Natoli Gioacchino, Chiocca Susanna
Department of Experimental Oncology, European Institute of Oncology (IEO), IFOM-IEO Campus, Via Adamello 16, 20139 Milan, Italy.
Sci Signal. 2008 Jan 8;1(1):pe1. doi: 10.1126/stke.11pe1.
Transcriptional control of the vast majority of genes involved in the inflammatory response requires the nuclear factor kappaB (NF-kappaB) family of transcription factors. Stimulation and termination of NF-kappaB activity are subject to stringent spatiotemporal control. According to the classical model of NF-kappaB regulation, both activation and termination mechanisms are centered on inhibitor of NF-kappaB (IkappaB) proteins. Whereas activation of NF-kappaB requires degradation of the IkappaBs, the main mechanism responsible for termination of NF-kappaB activity is the resynthesis of a specific IkappaB, IkappaBalpha, which sequesters NF-kappaB dimers in the nucleus and translocates them to the cytoplasm in an inactive form. Studies now show that an additional mechanism that is required to prevent the uncontrolled activity of NF-kappaB proteins is their nuclear degradation. At least two E3 ubiquitin ligases, one of which seems to be essential for control of nuclear NF-kappaB p65 (also known as RelA) in myeloid cells, have been identified. Moreover, additional evidence indicates that individual NF-kappaB dimers with particular activating or repressive properties may be differentially controlled by nuclear degradation, thus paving the way for the exploitation of NF-kappaB degradation pathways for therapeutic purposes.
绝大多数参与炎症反应的基因的转录调控需要转录因子核因子κB（NF-κB）家族。NF-κB活性的激活和终止受到严格的时空控制。根据NF-κB调控的经典模型，激活和终止机制都以NF-κB抑制蛋白（IkappaB）为中心。NF-κB的激活需要IkappaB的降解，而负责NF-κB活性终止的主要机制是特定的IkappaB即IkappaBα的重新合成，它在细胞核中隔离NF-κB二聚体并将它们以无活性形式转运到细胞质中。现在的研究表明，防止NF-κB蛋白不受控制的活性所需的另一种机制是它们在细胞核中的降解。已经鉴定出至少两种E3泛素连接酶，其中一种似乎对髓样细胞中细胞核NF-κB p65（也称为RelA）的控制至关重要。此外，更多证据表明，具有特定激活或抑制特性的单个NF-κB二聚体可能受到细胞核降解的差异控制，从而为利用NF-κB降解途径用于治疗目的铺平了道路。
