NF-κB and JNK -: An intricate affair
NF-κB and JNK -: An intricate affair
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DOI：
10.4161/cc.3.12.1321
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发表时间：
2004-12-01
期刊：
影响因子：
4.3
通讯作者：
Franzoso, G
中科院分区：
文献类型：
--
作者：
Bubici, C;Papa, S;Franzoso, G
核因子-kappaB/Rel转录因子阻断肿瘤坏死因子α诱导的细胞凋亡或程序性细胞死亡(PCD)。核因子-kappaB的抗凋亡活性对免疫、淋巴细胞发育、肿瘤发生和癌症化疗耐药也是至关重要的。对于肿瘤坏死因子α，核因子-kappaB介导的细胞凋亡抑制涉及c-Jun-N末端激酶(JNK)级联反应的抑制。核因子-kappaB的这种抑制活性依赖于JNK级联的阻断剂的转录上调，如caspase抑制剂XIAP、锌指蛋白A20和MKK7/JNKK2激酶Gadd45β/Myd118的抑制剂。此外，核因子-kappaB可抑制肿瘤坏死因子α诱导的活性氧自由基(ROS)的积累，这种抗氧化作用也是抑制肿瘤坏死因子α诱导的JNK活化的关键。核因子-kappaB对ROS的抑制是通过铁蛋白重链(FHC)-细胞中主要的铁储存机制-以及可能通过线粒体酶Mn++超氧化物歧化酶(Mn-SOD)介导的。因此，FHC和Mn-SOD的诱导是核因子-kappaB控制促凋亡JNK信号的另一种间接途径。这些发现确定了抗炎和抗癌治疗的潜在新靶点。
NF-kappaB/Rel transcription factors block apoptosis or programmed cell death (PCD) induced by tumor necrosis factor (TNF)alpha. The antiapoptotic activity of NF-kappaB is also crucial for immunity, lymphocyte development, tumorigenesis, and cancer chemoresistance. With respect to TNFalpha, the NF-kappaB-mediated suppression of apoptosis involves inhibition of the c-Jun-N-terminal kinase (JNK) cascade. This inhibitory activity of NF-kappaB depends upon transcriptional upregulation of blockers of the JNK cascade such as the caspase inhibitor XIAP, the zinc-finger protein A20, and the inhibitor of the MKK7/JNKK2 kinase Gadd45beta/Myd118. Moreover, NF-kappaB blunts accumulation of reactive oxygen species (ROS) induced by TNFalpha, and this antioxidant effect of NF-kappaB is also critical for inhibition of TNFalpha-induced JNK activation. Suppression of ROS by NF-kappaB is mediated by Ferritin heavy chain (FHC)-the primary iron-storage mechanism in cells-and possibly, by the mitochondrial enzyme Mn++ superoxide dismutase (Mn-SOD). Thus, induction of FHC and Mn-SOD represents an additional, indirect means by which NF-kappaB controls proapoptotic JNK signaling. These findings identify potential new targets for anti-inflammatory and anti-cancer therapy.