核因子-κB与细胞凋亡关系的研究进展

摘要

核因子-κB是一类具有多向转录调节作用的核蛋白因子, 存在于多种组织的多种细胞中, 具有广泛的生物学活性, 激活后参与许多基因的转录调控, 在感染、炎症反应、氧化应激、细胞增生、细胞凋亡等过程中发挥作用. 近年的研究表明NF-κB与细胞凋亡的关系密切, 其参与多种凋亡相关基因的转录调控, 在肿瘤的发生、发展过程中发挥重要作用. 许多高表达NF-κB的细胞表现出对放疗、化疗、细胞因子介导的凋亡的抵抗作用, 而现在又发现NF-κB具有促进细胞凋亡的作用.因而NF-κB与细胞凋亡存在双向调节关系: 既可抑制细胞凋亡, 也可促进细胞凋亡. 是抑制凋亡, 还是促进凋亡依赖于细胞类型和刺激因素的不同, 但具体机制还不十分清楚. 本文对其与细胞凋亡关系的研究作一综述, 同时也为进一步改善肿瘤的有效治疗提供理论基础.

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Corresponding author: N/A

Received: October 9, 2002
Revised: October 20, 2002
Accepted: November 13, 2002
Published online: October 15, 2003

Abstract

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Key Words: N/A

0 引言

细胞核因子-κB (nuclear factor kappa B, NF-κB)是一个多功能核转录因子, 最先发现在B淋巴细胞中, 其能与免疫球蛋白κ轻链基因增强子κB序列(GGGACTTTCC)特异结合, 故称之为核因子-κB. NF-κB具有广泛的生物学活性, 激活后参与许多基因的转录调控, 在感染、炎症反应、氧化应激、细胞增生、细胞凋亡等过程中发挥作用. 近年研究表明NF-κB与细胞凋亡的关系密切.

1 NF-κB/Rel蛋白家族的特性

目前已证实, NF-κB存在于多种组织的多种细胞中. 到目前为止, 在哺乳动物细胞中发现的NF-κB/Rel蛋白家族成员包括[1-8]: p52(亦称p49)、p50、p65/RleA、c-Rel、Rel B; 在果蝇细胞中发现两个成员: Dorsal和Dif. 他们以不同的二聚体存在于几乎所有的细胞中. 这些蛋白都有一个大约由300个氨基酸组成的氨基末端, 称为Rel同源区RHD (relhomology dimain)或NRD (NF-κB/Rel/Dorsal), 其中包含二聚体化部位、DNA结合部位及核定位序列NLS(nuclear localization sianal). 另外, 在p65/Rel A、c-Rel、Rel B、Dorsal和Dif的c-末端含有一个或多个反式激活区, 而在p49/p52和p50亚单位中则不存在[1]. 因此, 只有p52或p50与p65、c-Rel、Rel B、Dorsal和Dif形成的异二聚体才具有转录活性, p52、p50同源二聚体对转录起抑制作用[9,10]. 通常所指的NF-κB是p50/p65异源二聚体, 结构型表达的NF-κB活性异源二聚体只存在于少数细胞中, 在大多数细胞中, NF-κB二聚体与IκB单体耦联; 或Rel蛋白与p52未裂解前体p100、p50未裂前体p105结合成二聚体, 以无活性的形式存在于细胞质. 所有的IκB分子均含有3-7个锚蛋白(Ank)重复序列, 每个重复序列约33个氨基酸, 形成与RHD结合位点. 已克隆的IκB包括: p100、p105、IκB-α、IκB-β、IκB-ε、IκB-γ、IκBR和Bcl-3[11,12]. 最重要的是IκB-α和IκB-β, IκB-α基因的启动子中含有多个NFκB结合序列, NF-κB活化后可上调IκB-α的基因表达, 而IκB-α则不受NF-κB的反馈调节, 其降解后导致NF-κB持续活化. NF-κB是一类蛋白质, 具有和一些基因的启动子或增强子的特定核苷酸序列结合而启动靶基因转录的功能. 最常见的结合序列是5'-GGGRNTY(C/Y)C-3', 其中R = A或G, Y = C或T, N = 任何核苷酸[1]. 不同的NF-κB/Rel蛋白二聚体具有不同的结合序列, 且具有各自的特性. 不同的二聚体可识别细微不同的DNA靶目标, 从而使NF-κB得以调节不同的靶基因[13-20].

2 NF-κB的激活

多种细胞外刺激信号可激活NF-κB, 如细胞因子IL-1、TNF-α等、脂多糖、病毒、活性氧自由基、紫外线、双链RNA等[21-25]. 其激活机制是一个复杂的过程, 尚未完全阐明, 但至少需要两个步骤: (1) IκB从NF-κB复合体上解离降解, 暴露NF-κB的核定位序列; (2)NF-κB发生核易位并与特定的DNA序列结合, 其中蛋白磷酸化和蛋白水解是两个主要环节[26-29]. NF-κB的激活途径可分为主要途径和次要途径[30], 主要途径是在受外界刺激后早期即发挥作用, 次要途径是在受处界刺激后晚期才发挥作用[31]. 主要途径表现在细胞因子通过自分泌或旁分泌的方式作用于细胞膜并与相应受体相结合, 如TNF与其特异性跨膜受体TNFR结合后, 在胞质中形成肿瘤坏死因子受体相关死亡结构域(TRADD)、受体作用蛋白(RIP)、肿瘤坏死因子受体相关因子(TRAF2)的复合物, 诱导NIK作用于IκB激酶IKK, IKK磷酸化IκB的两个特异的丝氨酸残基, 即IκB-α的Ser32、Ser36或IκB-β的Ser19、Ser23或IκB-ε的Ser18、Ser22. 在蛋白酶的作用下磷酸化的IκB从p50/p65异源二聚体上降解进而p50/p65异源二聚体活化, 进入胞核中发挥转录活性. 次要途径表现在磷酸酶C作用后产生的甘油二脂通过MAPK或JNK/p38引起p65磷酸化和从前体蛋白p105形成p50而使p50/p65异源聚体活化且进入核中发挥转录活性. 值得注意的是: 不同的刺激信号对NF-κB激活和信号通路不同, 产生的效果也不同. TNF-α诱导NF-κB激活在几分钟内出现, 而化疗药物诱导的NF-κB激活在几小时后才出现[32,33]. 原因可能与参与IκB降解的IκB激酶不同有关.

3 NF-κB与细胞凋亡的关系

以往对NF-κB的研究局限于在炎症、应激、免疫方面的作用[34-44], 近来很多研究证实NF-κB与细胞凋亡关系密切. 许多高表达NF-κB的细胞表现出对放疗、化疗、细胞因子介导的凋亡的抵抗作用[45-53]. 而现在又发现NF-κB具有促进细胞凋亡的作用[1,54].

3.1 NF-κB抗凋亡的可能机制

NF-κB的抗凋亡活性已从很多研究中得以证实[45-63], 如: RelA基因敲除鼠发生大量肝细胞凋亡而死亡[64]; 从RelA(-/-)中提取出的细胞系或是高表达IκB-α的细胞系都表现出NF-κB的低表达, 并且对TNF-α诱导的细胞凋亡的敏感性明显增强, 而RelA(+/+)细胞不受影响; 凋亡信号存在时, B淋巴细胞的存活依赖于NF-κB的活化; NF-κB活化能阻滞由电离辐射、TNF-α及柔红霉素诱导的细胞凋亡; 显性负性突变子IκB-α△抑制磷状细胞癌细胞存活. 但NF-κB抑制凋亡的机制尚未完全阐明, 可能存在以下两种途径的细胞凋亡[65]: (1)NF-κB诱导抗凋亡因子. 到目前为止, 这些已证实的抗凋亡因子包括: Bcl-2蛋白家族[66-68]、Hsp70、Hsp27、即早基因IEX-1、存活基因[69]、凋亡抑制基因(TRAF1、TRAF2、C-IAP1、C-IAP2和XIAP)[33]他们的基因启动子或增强子上存在κB位点, 活化的NF-κB能诱导他们发挥抗凋亡效应.如: 人B淋巴细胞分化过程中, NF-κB激活通过CD40信号通路诱导Bcl-Xl mRNA和Bcl-Xl蛋白水平上调, 从而抵抗Fas介导的细胞凋亡[70,71]. (2)通过蛋白间相互作用而干预凋亡信号通路[72]. Shinichi et al [65]应用CHX(Cycloheximide, 环已酰亚胺)一种蛋白合成抑制剂作用于人胰腺癌细胞系, 发现CHX不能阻止IL-1β (F-κB的高效刺激因子)的抗凋亡效应, 而高表达IκB-α人胰腺癌细胞系中IL-1β的抗凋亡活性却被阻止. 提示IL-1β的抗凋亡作用是由于NF-κB的激活, 并且NF-κB的抗凋亡作用可以不需重新的蛋白合成亦或是抗凋亡因子蛋白的合成, 而是通过蛋白间相互作用来干预凋亡信号通路, 实现其抗凋亡活性. 如: 活化的NF-κB与凋亡蛋白53BP2相互作用而抑制凋亡[72,73]. 但这两种途径都不十分精确, 都不能单独解释NF-κB的抗凋亡机制[65].

3.2 NF-κB促凋亡的可能机制

在发现NF-κB抗凋亡活性并应用于肿瘤治疗不久, 人们又惊奇的发现: NF-κB还具有促进凋亡的作用[1,73-78]. Shou et al [74]观察到鼠脑局部缺血时, 海马中NF-κB激活能上调促凋亡基因Bcl-Xs蛋白表达. Tamatani et al [75]也证实: 在鼠海马中, NF-κB激活能上调Bcl-Xs的表达, 且这些种作用能被IκB-α抑制. Carsten et al [79]提出: NF-κB在诱导细胞凋亡中的作用依赖于细胞的类型. 如: 在神经元细胞[80]、许旺氏细胞[81]、胚胎的肾细胞[82]中NF-κB促进细胞凋亡. 还有一些研究表明[77]: NF-κB的激活是促进还是抑制凋亡依赖于刺激信号的差异和细胞类型. Clemens et al[76]在研究鼠脑局部缺血脑神经元凋亡与NF-κB关系时发现: 短时间的局部缺血刺激活化NF-κB可抑制神经元凋亡; 长时间的局部缺血刺激活化NF-κB则促进神经元凋亡. 已有研究证实: B淋巴细胞的存活依赖于NF-κB的激活, 而T淋巴细胞的存活则不需NF-κB参与调节, 反而NF-κB活化能促进T淋巴细胞的凋亡[83]. 出现些两种对立的结果提示: NF-κB的激活可能是一个处于细胞生存与细胞凋亡之间的调节点[54]. NF-κB促进凋亡的机制可能为: 由于NF-κB的靶基因上存在众多功能性的NF-κB结合位点, 如NF-κB的靶基因Bcl-2基因家族包括抗凋亡基因Bcl-2、Bcl-Xl和Bcl-w; 促凋亡基因Bax、Bcl-Xs和Bad. NF-κB的激活可能诱导抗凋亡基因, 也可能诱导促凋亡基因, 至于诱导哪一类基因, 就依赖于刺激信号的差异和细胞类型[1].

总之, 自1986年, Sen和Baltimore首次从B淋巴细胞核抽提物中检测出NF-κB以来, 对其的研究一直是生命科学的热点. NF-κB作为一种具有多向性转录调节作用的蛋白, 他的激活机制、在细胞凋亡中的作用仍不十分清楚, 特别是NF-κB促凋亡的作用机制及其在凋亡中正性或负性作用依赖于刺激信号的差异和细胞类型, 人们更是知之甚少. 深入研究NF-κB在细胞凋亡中的作用, 探讨其机制, 将会为临床治疗肿瘤开创一条全新的途径.

备注

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