Jones W Keith, Brown Maria, Wilhide Michael, He Suiwen, Ren Xiaoping
Department of Pharmacology and Cell Biophysics, University of Cincinnati, Cincinnati, OH 45267, USA.
Cardiovasc Toxicol. 2005;5(2):183-202. doi: 10.1385/ct:5:2:183.
The transcription factor NF-kappaB regulates a wide variety of biological effects in diverse cell types and organs, particularly stress and adaptive responses. Recently, it has become recognized that NF-kappaB and its upstream regulator tumor necrosis factor (TNF)-alpha regulate specific antithetical effects. For instance, in the heart, NF-kappaB has been found to be required for development of late preconditioning against myocardial infarction and yet is critically involved in mediating cell death after ischemia/reperfusion injury. There remains a bias that NF-kappaB is a "general" transcription factor that is activated by a plethora of stimuli, including neurohormonal, pathophysiological, and stress stimuli, and affects regulation of numerous downstream genes. The question has become, how can such a "general" transcription factor be critically involved in mediating specific effects? An emerging hypothesis is that NF-kappaB is part of a complicated signaling network or web, and that different combinatorial interactions between various activated signaling pathway components produce specific outcomes. This idea is supported by the large number of interactions discovered in the past 14 years between NF-kappaB and other signaling pathways at multiple levels. Notwithstanding the complexities of signal-induced activation of NF-kappaB, since it is a transcription factor, specific effects of NF-kappaB activation must be underlain by the activation and/or suppression of distinct subsets of NF-kappaB-dependent genes. At this level, selectivity is conferred by the expression of specific NF-kappaB subunits, their post translational modifications, and by combinatorial interactions between NF-kappaB and other transcription factors and coactivators that form specific enhanceosome complexes in association with particular promoters. These enhanceosome complexes represent another level of signaling integration whereby the activities of multiple upstream pathways converge to impress a distinct pattern of gene expression upon the NF-kappaB-dependent transcriptional network. Understanding how the overall cellular signaling network translates NF-kappaB activation into the regulation of specific subsets of NF-kappaB-dependent genes will lead to a mechanistic understanding of how NF-kappaB mediates diverse and paradoxical biological effects.
转录因子核因子-κB（NF-κB）在多种细胞类型和器官中调节广泛的生物学效应，尤其是应激和适应性反应。最近，人们已经认识到NF-κB及其上游调节因子肿瘤坏死因子（TNF）-α调节特定的对立效应。例如，在心脏中，已发现NF-κB是晚期心肌梗死预处理发展所必需的，但在介导缺血/再灌注损伤后的细胞死亡中也起关键作用。仍然存在一种偏见，即NF-κB是一种“通用”转录因子，可被大量刺激激活，包括神经激素、病理生理和应激刺激，并影响众多下游基因的调控。问题在于，这样一种“通用”转录因子如何能在介导特定效应中起关键作用？一个新出现的假说是，NF-κB是复杂信号网络或信号网的一部分，并且各种激活的信号通路成分之间不同的组合相互作用产生特定的结果。在过去14年中在多个水平上发现的NF-κB与其他信号通路之间的大量相互作用支持了这一观点。尽管信号诱导的NF-κB激活很复杂，但由于它是一种转录因子，NF-κB激活的特定效应必定由NF-κB依赖性基因不同亚群的激活和/或抑制所决定。在这个层面上，选择性是由特定NF-κB亚基的表达、它们的翻译后修饰以及NF-κB与其他转录因子和共激活因子之间的组合相互作用赋予的，这些因子与特定启动子结合形成特定的增强体复合物。这些增强体复合物代表了信号整合的另一个层面，通过它多个上游通路的活性汇聚在一起，在NF-κB依赖性转录网络上留下独特的基因表达模式。了解整个细胞信号网络如何将NF-κB激活转化为对NF-κB依赖性基因特定亚群的调控，将有助于从机制上理解NF-κB如何介导多样且矛盾的生物学效应。
