Role of the JNK/c-Jun/AP-1 signaling pathway in galectin-1-induced T-cell death.
Role of the JNK/c-Jun/AP-1 signaling pathway in galectin-1-induced T-cell death.
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DOI：
10.1038/cddis.2010.1
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发表时间：
2010
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
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半乳糖凝集素-1（Galectin-1，gal-1）是一种内源性β-半乳糖苷结合蛋白，通过死亡受体和线粒体凋亡途径等多种机制触发T细胞死亡。在这项研究中，我们首先表明，gal-1启动激活c-Jun N-末端激酶（JNK），促分裂原活化蛋白激酶激酶4（MKK 4），和MKK 7作为上游JNK激活剂在Jurkat T细胞。用鞘磷脂酶抑制剂（20 μM地昔帕明，20 μM丙咪嗪）、蛋白激酶C-δ（PKCδ）抑制剂rottlerin（10 μM）和特异性PKCθ假底物抑制剂（30 μM）抑制JNK活化表明，神经酰胺和PKCδ和PKCθ的磷酸化介导gal-1诱导的JNK活化。在JNK下游，我们观察到c-Jun磷酸化增加，激活蛋白-1（AP-1）荧光素酶报告增强，以及AP-1/DNA结合响应于gal-1。JNK/c-Jun/AP-1通路在gal-1诱导的细胞凋亡中的关键作用通过SP 600125（20 μM）抑制JNK或姜黄素（2 μM）抑制AP-1活化后DNA片段减少来证明。Gal-1不能诱导CD 3缺陷型Jurkat 31-13细胞中AP-1活化和DNA片段化。在Jurkat E6.1细胞中，gal-1诱导了促凋亡信号模式，如抗凋亡Bcl-2表达降低、促凋亡Bad诱导和Bcl-2磷酸化增加所示。这些结果提供了证据表明JNK/c-Jun/AP-1通路在响应gal-1刺激的T细胞死亡调节中起关键作用。
Galectin-1 (gal-1), an endogenous β-galactoside-binding protein, triggers T-cell death through several mechanisms including the death receptor and the mitochondrial apoptotic pathway. In this study we first show that gal-1 initiates the activation of c-Jun N-terminal kinase (JNK), mitogen-activated protein kinase kinase 4 (MKK4), and MKK7 as upstream JNK activators in Jurkat T cells. Inhibition of JNK activation with sphingomyelinase inhibitors (20 μM desipramine, 20 μM imipramine), with the protein kinase C-δ (PKCδ) inhibitor rottlerin (10 μM), and with the specific PKCθ pseudosubstrate inhibitor (30 μM) indicates that ceramide and phosphorylation by PKCδ and PKCθ mediate gal-1-induced JNK activation. Downstream of JNK, we observed increased phosphorylation of c-Jun, enhanced activating protein-1 (AP-1) luciferase reporter, and AP-1/DNA-binding in response to gal-1. The pivotal role of the JNK/c-Jun/AP-1 pathway for gal-1-induced apoptosis was documented by reduction of DNA fragmentation after inhibition JNK by SP600125 (20 μM) or inhibition of AP-1 activation by curcumin (2 μM). Gal-1 failed to induce AP-1 activation and DNA fragmentation in CD3-deficient Jurkat 31-13 cells. In Jurkat E6.1 cells gal-1 induced a proapoptotic signal pattern as indicated by decreased antiapoptotic Bcl-2 expression, induction of proapoptotic Bad, and increased Bcl-2 phosphorylation. The results provide evidence that the JNK/c-Jun/AP-1 pathway plays a key role for T-cell death regulation in response to gal-1 stimulation.
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影响因子：
4.4
作者：
Chung, CD;Patel, VP;Miceli, MC
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DOI：
10.1073/pnas.88.12.5292
发表时间：
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