NF-κB信号通路.doc

.NF-B信号通路NF-B是属于Rel家族的转录因子，参与调节与机体免疫、炎症反应、细胞分化有关的基因转录。哺乳动物细胞中有五种NF-B/Rel都具有Rel同源区，能形成同或异二聚体，启动不同的基因转录。静息状态下，NF-B二聚体与抑制蛋白IB结合成三聚体而被隐蔽于细胞质，胞外刺激可激活IB的泛素化降解途径，而使NFB二聚体进入胞核，调节基因转录。Mechanism of NF-B action. In this figure, the NF-B heterodimer between Rel and p50 proteins is used as an example. While in an inactivated state, NF-B is located in the cytosol complexed with the inhibitory proteinIB. Through the intermediacy of integral membrane receptors, a variety of extracellular signals can activate the enzymeIB kinase(IKK). IKK, in turn, phosphorylates the IB protein, which results inubiquitination, dissociation of IB from NF-B, and eventual degradation of IB by theproteosome. The activated NF-B is then translocated into the nucleus where it binds to specific sequences of DNA called response elements (RE). The DNA/NF-B complex then recruits other proteins such ascoactivatorsandRNA polymerase, which transcribe downstream DNA into mRNA, which, in turn, is translated into protein, which results in a change of cell function.Schematic diagram of NF-B protein structure. There are two structural classes of NF-B proteins: class I (top) and class II (bottom). Both classes of proteins contain aN-terminalDNA-binding domain(DBD), which also serves as a dimerization interface to other NF-B transcription factors and, in addition, binds to the inhibitoryIBprotein. TheC-terminusof class I proteins contains a number ofankyrin repeatsand hastransrepressionactivity. In contrast, the C-terminus of class II proteins has atransactivationfunction.NF-kB信号通路与癌症NF-kB具有明显的抑制细胞凋亡的功能，与肿瘤的发生、生长和转移等多个过程密切相关。在人类肿瘤尤其是淋巴系统的恶性肿瘤中，常可发现NF-kB家族基因的突变。NF-kB家族与癌症相关性的第一个线索是c-Rel基因的发现，它是禽类逆转录病毒癌基因v-Rel在细胞内的同源基因。该病毒在鸡体中造成多种造血细胞恶性转化，引起淋巴癌的发生。由于NF-kB的下游基因包括CyclinD1和c-Myc，因此NF-kB的持续激活会刺激细胞生长，导致细胞增殖失控。NF-kB在很多癌细胞中表达异常，如在75的乳腺癌样品中NF-kB2的表达比邻近的正常组织高很多倍。肿瘤细胞迁移并浸润到周围组织是肿瘤扩散和转移的前提条件。NF-kB对肿瘤转移具有明显的促进作用，它能促进肿瘤转移相关基因ICAM-1、VCAM-1、MMP-9等的表达。NF-kB还能诱导血管内皮生长因子VEGF的表达，促进血管形成。此外，NF-kB还能通过调节COX2等基因的表达来促进肿瘤生长。NF-kB与肿瘤治疗息息相关。IFN-a、IFN-b、TNF-a、IL-2、G-CSF、GM-CSF和EPO是迄今为止被批准用于临床肿瘤治疗的几种细胞因子，其中前6种生长因子已被证实与NF-kB的信号通路有关。目前，国内外主要以NF-kB为靶点，使用抗氧化剂抑制NF-kB活性以及针对p65和p50设计小分子干扰RNA（siRNA）抑制NF-kB合成等方法作为癌症的治疗策略，而且在动物实验及细胞培养中取得不同程度的疗效，但是离临床应用还有很大距离。由于TNF-a具有很好的抗肿瘤作用和多种免疫调节功能，许多国家开展了用TNF治疗癌症的临床研究。动物实验和临床实验均表明，TNF-a对某些肿瘤具有明显的抑制作用，但是由于不能很好地区分癌细胞和正常细胞，使用TNF-a后副作用较大，这为其大规模临床应