死亡受体介导的凋亡与肿瘤化疗

凋亡是细胞胞内在程序性死亡,是调节组织稳态的中心环节。肿瘤的发生以及其化疗与细胞凋亡密切相关。肿瘤化疗药物的作用机制与死亡受体（DR）介导的凋亡在不同层次存在着多重交叉点,因而探索参与DR凋亡途径的蛋白信号分子与化疗药物作用位点的潜在联系将为人类肿瘤治疗提供新的靶点和思路。     

死亡受体介导的凋亡与肿瘤化疗

凋亡是细胞胞内在程序性死亡,是调节组织稳态的中心环节.肿瘤的发生以及其化疗与细胞凋亡密切相关.肿瘤化疗药物的作用机制与死亡受体(DR)介导的凋亡在不同层次存在着多重交叉点,因而探索参与DR凋亡途径的蛋白信号分子与化疗药物作用位点的潜在联系将为人类肿瘤治疗提供新的靶点和思路.     

死亡受体与肿瘤凋亡疗法的研究进展

肿瘤的发生在很大程度上是因为转化的细胞不能正常凋亡所致,因此,研究如何促进肿瘤细胞凋亡为肿瘤治疗提供了新的途径,特别是多种死亡受体及其配基的发现为肿瘤凋亡疗法的研究开辟了新的道路,本文介绍了多种死亡受体及其配基以及它们的功能调节、信号传导途径和在肿瘤治疗中的研究进展。     

死亡受体与肿瘤凋亡疗法的研究进展

肿瘤的发生在很大程度上是因为转化的细胞不能正常凋亡所致。因此 ,研究如何促进肿瘤细胞的凋亡为肿瘤治疗提供了新的途径 ,特别是多种死亡受体及其配基的发现为肿瘤凋亡疗法的研究开辟了新的道路。本文介绍了多种死亡受体及其配基以及它们的功能调节、信号传导途径和在肿瘤治疗中的研究进展     

007 死亡受体与肿瘤凋亡疗法的研究进展

肿瘤的发生在很大程度上是因为转化的细胞不能正常凋亡所致.因此,研究如何促进肿瘤细胞的凋亡为肿瘤治疗提供了新的途径,特别是多种死亡受体及其配基的发现为肿瘤凋亡疗法的研究开辟了新的道路.本文介绍了多种死亡受体及其配基以及它们的功能调节、信号传导途径和在肿瘤治疗中的研究进展.     

死亡分子受体介导凋亡信号的研究进展

死亡分子受体与死亡分子相互作用引发的细胞凋亡倍受人们关注。Fas、TNFR、DR3/Wsl-1和CAR 4个死亡分子受体已被确定,它们参与免疫调节、CTL杀伤活性、肿瘤消退、移植排斥反应等并发挥着重要的生物学作用。     

头帕肿瘤综合征蛋白与肿瘤坏死因子受体介导的坏死样凋亡

头帕肿瘤综合征蛋白(cylindromatosis,CYLD)是一种去泛素化酶,其C-末端USP结构域具有催化功能,可移除受体相互作用蛋白激酶1(receptor interacting protein kinase 1,RIPK1)的K63连接泛素链,调节RIPK1的泛素化水平,从而参与调节肿瘤坏死因子受体1(tumor necrosis factor receptor 1, TNFR1)介导的RIPK依赖的细胞坏死样凋亡等病理生理过程。阐明CYLD对RIPK1去泛素化调节的详细机制,寻找针对CYLD的特异性抑制剂,可为与坏死样凋亡相关的损伤与疾病提供治疗的新策略。     

肿瘤坏死因子受体超家族成员死亡受体在病毒感染中的作用

死亡受体是一组具有死亡结构域的膜受体，属于肿瘤坏死因子受体超家族成员。表达死亡受体的细胞与其相应的配体结合后可引发细胞凋亡，因此死亡受体参与机体的多种生理和病理过程，特别是在多种病毒感染中发挥着双重作用。本就最新发现的死亡受体在肝炎病毒、HIV以及巨细胞病毒等多种病毒感染中的作用作一综述。     

凋亡与肿瘤及其治疗进展

Apoptosis, a common and evolutionarily conserved property of all metazoan, is an essential part of life. The loss of cellular homeostasis balance is a character of tumor. The mitochondria (the intrinsic pathway) and the death receptors (the extrinsic pathway) are two major signal transduction pathways. With elucidation of the apoptotic molecular mechanism, some key proteins and genes related with apoptosis had been as the molecular targets for anticancer new drugs. There is the fundamental signficance to research further both apoptotic molecular mechanism and tumor therapy.     

肿瘤坏死因子受体超家族成员死亡受体在病毒感染中的作用

死亡受体是一组具有死亡结构域的膜受体,属于肿瘤坏死因子受体超家族成员.表达死亡受体的细胞与其相应的配体结合后可引发细胞凋亡,因此死亡受体参与机体的多种生理和病理过程,特别是在多种病毒感染中发挥着双重作用,本文就最新发现的死亡受体在肝炎病毒、HIV以及巨细胞病毒等多种病毒感染中的作用作一综述.     

B-cell antigen receptor-induced apoptosis: looking for clues

Triggering of the B cell antigen receptor (BCR) can initiate divergent responses ranging from activation and cell division to apoptosis, depending on the differentiation stage and additional signals the cell receives. Despite considerable progress in unraveling general apoptosis pathways, the route from the BCR to apoptosis execution is still quite obscure, and there is no consensus yet concerning the mechanism or the players involved. Here, we will summarize current developments in this field and will attempt to pinpoint key questions and perspectives for future research.     

死亡底物PARP与细胞凋亡

细胞凋亡是多细胞生物体内的一个重要生命现象.PARP[poly(ADP-ribose)polymerase]的蛋白酶解为半胱氨酸蛋白酶激活的分子事件,是细胞程序死亡的一个早期分子标志.PARP酶作为死亡底物参与凋亡的实施是近年国内外现代生物学研究的热点之一.     

Kinetics and signaling requirements of CD40-mediated protection from B cell receptor-induced apoptosis

In the present study we used a human follicular lymphoma cell line, HF1A3, as an in vitro model for the antigen-driven selection process in germinal centers. Apoptosis can be induced in HF1A3 cells by B cell receptor (BCR) stimulation, but the molecular mechanisms and kinetics of this process are largely unknown. We demonstrate here that there is over 12 h delay between receptor activation and the execution phase of apoptosis, i.e. disruption of mitochondrial membrane potential, release of cytochrome c from mitochondria, caspase-3 activation and DNA fragmentation. New protein synthesis is required for mitochondrial alterations and subsequent apoptosis to occur, as these processes are completely blocked by the protein synthesis inhibitor cycloheximide. All the apoptotic events induced by BCR triggering are completely reversed by CD40 ligation with anti-CD40 antibody. CD40 ligation can reverse the apoptotic process in HF1A3 cells almost until the first mitochondrial events take place demonstrating that CD40-mediated protection operates very fast and at or before mitochondrial phase of apoptosis. Using specific inhibitors of cell signaling we could demonstrate that Raf-extracellular signal-regulated kinase, phosphatidylinositol 3-kinase, p38 or protein kinase C activation pathways are not involved in CD40-mediated protection from BCR-induced apoptosis in HF1A3 cells.     

Death ligand-mediated apoptosis in HIV infection

Apoptosis has been suggested to cause severe CD4+ T cell depletion in patients infected with HIV. This review focuses on the biological events involved in death ligand-induced apoptosis during HIV infection. Among these ligands, TRAIL appears critical in HIV-infection. Death ligand-induced apoptosis might be a major pathogenic event in many virus-induced diseases including AIDS and the clarification of its mechanism will aid in the development of therapeutic strategies.     

Requirement for Casper (c-FLIP) in regulation of death receptor-induced apoptosis and embryonic development

Casper (c-FLIP) associates with FADD and caspase-8 in signaling complexes downstream of death receptors like Fas. We generated Casper-deficient mice and cells and noted a duality in the physiological functions of this molecule. casper-/- embryos do not survive past day 10.5 of embryogenesis and exhibit impaired heart development. This phenotype is reminiscent of that reported for FADD-/- and caspase-8-/- embryos. However, unlike FADD-/- and caspase-8-/- cells, casper-/- embryonic fibroblasts are highly sensitive to FasL- or TNF-induced apoptosis and show rapid induction of caspase activities. NF-kappaB and JNK/SAPK activation is intact in TNF-stimulated casper-/- cells. These results suggest that Casper has two distinct roles: to cooperate with FADD and caspase-8 during embryonic development and to mediate cytoprotection against death factor-induced apoptosis.     

Antigen receptor-induced B lymphocyte apoptosis mediated via a protease of the caspase family

An extensive body of data, in a variety of systems, denoted the caspase family of proteases as a key player in the execution of programmed cell death. This family consists of cysteine proteases that cleave after asparagine-containing motifs. It is well established that the caspases are essential for the apoptosis mediated by Fas (CD95) and TNF receptor p55, molecules that contain the “death domain” in the cytoplasmic tail. However, little is known about the mechanisms underlying the antigen receptor-mediated cell death in B lymphocytes, a process instrumental in negative selection of potentially autoreactive B cells. Here, we investigated the involvement of caspases in cell death triggered via the antigen receptor in B lymphocytes (BCR) by using specific inhibitors. Initially, we used a well-established cell line, CH31, which is a model of B cell tolerance, to demonstrate that these proteases indeed participate in the BCR-induced apoptotic pathway. Next, we confirmed the physiological relevance of the caspase-mediated cell death pathway in splenic B cell populations isolated ex vivo that were induced to undergo apoptosis by extensive cross-linking of their BCR. Most interestingly, our data demonstrated that caspases regulate not only the nuclear DNA fragmentation, but also the surface membrane phosphatidylserine translocation as well as the degradation of a specific nuclear substrate. Taken together, this report supports the hypothesis that regulation of the caspase family is crucial in controlling the life/death decision in B lymphocytes mediated by the antigen receptor signal transduction.