Induction of gadd45β by NF-κB downregulates pro-apoptotic JNK signalling
Induction of gadd45β by NF-κB downregulates pro-apoptotic JNK signalling
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DOI：
10.1038/35104560
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发表时间：
2001-11-15
期刊：
影响因子：
64.8
通讯作者：
Franzoso, G
中科院分区：
文献类型：
--
作者：
De Smaele, E;Zazzeroni, F;Franzoso, G
除了协调免疫和炎症反应外，NF-kappaB/Rel 转录因子还控制细胞存活(1)。通常，NF-kappaB 二聚体通过与抑制性 I kappaB 蛋白结合而隔离在细胞质中，并且可以被诱导 I kappa Bs 连续磷酸化和蛋白水解的信号快速激活 (1)。 NF-kappaB 的激活可通过多种触发因素来拮抗细胞凋亡或程序性细胞死亡，包括肿瘤坏死因子 (TNF) 受体 (2) 等“死亡受体”的配体结合。 NF-kappaB 的抗凋亡活性对于肿瘤发生以及癌症的化学和放射抗性也至关重要(2)。 NF-kappaB 的细胞保护涉及促生存基因的激活 (2)；然而，其基础仍然知之甚少。在此，我们报告 NF-kappaB 复合物下调 c-Jun 氨基末端激酶 (JNK) 级联 (3)，从而在 NF-kappaB 和 JNK 通路之间建立联系。这种联系涉及 gadd45 beta /myd118 的转录上调（参考文献 4），从而下调 TNF 受体 (TNF-R) 诱导的 JNK 信号传导。这种 NF-κB 依赖性 JNK 通路抑制对于细胞死亡的控制至关重要。我们的研究结果定义了由 NF-kappaB 复合物介导的保护机制，并确定了 JNK 持续激活在 TNF-α 凋亡反应中的作用。
In addition to coordinating immune and inflammatory responses, NF-kappaB/Rel transcription factors control cell survival(1). Normally, NF-kappaB dimers are sequestered in the cytoplasm by binding to inhibitory I kappaB proteins, and can be activated rapidly by signals that induce the sequential phosphorylation and proteolysis of I kappa Bs(1). Activation of NF-kappaB antagonizes apoptosis or programmed cell death by numerous triggers, including the ligand engagement of 'death receptors' such as tumour-necrosis factor (TNF) receptor(2). The anti-apoptotic activity of NF-kappaB is also crucial to oncogenesis and to chemo- and radio-resistance in cancer(2). Cytoprotection by NF-kappaB involves the activation of pro-survival genes(2); however, its basis remains poorly understood. Here we report that NF-kappaB complexes downregulate the c-Jun aminoterminal kinase (JNK) cascade(3), thus establishing a link between the NF-kappaB and the JNK pathways. This link involves the transcriptional upregulation of gadd45 beta /myd118 (ref. 4), which downregulates JNK signalling induced by the TNF receptor (TNF-R). This NF-kappaB-dependent inhibition of the JNK pathway is central to the control of cell death. Our findings define a protective mechanism that is mediated by NF-kappaB complexes and establish a role for the persistent activation of JNK in the apoptotic response to TNF-alpha.