细胞凋亡的分子机制

多细胞生物在发生,发展过程中,为了保持正常的生理机能,一部分的细胞发生自发性细胞死亡,这种细胞死亡是被细胞内一系列相关性的分子所调控,并伴随有典型的形态学改变,这种现象被称为细胞凋亡（ａｐｏｐｔｏｓｉｓ）作为一种积极排队生物体内的过剩细胞和有害细胞的机制在个体形态形成,形态改变等发生过程中,成体的恒常性的维持以及生物体的防御等方面发挥作用,此外在许多病理状态下也存在着细胞凋亡,近年的研究已经明确了     

细胞凋亡的分子机制研究进展

细胞凋亡的分子机制尚不清楚,本从影响细胞凋亡的因素、细胞凋亡相关基因及其调节和细胞凋亡发生的代谢改变等几个方面,以细胞凋亡相关基因为重点,对细胞凋亡的分子机制加以阐述,以期进一步阐明细胞凋亡的分子机理。     

尼古丁调控细胞凋亡的分子机制

尼古丁是烟草中生物碱的主要成分,其生物学作用广泛。尼古丁参与影响神经系统、呼吸系统和心血管系统等重要器官的发育,并与癌症的发生有着密切的关系。尼古丁通过对细胞凋亡的调控,发挥其生物学作用。现对尼古丁调控细胞凋亡相关的各种信号通路及其分子机制进行综述。     

重金属诱导细胞凋亡的分子机制

重金属诱导的细胞凋亡是一个十分复杂的过程,不同种类的重金属以及同类重金属离子的不同价态所诱导的凋亡效应及其分子机制不尽相同。目前的研究表明,重金属与DNA形成加合物而导致DNA损伤可能是引发细胞凋亡的重要步骤：多种重金属能通过激活内质网、线粒体钙通道,使Ca^2 释放进入细胞质而引发凋亡;重金属还能使细胞中ROS升高,在直接导致DNA损伤的同时,启动与线粒体相关的细胞凋亡信号通路。此外,ROS还能通过MAPKs增强JNK介导的：FasL和Fas表达,最终使caspase-3和caspase-7激活,从而促进凋亡的发生。重金属诱导细胞凋亡还涉及一系列重要基因和蛋白质的参与,包括促进凋亡的Src家族酪氨酸激酶、bax、fas和p53等基因及相关蛋白,抑制凋亡的Sp1锌指转录因子、bcl-2和myc等基因及相关蛋白。部分重金属如镉、锌等对细胞凋亡具有诱导和拮抗双重效应,其中拮抗效应主要是通过与自由钙离子协同进行的,而诱导效应则可能是通过调节caspase-3活性而实现的。     

凋亡细胞清除的分子和细胞生物学机制

凋亡细胞的正确清除是细胞程序性死亡的必要环节,对生物体的器官发育和组织稳态维持起至关重要的作用.凋亡细胞的清除涉及凋亡细胞与吞噬细胞之间的相互识别、吞噬小体形成、吞噬小体与溶酶体融合、凋亡细胞降解等多个环节.基于模式动物秀丽词线虫的研究使人们对这一过程的调控机制有了系统的认识,本文将简要综述该方面的研究进展.     

风疹病毒诱导细胞凋亡分子机制的研究进展

风疹病毒是披膜病毒科风疹病毒属的唯一成员,能够诱导细胞发生细胞凋亡。Ras-Raf-MEK-ERK和PI3KAkt信号通路是病毒增殖与细胞生存的必要通路,在细胞凋亡过程中起着必不可少的作用。p53蛋白和TAp63蛋白能够进入细胞核与DNA特异结合,抑制Bcl-2的表达,促进Bax的表达,导致线粒体内外膜间的物质(细胞色素C等)释放,进而引起caspase级联反应,最终导致细胞凋亡。本文从风疹病毒感染的细胞系,病毒感染导致的细胞病理改变和病毒诱导的细胞凋亡信号通路及其相关因子等方面对风疹病毒诱导细胞凋亡的分子机制进行了综述。     

DFF和CIDE介导细胞凋亡的分子机制

DNA裂解因子（DFF）是由分子量分别为45kD和40kD两个亚单位组成的异源二聚体。在细胞凋亡信号启动的caspase级联活化过程中作为下游caspase的底物被活化并形成脱氧核糖核酸酶（DNase)。从而介导并调节DNA断裂和染色质凝聚,DFF作为细胞凋亡信号传递的主要途径在细胞凋亡中起着关键作用。诱导细胞死亡的DFF45样效应因子（CIDE）是与DFF同源的诱导凋亡因子,CIDE与DFF在结构,功能和作用上有很大的相似性,可发挥诱导凋亡的作用。本阐述了DFF和CIDE在诱导细胞凋亡过程中担当的角色和它们相互作用的机制。从而揭示DFF和CIDE在细胞凋亡过程中作为传递凋亡信号-caspase级联反应的下游因子在诱导凋亡时所处的关键地位和重要功能。     

细胞凋亡的分子机理

细胞凋亡是机体生长发育,细胞分化和病理状态中细胞自主性死亡的过程,调节控制细胞凋亡的基因有存活基因和致死基因两大类,存活基因包括Ｂｃｌ－２及其家族某些成员的基因,原癌基因和病毒基因,这些基因的过量表达可阻止细胞的凋亡,致死基因包括Ｂｃｌ－２家族的另一些成员的的基因、ＩＣＥ家族基因以及ｍｙｃ、ｐ５３和Ｒｂ基因等。细胞因子、激素和细胞间质等细胞外部因素可能通过信号传递途径影响上述基因表达而间接地调节细     

Caspases和Caspases抑制剂控制细胞凋亡的分子机制

目前关于细胞凋亡的概念,基因克隆,基因敲剔,基因调控,信号传导及其疾病发生中的作用得到较为深入的研究,在哺乳动物中发现至少有１２种Ｃａｓｐａｓｅｓ家族成员,它们具有两种酶催化活性,参与打靶,激活及调控起着级联反应,在执行和控制细胞凋亡的过程中过程中发挥着重要作用,已发现Ｃａｓｐａｓｅｓ抑制剂对控制Ｃａｓｐａｓｅｓ联级反应具有重要价值,将为细胞凋亡的分子机制和控制疾病的认识提供了新的思路。     

IRE1/TRAF2诱导细胞凋亡的分子机制

在细胞内质网应激中,IRE1/TRAF2/ASK1复合物可激活JNK信号通路,诱导细胞凋亡。IRE1-Lys828可被E3连接酶CHIP泛素化而激活。而TRAF2本身也具有RING结构域的E3泛素连接酶活性,可结合于IRE1的泛素化位点Lys828,促进IRE1磷酸化活化。IRE1/TRAF2复合物可募集ASK1,进而磷酸化激活JNK信号通路。另外,IRE1/TRAF2也可激活MAPK/p38、NF-κB以及caspase-12等信号途径,促进细胞凋亡。ASK1也是内质网应激IRE1/TRAF2诱导激活细胞凋亡所必需的。因此,TRAF2在调控细胞内质网应激,激活IRE1途径,诱导细胞凋亡中具有重要的作用,可作为一个靶点进行药物开发。     

Caspase的活化及其在细胞凋亡中的作用

Caspase是执行细胞凋亡的主要酶类,目前已鉴定的哺乳动物Caspase有14种。Caspase以酶原的形式合成,催化活性很低,必须激活以后才能发挥作用。活化的Caspase通过特异性的裂解一套底物而导致细胞凋亡。与Caspase有关的细胞凋亡通路至少有三种：线粒体／细胞色素c通路、死亡受体通路和内质网通路。Caspase总是与其抑制剂共存,以防止Caspase酶原意外激活而对正常细胞造成损伤。     

Fast neutrons-induced apoptosis is Fas-independent in lymphoblastoid cells

We have previously shown that ionizing radiation-induced apoptosis in human lymphoblastoid cells differs according to their p53 status, and that caspase 8-mediated cleavage of BID is involved in the p53-dependent pathway. In the present study, we investigated the role of Fas signaling in caspase 8 activation induced by fast neutrons irradiation in these cells. Fas and FasL expression was assessed by flow cytometry and by immunoblot. We also measured Fas aggregation after irradiation by fluorescence microscopy. We found a decrease of Fas expression after irradiation, but no change in Fas ligand expression. We also showed that, in contrast to the stimulation of Fas by an agonistic antibody, Fas aggregation did not occur after irradiation. Altogether, our data strongly suggest that fast neutrons induced-apoptosis is Fas-independent, even in p53-dependent apoptosis.     

UVB诱导NIH3T3细胞凋亡时的信号转导机制:Ⅱ.神经酰胺所致细胞内Ca~(2+)和pH的变化

利用粘附式细胞仪（ＡＣＡＳ－５７０）结合相应的荧光探针分别测定了外源性神经酰胺诱导ＮＩＨ３Ｔ３细胞凋亡时胞浆游离Ｃａ＾２＋水平和ＵＶＢ照射ＮＩＨ ３Ｔ３细胞所致细胞内ＰＨ的变化以及神经酰胺的生民对这一变化的影响。结果表明,１．神经酰胺能够导致ＮＩＨ ３Ｔ３细胞胞浆游离Ｃａ＾２＋升高既来源于胞外叠为源于胞内钙池,但外钙内流是引起和维持胞内Ｃａ＾２＋处于高水平所必要条件,ＮＩＨ ３Ｔ３细胞也上存在着两     

UVB诱导NIH 3T3细胞凋亡时的信号转导机制:Ⅱ.神经酰胺所致细胞内Ca2+和pH的变化

利用粘附式细胞仪 (ACAS -570)结合相应的荧光探针分别测定了外源性神经酰胺诱导NIH3T3细胞凋亡时胞浆游离Ca2 水平和UVB照射NIH3T3细胞所致细胞内 pH的变化以及神经酰胺的生成对这一变化的影响。结果表明 :1.神经酰胺能够导致NIH3T3细胞胞浆游离Ca2 升高 ;胞浆Ca2 升高既来源于胞外钙 ,又来源于胞内钙池 ,但外钙内流是引起和维持胞内Ca2 处于高水平的必要条件 ;NIH3T3细胞钙池上存在着两种受体 :IP3 受体和Ryanodine受体 ,其中IP3受体较占优势。2.UVB照射导致NIH3T3细胞凋亡时胞浆碱化并持续约2小时左右恢复正常 ,pH的变化参与了细胞凋亡的过程并受到神经酰胺生成的调控。这可能是UVB照射启动了磷脂肌醇通路激活磷脂酶C ,导致神经酰胺的生成、Ca2 动员和蛋白激酶C的活化 ,从而激活Na /H 对流引起胞浆碱化。所以 ,胞浆游离Ca2 的增加和 pH的升高不是两个孤立的事件。     

紫外照射神经酰胺的生成及神经酰胺引起的细胞凋亡

参照文献报道的方法建立了测定细胞神经酰胺的激酶催化法,以该法所做的标准曲线在一定浓度范围内有很好的线性关系。以ＵＶＢ照射ＮＩＨ ３Ｔ３细胞,可以使细胞神经酰胺的水平在１分钟之内迅速升高１．５倍以上,基本上达到了细胞所能生成神经酰胺的最高峰值。可细胞膜的外源性神经酰胺（Ｃ２－ｃｅｒａｍｉｄｅ）作用于ＮＩＨ ３Ｔ３细胞后能够导致细胞的凋亡和坏死,其凋亡率在一定剂量范围内随神经酰胺浓度的增加而增加;而在     

Differential regulation of signal transduction pathways in wild type and mutated p53 breast cancer epithelial cells by copper and zinc

Previous studies have suggested that cells may differ in their response to metal stress. This study was undertaken to investigate the role of PI3K/Akt signaling pathway in metal resistance in human breast cancer epithelial cells with different p53 and estrogen receptor status. Exposure to copper and zinc increased Akt phosphorylation with its nuclear localization only in MDA-MB-231 cells with no estrogen receptor and mutated p53. Cyclin D1 expression and cell-cycle progression followed the metal-induced Akt phosphorylation. Treatment with LY294002 abrogated these effects, suggesting the essential role of PI3-kinase. In contrast, in MCF-7 cells with wild type p53 and estrogen receptor, there was no change in Akt activation, while suppression of p53 activity by pifithrin-alpha increased phosphorylation of Akt after the treatment with copper. In MCF-7 cells, the metal treatment increased the phosphorylation of p53 at serine 15, up-regulated p21 expression, and resulted in cell-cycle arrest in G1 phase with apoptosis. These results demonstrate that copper-induced apoptosis in MCF-7 cells is p53 dependent, whereas the metal resistance in MDA-MB-231 cells may be due to activation of Akt in the absence of a functional p53.     

Contribution of membrane localization to the apoptotic activity of PUMA

The BH3-only protein PUMA plays an important role in the activation of apoptosis in response to p53. In different studies, PUMA has been described to function by either directly activating the pro-apoptotic proteins Bax and Bak, or by neutralizing anti-apoptotic members of the Bcl2 family. We have examined the contribution of regions of PUMA other than the BH3 domain to its localization and function. Although the hydrophobic domain in the C-terminus of PUMA is necessary for efficient mitochondrial localization of PUMA itself, PUMA proteins lacking this region can still induce apoptosis and localize to the mitochondria through binding to Bcl2. Even a nuclear localization signal (NLS)-tagged PUMA protein retains apoptotic activity and can be efficiently relocalized from the nucleus after interaction with ectopically expressed Bcl2, underscoring the efficiency of this interaction. Interestingly, unlike the Bcl2 interaction, the binding of PUMA to Bax is severely compromised by the loss of the C-terminal domain of PUMA. However, since the loss of the C-terminus does not compromise the ability of PUMA to induce cell death, our results indicate that the key apoptotic function of PUMA is through interaction with anti-apoptotic proteins such as Bcl2.     

FGF-2 在细胞凋亡中的作用机制

成纤维细胞生长因子2(fibroblast growth factor 2,FGF-2)具有多种细胞生物学功能。FGF-2在肿瘤组织中呈高水平表达状态,且可抑制多种化疗药物的促凋亡作用,从而曾为肿瘤细胞存活的重要刺激因素。但也有研究表明FGF-2可诱导部分细胞的分化和凋亡。鉴于FGF-2在肿瘤的发生发展中发挥的重要作用,FGF-2与细胞凋亡的关系及其相应的调节机制成为有待于深入研究和迫切需要解决的问题。本文主要阐述在细胞凋亡通路中,FGF-2关键分子的作用机制及其最新研究进展。     

Apoptosis induced by doxorubicin in neurotumor cells is divorced from drug effects on ceramide accumulation and may involve cell cycle-dependent caspase activation

Doxorubicin (0.5 microgram/ml) induced caspase-dependent apoptosis in SH-SY5Y neuroblastoma and CHP-100 neuroepithelioma cells. The apoptotic response started to be evident approximately 15 h after drug administration and, as monitored over a 48-h period, was more pronounced in CHP-100 than in SH-SY5Y cells. In both systems, apoptosis was accompanied by elevation of intracellular ceramide levels. Ceramide accumulation was blocked by the ceramide synthase inhibitor fumonisin B(1) (25 microM); this compound, however, did not prevent drug-induced apoptosis. Untreated cells from both lines expressed negligible p53 levels; on the other hand, whereas p53 and p21(Cip1/Waf1) were rapidly up-regulated in doxorubicin-treated SH-SY5Y cells, such a response was not observed in CHP-100 cells. Doxorubicin induced a G(2)/M phase block in both cell lines, but whereas the G(1) phase was markedly depleted in CHP-100 cells, it was substantially retained in SH-SY5Y cells. In the latter system, double G(1) and G(2)/M block largely preceded cell death; however, as apoptosis underwent completion, it selectively targeted late S and G(2)/M cells. Moreover, apoptosis suppression by caspase inhibition did not result in a recovery of the G(1) cell population. These results support the notion that doxorubicin-induced apoptosis and ceramide elevation are divorced events in neuroectodermal tumors and that p53 function is at least dispensable for apoptosis completion. Indeed, as G(1) cells appear to be refractory to doxorubicin-induced apoptosis, p53 up-regulation and p21(Cip1/Waf1) expression may provide an unfavorable setting for the apoptotic action of the drug.