修回日期: 2007-02-10
接受日期: 2007-03-28
在线出版日期: 2007-04-28
NF-κB家族及其介导的细胞信号转导通路在细胞凋亡中的作用是国内外研究的热点. 研究发现, NF-κB信号转导途径可以通过多种途径抑制细胞凋亡, 与IAPs家族、Bcl-2家族、TRAF家族、JNK、FLIP、A20、Gadd45b、MnSOD等有很大关系, 但其具体机制尚未完全清楚. 通过抑制NF-κB信号转导途径的激活, 促进细胞凋亡, 可能成为治疗免疫、炎症、肿瘤等疾病的新途径. 此外, 近年的研究证明NF-κB尚具有促细胞凋亡的作用, 并发现NF-κB亚单位的种类及数量在细胞凋亡中起着决定性的作用, 为疾病的治疗提供了新的策略. 本文就NF-κB与细胞凋亡关系的研究进展作一综述.
引文著录: 苏剑东, 吴灵飞. NF-κB与细胞凋亡. 世界华人消化杂志 2007; 15(12): 1411-1416
Revised: February 10, 2007
Accepted: March 28, 2007
Published online: April 28, 2007
The roles of nuclear factor-kappa B (NF-κB) fa-mily and its signaling transduction pathway in apoptosis has been the focus of intense investigation all over the world. Researches show that NF-κB signaling pathway exerts anti-apoptotic function via many other proteins, including IAPs, Bcl-2, TRAF, JNK, FLIP, A20, Gadd45b, MnSOD and so on, but the exact mechanism remains unclear. Inhibition of NF-κB activation can promote the process of programmed cell death, and may become new avenues for therapeutic intervention in immune diseases, chronic inflammatory diseases and certain cancers. Furthermore, recent studies reveal that NF-κB can promote apoptosis, and the types and quantity of NF-κB subunits play a key role in apoptosis. In this review, we presented an overview of the progress in the relationship between NF-κB and apoptosis.
- Citation: Su JD, Wu LF. Relationship between nuclear factor-kappa B and cell apoptosis. Shijie Huaren Xiaohua Zazhi 2007; 15(12): 1411-1416
- URL: https://www.wjgnet.com/1009-3079/full/v15/i12/1411.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v15.i12.1411
细胞死亡的方式有凋亡和坏死两种. 凋亡是由体内外因素触发细胞内预存的死亡程序而导致的细胞死亡过程, 又称程序性细胞死亡(programmed cell death, PCD), 形态上以胞膜及细胞器相对完整, 细胞皱缩、核固缩为特征, 与坏死时细胞结构全面溶解、破坏完全不同[1]. 目前的研究揭示引起凋亡主要有两条途径: 细胞外的死亡受体途径及细胞内的线粒体途径[2]. 前者主要是刺激因素激活细胞内P53, Fas, Bcl-2, NF-κB等基因, 由肿瘤坏死因子(TNF)受体家族介导, 使Caspase-8激活[3-4]; 后者是通过刺激因素影响细胞内线粒体的膜电位, 导致线粒体内细胞色素C释放, 胞内Ca++浓度升高, pH值下降, 使Caspase-9激活. 两个途径最后都导致效应性Caspase-3活化, 效应性Caspase-3, -6, -7激活内切核酸酶, 使DNA链断裂, 最终细胞结构的全面解体[5-7].
NF-κB是一类具有多向转录调节作用的核蛋白因子, 广泛存在于多种组织细胞中, 激活后参与许多基因的转录调控, 在免疫、炎症、氧化应激、细胞增殖、细胞凋亡等生理病理过程中发挥作用. 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, 具有抑制细胞凋亡作用及促细胞凋亡的双向作用[8]. 但具体机制还不十分清楚. 本文就NF-κB信号转导途径与细胞凋亡关系的研究作一综述.
NF-κB是属于Rel家族的转录因子. 目前, 人们已发现哺乳动物细胞内NF-κB家族包括5个成员, 分别是p65(RelA), RelB, c-Rel, p50/p105(NF-κB1)和p52/p100(NF-κB2). 结构上他们的N端都具有一个由300个氨基酸组成的Rel同源区(Rel homology domain, RHD). 该区域含有二聚体化区、DNA结合区和核定位信号区(NLS), 分别具有与同源或异源亚基形成二聚体、与DNA上的κB序列结合、与IκB家族成员相互结合等功能. 此外, p65、RelB和c-Rel的C端含有转录激活域(transactivation domain), 其中富集丝氨酸、酸性氨基酸和疏水性氨基酸, 能直接作用于转录元件而激活转录过程, 而p50和p52则无此结构. 静息状态下, 他们以同源或异源二聚体的形式与IκB家族蛋白结合并存在于细胞质内. 其中以p50/p65二聚体(即通常所指的NF-κB)最普遍, 几乎存在于所有细胞中[9-10].
NF-κB的内源性抑制因子主要是IκB抑制蛋白家族, 后者有7个成员, 包括IκBα, IκBβ, IκBε, IκBγ, Bcl3, p105和p100. 他们均有一个保守的结构域, 在该结构域内有5-7个与NF-κB蛋白相互作用的锚蛋白(ANK)重复序列和与降解有关的C端PEST序列. 不同的IκB抑制NF-κB/Rel二聚体的能力不同, 他们与NF-κB二聚体上RHD的氨基酸残基发生作用, 掩盖NF-κB的NLS, 使之停留在胞质而抑制NF-κB核易位[11-12].
IκB激酶(IKK)由一个大的蛋白激酶复合体组成, 大小700-900 kDa, 包括3个亚单位, 即具有催化活性的IKKα(IKK1)、IKKβ(IKK2)和一个有调节功能的IKKγ(NEMO, IKKAP). IKKα和IKKβ均具有3个相同的结构, 分别是N端丝/苏氨酸蛋白激酶催化结构域、C端螺旋-环-螺旋(HLH)结构域及中间的锌指结构域. 他们都能催化IκB, 但磷酸化位点有所不同, IKKα可以使IκBa上Ser32和Ser36磷酸化, 而IKKβ不仅可以使IκBα上Ser32和Ser36磷酸化, 还能使IκBβ上的Ser19、Ser23磷酸化. 具有调节功能的IKKγ具有两个伸展的α-螺旋区域和一个锌指结构域. 他虽然没有催化活性, 但IKK的活性依赖于IKKγ亚单位的完整性[13-16].
大量的实验证明, 许多因素可以引起NF-κB信号转导途径的激活. 目前公认的主要包括两个途经: 经典途径及旁路途经[17-18]. 细胞在静息状态下, 细胞质中的p50/p65与IκB结合成三聚体, 使p50/p65不能核易位. 在经典途径中, 当细胞受到如细胞因子、有丝分裂原、内毒素、病毒蛋白、过氧化物、蛋白激酶C、钙离子载体、蛋白合成抑制剂及X射线等细胞外信号刺激时, IKK的IKKβ亚单位被磷酸化激活, 继而引起IκBα的Ser32和Ser36位点被磷酸化. 磷酸化的IκBα再被泛素化后在26S蛋白水解酶复合体作用下降解. 而被释放的p50/p65则进行核易位, 与基因上的κB位点发生特异性结合, 从而发挥调节细胞功能的作用[19]. 与经典途径不同, 旁路途径主要是指含有p100或p105的二聚体的NF-κB的激活. 在特定细胞类型中, 细胞外信号刺激细胞后, 在NF-κB诱导激酶(NIK)的作用下引起IKKα磷酸化活化, 从而进一步活化p100, 导致p100发生磷酸化依赖性剪切, 生成有活性的p52: RelB复合物并进入细胞核与靶基因结合, 调节基因的表达[20]. 除此之外, 近年的研究发现, 紫外线激活NF-κB的机制与以上途径不同. 紫外线通过激活酪蛋白激酶2(CK2)引起IkBα的C端磷酸化, 从而引起IκBα泛素化后降解. CK2的激活不依赖IKK而是通过p38丝裂原活化蛋白激酶, 因此p38-CK2-IκBα也是激活NF-κB的途径之一[21-22].
NF-κB激活的调节包括正反馈调节和负反馈调节[23]. 细胞外信号刺激引起NF-κB的激活可以增加细胞内的激活因子的表达增加, 如细胞因子TNF和IL-1等的表达增加, 这些因子的表达增加又反过来激活NF-κB[24]. NF-kB的负反馈调节主要通过p105及IkBα来执行. p105及IkBa的基因均有NF-κB的结合位点. 核易位的NF-κB与这些位点结合后增加p105及IκBα的表达. p105的增加导致p50二聚体也增加, 由于p50缺乏反式转录激活域, 与DNA结合可以抑制转录, 所以p50二聚体可以通过竞争DNA结合位点降低NF-κB介导的效应. 另一方面, 由于NF-κB与IκBα亲和力大于其与DNA的亲和力, 新合成的IκBα进入核内与NF-κB结合, 使其从DNA上解离下来, 然后在IκBα分子中的核输出序列(NES)作用下促使NF-κB重新回到细胞质中[25].
首先证实NF-kB具有抑制细胞凋亡作用是在对RelA-/-小鼠模型的研究中被发现. 实验中发现剔除RelA基因的胎鼠发育到妊娠中期时死于大片肝细胞的凋亡[26], 其机制是通过肿瘤坏死因子受体1(tumor necrosis factor receptor 1, TNFR1)介导[27]. 进一步的研究发现, NF-κB的激活对成年鼠肝细胞损伤也具有保护作用[28]. 目前的许多研究提示NF-κB的激活对细胞的生存具有重要意义. NF-κB抗细胞凋亡是一个涉及多个信号通路的复杂过程, 但其主要方式是通过诱导或上调抗凋亡基因的表达实现的. 这些基因调节位点上有NF-κB的结合位点, 他们的表达产物通过抑制细胞凋亡的死亡受体途径或线粒体途径发挥作用. 到目前为止, 研究发现细胞凋亡抑制蛋白(inhibitor of apoptosis proteins, IAPs)、Bcl-2家族、TNFR-associated factor (TRAF1, TRAF-2)、JNK、c-FLIP、IEX-1L等都参与NF-κB激活后的抗细胞凋亡过程[29].
大量研究表明, 细胞凋亡抑制蛋白(IAPs)家族通过结合Caspase3, Caspase7, 阻止Caspase9的活化起到抗细胞凋亡的作用. IAPs家族中与NF-κB抗细胞凋亡作用密切相关的是c-IAP1、c-IAP2和XIAP[30-31]. Chu et al[32]研究发现, TNF-α通过刺激NF-κB诱导c-IAP2表达, 而c-IAP2大量表达降解IκB导致NF-κB活化, 从而抑制细胞凋亡. Wang et al[33]也报道, NF-κB通过诱导c-IAP1, c-IAP2及TRAF1, TRAF-2的表达, 抑制Caspase8而起到抗细胞凋亡的作用. 近几年的研究发现, XIAP除了具有抑制Caspase3, Caspase7作用外, 还有阻止JNK激活的作用[34].
Bcl-2家族包括抗细胞凋亡的Bcl-2, Bcl-Xl, BHRF1, Ced-9和促细胞凋亡的Bax, Bcl-Xs, Bad, Bak及参与细胞存活调节的A1, Mcl-1等. 研究发现, Bcl-2, Bcl-Xl基因上有κB位点, 而Bax、Bad则无κB位点. NF-κB激活可引起Bcl-2家族中抗细胞凋亡的基因表达增加, 尤其是Bcl-Xl及A1, 进而发挥此类因子降低线粒体膜的通透性、抑制线粒体去极化及细胞色素C释放的抗凋亡作用[35-37].
TRAF家族是一种重要的接头分子, 在目前发现的6种人类TRAF分子中, 以TRAF2研究较广泛. TRAF2分子在NF-κB激活的信号传导过程中扮演重要的角色[38-39]. 在TNF诱导细胞凋亡过程中, TNF与TNFR1结合并使TNFR1胞内三聚化, 后者与TRADD (TNF-receptor-associated death domain)连接. TRADD与RIP(Receptor-interacting protein)及TRAF2连接形成的信号复合物进一步募集含有TRAF的蛋白分子或其他一些具有酶活性的效应分子,形成一个大的信号传导复合物, 此复合物中含有NIK(NF-κB诱导激酶), NIK活化后可磷酸化IKKα并使之激活, 后者反过来又磷酸化IκB, 使之泛素化、降解. NF-κB随之活化并可转位至核内与DNA相应部位特异结合[40]. 另外, Chandel et al[41]发现TRAF分子可通过改变ROS(活性氧)水平增强NF-κB活化而不依赖于NIK.
c-Jun氨基末端激酶(c-Jun N-terminal kinase, JNK)通路是丝裂原激活的蛋白激酶(mitogen-activated protein kinase, MAPK)信号传导通路之一[42]. 研究表明, JNK通路的激活与促凋亡作用有关[43-45]. 在基因敲除实验中, jnk1, jnk2或jnk3基因单突变失活小鼠和jnk1/jnk3或jnk2/jnk3基因双突变失活小鼠均正常存活, 而jnk1/jnk2基因的双突变失活导致胚胎死亡, 出现严重的脑细胞凋亡调节障碍, 表明jnk1 和jnk2基因在脑发育早期的细胞生理性凋亡中有重要调节作用[46]. 许多研究表明, NF-κB可以抑制JNK介导的细胞凋亡[47-51]. 例如, 在TNF-α诱导的细胞凋亡的过程中, 应用抑制剂抑制NF-κB活化, 可以引起JNK的持续活化, 最终引起细胞凋亡[34,52]. 动物实验证明, LPS或ConA引起的肝细胞毒性是通过TNFR诱导, 在此过程中NF-κB可被激活而起到保护肝细胞的作用. 当剔除IKKβ后, 可引起JNK表达明显而增加促进肝细胞损伤. 而在剔除JNK1或JNK2抑制JNK的表达后, 减轻了TNFR介导的肝细胞损伤[53-54]. 上述研究表明, NF-κB可通过抑制JNK激活而起到抗细胞凋亡的作用.
Fas相关死亡区域蛋白样白介素-1b转化酶抑制蛋白(FLIP)是一种阻遏蛋白, 他主要通过抑制Fas/FasL-FADD-Caspase-8通路活化而发挥抗凋亡作用. FLIP基因编码序列中存在κB位点, NF-κB蛋白可以上调FLIP的转录表达而使细胞免于Fas介导的细胞凋亡[55]. 研究发现FLIP除了阻断上述通路外, 还可抑制肿瘤坏死因子凋亡诱导配体(TRAIL)介导的促凋亡通路, 在这过程中FLIP通过竞争结合FADD而发挥作用[56]. 有许多文献报道抑制肿瘤细胞的NF-κB活性, 可提高TRAIL的促凋亡作用并伴随FLIP表达下降[57-58], 提示NF-κB通路可能通过FLIP来抑制TRAIL的促凋亡作用.
随着研究的深入, 发现越来越多的信号通路与NF-κB抗细胞凋亡的机制有关. A20是一种锌指蛋白, 过去的研究发现A20蛋白在终止NF-κB的激活中起着重要的作用[59]. 最近的研究发现, NF-κB可通过调控A20蛋白的表达影响TNF诱导的细胞凋亡过程[60]. Gadd45β是Gadd45家族中的一员, 属于核蛋白. 研究发现, NF-κB是Gadd45β的上游调节因子, 可调节Gadd45β的表达, 后者则可通过调控JNK来抑制细胞凋亡的过程[61]. Hirose et al[62]研究发现超氧化物歧化酶(MnSOD)的过量表达可抑制TNF-α的毒性作用, 可能的机制是TNF-α引起NF-κB激活, 从而使MnSOD的表达增加, MnSOD可通过清除ROS而起到抑制细胞凋亡的作用[63].
随着NF-κB抑制细胞凋亡作用机制的研究深入, 并应用于炎症、肿瘤等疾病的治疗, 人们发现NF-κB在不同的刺激因素及特定的细胞类型中还有促进细胞凋亡的作用[64-67]. Ivanov et al[68]在UV诱导人类黑色素瘤细胞凋亡过程中发现下调NF-κB的表达同时伴有细胞凋亡的减少. Campbell et al[66]研究则发现NF-κB可通过抑制抗凋亡基因的表达而使细胞发生凋亡. 在肿瘤坏死因子相关凋亡诱导配体(TRAIL)信号途径的研究中, Chen et al[69]研究发现, NF-κB亚单位的种类及数量在细胞凋亡中起着决定性的作用, 当p65(RelA)过表达时, 发生凋亡抑制; 当c-Rel表达增加时, 则促进凋亡的发生. 这些研究结果表明, NF-κB在细胞凋亡中是起抑制凋亡还是促进凋亡作用取决于不同的刺激因素及细胞类型, 并与激活的NF-κB亚单位的种类及数量有关, 其具体机制有待进一步的研究.
总之, 在细胞凋亡过程中, 许多蛋白因子参与了其信号转导. 在免疫、炎症、肿瘤的形成、肿瘤细胞对化疗药物的耐药性等病理生理过程中NF-κB起着抑制细胞凋亡的作用. 然而, 在特定的刺激及细胞类型中NF-κB也有促细胞凋亡的作用, 尤其是NF-κB亚单位的种类及数量在细胞凋亡中起着决定性的作用提示我们, 对NF-κB及相关信号转导通路具体机制的研究, 将有助于加深对不同疾病发生的分子机制的认识, 也可为治疗这些疾病开拓新的途径[70-72].
NF-κB信号转导途径具有抑制细胞凋亡和促细胞凋亡的双向作用. NF-κB抑制细胞凋亡的作用与IAP家族, Bcl-2家族, TRAF家族, JNK, FLIP, A20, Gadd45b, MnSOD等有关, 但其具体机制未完全清楚. 抑制NF-κB的激活, 可能成为治疗免疫、炎症、肿瘤等疾病的新途径.
NF-κB抑制细胞凋亡的具体机制是多年来研究的重点, 如何抑制NF-κB的激活和开发特异性高的抑制剂则是近年研究的热点.
Calzado最近报道, 通过抑制NF-κB的激活治疗炎症性疾病和肿瘤的药物研究取得很大进展, 部分NF-κB抑制剂已经进入临床II期试验.
本文系统地回顾了NF-κB家族的生物学特性及其在细胞凋亡中的双向作用, 详细总结了NF-κB抑制细胞凋亡的机制及NF-κB亚单位的种类及数量在细胞凋亡中的作用.
NF-κB在炎症疾病、肿瘤形成、肿瘤细胞对化疗药物的耐药等过程中起着重要的作用. 对NF-κB如何抑制细胞凋亡及促细胞凋亡的研究, 将有助于开发新的治疗途径及药物.
核易位: 存在于细胞浆中的蛋白被激活后, 通过核膜进入细胞核内发挥生物活性的过程.
本文综述了NF-κB与细胞凋亡的关系, 文章文字简洁, 层次清楚, 引用的文献较新, 有较高的学术价值.
电编:张敏 编辑:张焕兰
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