c-JUN的jnk结合（delta）结构域的细胞渗透性肽靶向这种相互作用。该肽强烈且特异性地诱导HeLa肿瘤细胞凋亡，这与抑制血清诱导的c-JUN磷酸化和上调细胞周期抑制剂p21（cip/waf）是平行的。将c-JUN肽应用于白细胞介素(IL)-1刺激的人原代成纤维细胞，可上调COX-2、MnSOD、IkappaBalpha和MAIL 4个基因，下调CCL8、mPGES、SAA1、hIAP-1、hIAP-2、pent(r)axin-3、CXCL10、IL-1 β、ICAM-1和CCL2 10个基因。只有一小部分基因，即pent(r)axin-3、CXCL10、ICAM-1和il -1 β被c-JUN肽和JNK抑制剂SP600125抑制。因此，通过使用小干扰RNA抑制内源性c-JUN的额外实验，我们首次确定了三组不同的炎症基因，其il -1诱导的表达依赖于c-JUN、JNK或两者。这些结果进一步揭示了c- jun -JNK介导的基因调控的复杂性，也强调了分析JNK下游信号通路特异性靶向增殖性疾病或炎症反应的潜在用途。
The transcription factor activator protein (AP)-1 plays crucial roles in proliferation, cell death, and the immune response. c-JUN is an important component of AP-1, but only very few c-JUN response genes have been identified to date. Activity of c-JUN is controlled by NH2-terminal phosphorylation (JNP) of its transactivation domain by a family of JUN-NH2-terminal protein kinases (JNK). JNK form a stable complex with c-JUN in vitro and in vivo. We have targeted this interaction by means of a cell-permeable peptide containing the JNK-binding (delta) domain of human c-JUN. This peptide strongly and specifically induced apoptosis in HeLa tumor cells, which was paralleled by inhibition of seruminduced c-JUN phosphorylation and up-regulation of the cell cycle inhibitor p21(cip/waf). Application of the c-JUN peptide to interleukin (IL)-1-stimulated human primary fibroblasts resulted in up-regulation of four genes, namely COX-2, MnSOD, IkappaBalpha, and MAIL and down-regulation of 10 genes, namely CCL8, mPGES, SAA1, hIAP-1, hIAP-2, pent(r)axin-3, CXCL10, IL-1beta, ICAM-1, and CCL2. Only a small group of genes, namely pent(r)axin-3, CXCL10, ICAM-1, and IL-1beta, was inhibited by both the c-JUN peptide and the JNK inhibitor SP600125. Thereby, and by additional experiments using small interfering RNA to suppress endogenous c-JUN we identify for the first time three distinct groups of inflammatory genes whose IL-1-induced expression depends on c-JUN, on JNK, or on both. These results shed further light on the complexity of c-JUN-JNK-mediated gene regulation and also highlight the potential use of dissecting signaling downstream from JNK to specifically target proliferative diseases or the inflammatory response.