De Smaele E, Zazzeroni F, Papa S, Nguyen D U, Jin R, Jones J, Cong R, Franzoso G
The Gwen Knapp Center for Lupus and Immunology research, The University of Chicago, Illinois 60637, USA.
Nature. 2001 Nov 15;414(6861):308-13. doi: 10.1038/35104560.
In addition to coordinating immune and inflammatory responses, NF-kappaB/Rel transcription factors control cell survival. Normally, NF-kappaB dimers are sequestered in the cytoplasm by binding to inhibitory IkappaB proteins, and can be activated rapidly by signals that induce the sequential phosphorylation and proteolysis of IkappaBs. 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. The anti-apoptotic activity of NF-kappaB is also crucial to oncogenesis and to chemo- and radio-resistance in cancer. Cytoprotection by NF-kappaB involves the activation of pro-survival genes; however, its basis remains poorly understood. Here we report that NF-kappaB complexes downregulate the c-Jun amino-terminal kinase (JNK) cascade, thus establishing a link between the NF-kappaB and the JNK pathways. This link involves the transcriptional upregulation of gadd45beta/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.
除了协调免疫和炎症反应外，核因子κB/Rel转录因子还控制细胞存活。正常情况下，核因子κB二聚体通过与抑制性IκB蛋白结合而被隔离在细胞质中，并可被诱导IκB蛋白顺序磷酸化和蛋白水解的信号迅速激活。核因子κB的激活可通过多种触发因素拮抗凋亡或程序性细胞死亡，包括肿瘤坏死因子（TNF）受体等“死亡受体”的配体结合。核因子κB的抗凋亡活性对肿瘤发生以及癌症中的化疗和放疗抗性也至关重要。核因子κB的细胞保护作用涉及促存活基因的激活；然而，其机制仍知之甚少。我们在此报告，核因子κB复合物下调c-Jun氨基末端激酶（JNK）级联反应，从而在核因子κB和JNK途径之间建立联系。这种联系涉及gadd45β/myd118（参考文献4）的转录上调，它下调由TNF受体（TNF-R）诱导的JNK信号传导。核因子κB依赖的对JNK途径的抑制对于细胞死亡的控制至关重要。我们的研究结果确定了一种由核因子κB复合物介导的保护机制，并确定了JNK持续激活在对TNF-α的凋亡反应中的作用。
