凋亡相关蛋白Noxa在自身免疫性疾病中的作用

Noxa是Bcl-2家族中BH3-only亚家族成员之一,定位于线粒体,主要与Bcl-2家族中抗凋亡蛋白Mcl-1结合而起促凋亡作用.Noxa受p53依赖和非p53依赖途径激活调控而起促凋亡作用,在自身免疫性疾病的发生和发展中起重要作用.本文对Noxa在自身免疫性疾病中的作用作一综述.     

姜黄素抗肿瘤作用机制的研究进展

多种恶性肿瘤细胞中表达细胞凋亡抑制蛋白（IAPs）,如：Survivin、NAIP、XIAP、Livin等,同样表达抗细胞凋亡Bcl-2家族蛋白。IAPS介导的凋亡抑制可能是肿瘤细胞耐药而存活的原因之一;Bcl-2家族蛋白在抗肿瘤凋亡及促其凋亡中发挥作用。姜黄素具有抗炎、抗氧化、抑制血管新生等,可以通过调控蛋白表达及相关信号通路促进细胞凋亡、抗肿瘤作用。     

035 选择性诱导表达Bcl-2的乳腺癌细胞凋亡[英]／Westwell A／／Drug Discov Today.

肿瘤细胞的基本特点之一就是逃避细胞凋亡。Bcl-2家族既有抗凋亡蛋白也有促凋亡蛋白。由于抗凋亡Bcl-2蛋白的高水平表达与许多恶性肿瘤相关，抑制Bcl-2或有关抗凋亡蛋白已经成为诱导肿瘤细胞凋亡或提高这些细胞对化疗敏感性的一种策略。     

Bcl-2蛋白的小分子抑制剂

Bcl-2蛋白家族在调节细胞凋亡中发挥重要作用，人类恶性肿瘤细胞高表达Bcl-2和Bcl-XL，而高表达这些抗凋亡分子的细胞对于化疗药物有抗性，因此，以Bcl-2家族蛋白为靶点的小分子抑制剂成为很有潜力的可用于多种肿瘤治疗的药物，通过下调Bcl-2和Bcl-XL的表达直接影响肿瘤细胞的存活及其对化疗药物的抗性。     

白介素-11预处理对大鼠肠缺血再灌注损伤肠黏膜中促凋亡蛋白Bid表达的影响

1996年korsmeyer研究组首先克隆出Bid蛋白,Bid蛋白是Bcl-2家族中BH3亚家族成员之一,结构中只有一个BH3区域．具有促进细胞凋亡发生作用。目前尚无文献报道白介素-111预处理后Bid与大鼠肠道细胞凋亡的关系。本实验旨在通过模拟肠道缺血再灌注损伤,探讨Bid在肠粘膜细胞凋亡中的作用及其可能的机制。     

基于蛋白结构的Bcl-2抑制剂设计与开发

Bcl-2家族抗凋亡蛋白的过度表达通常与肿瘤的发生有着密切的关系,而细胞凋亡信号均要经Bcl-2蛋白家族传递。因此,针对Bcl-2家族蛋白的结构特征和功能,设计其特异性抑制剂,以诱导肿瘤细胞凋亡,已成为肿瘤治疗的新策略。综述Bcl-2家族蛋白的结构与功能及其活性位点的分布,介绍基于结构的若干Bcl-2抑制剂的设计与开发。     

Mcl-1蛋白的结构、功能及其抑制剂的研究进展

细胞凋亡与许多人类疾病的发生密切相关,过度凋亡引发神经退行性疾病,而抑制凋亡则与肿瘤等疾病的产生有关.研究表明,Bcl-2蛋白家族在细胞凋亡中发挥重要作用,特别是近几年对Bcl-2蛋白家族成员Mcl-1及其抑制剂研究越来越多.本文介绍了Mcl-1蛋白的结构与功能特点,综述了近几年作为抗肿瘤药物的Mcl-1抑制剂的研究进展.     

促凋亡基因PUMA的研究进展及其与肿瘤的关系

PUMA(p53 upregulated modulator of apoptosis,p53上调凋亡调控因子)属于Bcl-2家族中的BH3仅有蛋白,可在包括基因毒性应激、癌基因无受控表达、毒素、氧化还原状态改变、感染及生长因子/细胞因子减少等多种应激诱发的细胞依赖p53及非依赖p53机制凋亡中起关键调节作用。PUMA主要机制是将各种凋亡信号传导给胞体内线粒体,线粒体经过各种过程间接作用于Bcl-2家族成员中的Bax和(或)Bak抑制凋亡作用,阻断抑制凋亡家族因子的抗凋亡作用。PUMA直接与所有已知的抗凋亡Bcl-2家族结合并对抗其阻断的线粒体功能障碍和caspase的激活,将细胞推向凋亡程序。PUMA基因的敲除或抑制会导致凋亡抑制,从而潜在的增加了癌症的危险性和治疗的对抗性。PUMA表达的上调可增加癌细胞对放化疗的敏感性,而抑制PUMA的表达可能会遏制组织损伤和退行性疾病细胞的过度死亡,因此PUMA是细胞死亡刺激的总体感应器,为肿瘤和组织损伤治疗提供了有重要意义的药物靶点方向。     

以IAPs为靶点的抗肿瘤研究进展

凋亡抑制因子(inhibitor of apoptosis proteins,IAPs)是一类高度保守的内源性抗细胞凋亡因子家族,主要通过抑制caspase活性和参与调节核因子NF-κB的作用抑制细胞凋亡。caspases蛋白酶的级联激活是凋亡过程的中心环节,Bcl-2家族蛋白和IAPs家族蛋白是主要控制因素。近年来发现,某些IAPs成员异常表达与肿瘤密切相关,成为肿瘤治疗的潜在靶点。因此,该文主要综述了与IAPs家族相关的蛋白以及以IAPs为靶点的抗肿瘤研究。     

小分子Bcl-2抑制剂的研究与开发

综述细胞凋亡的主要机制、Bcl-xL蛋白结构以及各类小分子Bcl-2抑制剂的研究与开发。高水平表达Bcl-2家族抗凋亡蛋白（如Bcl-2、Bcl-xL等）可导致肿瘤细胞的凋亡过程受阻，并对传统放、化疗产生抵抗性，而下调过表达Bcl-2和Bcl-xL蛋白则可诱导肿瘤细胞凋亡，且逆转肿瘤细胞对治疗的抵抗性或耐药性。因此，作为潜在的癌症治疗策略，以Bcl-2家族蛋白为靶点的小分子抑制剂已成为当今研究热点，X-射线晶体衍射、核磁共振技术、小分子数据库和计算机辅助药物设计等技术也广泛应用于小分子Bcl-2抑制剂的开发。     

Bcl-2蛋白家族作用机制及其抑制剂的研究

综述了Bcl-2蛋白家族成员的结构、作用机制模式及抑制剂，特别是小分子抑制剂的研究进展。凋亡对于调节多细胞生物的个体发育和体内平衡具有重要作用，其异常可导致许多疾病的发生，而Bcl-2蛋白家族在凋亡通路中起重要的调节作用，它们与肿瘤的产生及耐药非常相关，可能成为抗肿瘤药物的新靶点。近几年研究者对它们的抑制剂也进行了初步研究。     

Bcl-2家族蛋白小分子抑制剂的研究进展

Bcl-2家族蛋白是细胞凋亡途径中一种重要的蛋白,在肿瘤的发生及转移中起着重要的作用.由于Bcl-2家族蛋白在多种癌细胞中高度表达,因此,对其干预成为一种新型肿瘤治疗策略,Bcl-2家族蛋白也成为抗肿瘤的热门靶点之一.本文总结了近年来Bcl-2家族蛋白小分子抑制剂的研究进展.     

Bcl-xL and Mcl-1 are involved in prevention of in vitro apoptosis in rat late-stage erythroblasts derived from bone marrow

Apoptosis controls erythroid homeostasis by balancing survival and death of erythroid cells. The mitochondrial pathway of apoptosis involves regulation of apoptotic events caused by the Bcl-2 family proteins, including the anti-apoptotic and pro-apoptotic members. However, little has been reported on the role of the anti-apoptotic Bcl-2 family members in rat late-stage erythroblasts that are no longer erythropoietin (EPO)-dependent. In the present study, to investigate this we analyzed changes in apoptosis-related factors that occurred in vitro. EPO stimulation resulted in reduced apoptotic cell death of the late-stage erythroblasts accompanied by decreased caspase-3 and caspase-9 activities, which is indicative of the induction of apoptosis through the mitochondrial pathway. Analysis of mRNA expression of the Bcl-2 family proteins demonstrated that EPO stimulation up-regulated the Bcl-xL mRNA, resulting in decreases in the mRNA ratios of Bak, Bax, and Bad to Bcl-xL. Also, the mRNA ratios of Bak and Noxa to Mcl-1 were decreased, mainly due to up-regulation of Mcl-1 mRNA. These results showed a close association between reduced apoptotic cell death and increased mRNA levels of Bcl-xL and Mcl-1 in the presence of EPO. Thus, the present study suggests that Bcl-xL may be an important anti-apoptotic factor of rat late-stage erythroblasts as has been reported in murine erythroblasts. Moreover, the results also indicate the possibility that Mcl-1 may act on the rat late-stage erythroblasts as an anti-apoptotic factor.     

Proteins of the bcl-2 family in apoptosis signalling: from mechanistic insights to therapeutic opportunities

1. Proteins of the Bcl-2 family are central regulators of apoptosis and are thought to act primarily on the mitochondria. 2. Members of the Bcl-2 family possess either anti-apoptotic or pro-apoptotic function. They are characterized by the presence of conserved sequence motifs, known as Bcl-2 homology (BH) domains. Anti-apoptotic members share all four BH domains, designated as BH1-4; the multidomain pro-apoptotic members contain BH1-3 domains, whereas another subgroup of pro-apoptotic members only have a BH3 domain. 3. The BH3-only proteins act as sensors for distinct apoptosis pathways, whereas multidomain pro-apoptotic Bax and Bak are executioners of death orders relayed by the BH3-only proteins. 4. Anti-apoptotic Bcl-2 family members appear to function, at least in part, by interacting with and antagonizing pro-apoptotic family members. The BH1-3 domains of BclXL form an elongated hydrophobic groove, which is the docking site for the BH3 domains of pro-apoptotic binding partners. 5. The deregulation of the various Bcl-2 proteins has been implicated in many pathological conditions. 6. Knowledge derived from the understanding of the function and regulation of the Bcl-2 family of proteins has allowed us to contemplate new therapeutic strategies for diseases where apoptosis signalling mechanisms can potentially be manipulated. 7. The anti-apoptotic Bcl-2 members have been targeted successfully using an antisense approach, BH3-peptides and small molecular weight chemicals that are inhibitors of their anti-apoptotic function.     

Targeting apoptosis as an approach for gastrointestinal cancer therapy

Cancers in the gastrointestinal system account for a large proportion of malignancies and cancer-related deaths with gastric cancer and colorectal cancer being the most common ones. For those patients in whom surgical resection is not possible, other therapeutic approaches are necessary. Disordered apoptosis has been linked to cancer development and treatment resistance. Apoptosis occurs via extrinsic or intrinsic signaling each triggered and regulated by many different molecular pathways. In recent years, the selective induction of apoptosis in tumor cells has been increasingly recognized as a promising approach for cancer therapy. A detailed understanding of the molecular pathways involved in the regulation of apoptosis is essential for developing novel effective therapeutic approaches. Apoptosis can be induced by many different approaches including activating cell surface death receptors (for example, Fas, TRAIL and TNF receptors), inhibiting cell survival signaling (such as EGFR, MAPK and PI3K), altering apoptosis threshold by modulating pro-apoptotic and anti-apoptotic members of the Bcl-2 family, down-regulating anti-apoptosis proteins (such as XIAP, survivin and c-IAP2), and using other pro-apoptotic agents. In this review, the authors reviewed the currently reported apoptosis-targeting approaches in gastrointestinal cancers.     

Bcl-2 family members as molecular targets in cancer therapy

Escape from apoptosis is often a hallmark of cancer cells, and is associated to chemotherapy resistance or tumor relapse. Proteins from the Bcl-2 family are the key regulators of the intrinsic pathway of apoptosis, controlling the point-of no-return and setting the threshold to engage the death machinery in response to a chemical damage. Therefore, Bcl-2 proteins have emerged as an attractive target to develop novel anticancer drugs. Current pharmacological approaches are focused on the use of peptides, small inhibitory molecules or antisense oligonucleotides to neutralize antiapoptotic Bcl-2 proteins, lowering the threshold and facilitating apoptosis of cancer cells. We discuss here recent advances in the development of Bcl-2 targeted anticancer therapies.     

The role of major apoptotic proteins in Ca<Superscript>2+</Superscript> dependent cell homeostasis

The key role of Bcl-2 (B-cell lymphoma) family proteins in programmed cell death (apoptosis) is reliably established, but particular molecular mechanisms of downregulation involving these anti-and pro-apoptotic proteins are still insufficiently clear. There are several hypotheses explaining the cell-protective (Bcl-2, Bcl-X_L) and pro-apoptotic (Bcl-x, Bak) functions of Bcl-2 family proteins. This paper briefly summarizes the available information concerning the molecular mechanisms of action of the pro-and anti-apoptotic proteins of Bcl-2 family. In particular, an original hypothesis is put forward according to which homo-and heterodimerization of these proteins are the key events in the mechanism of Ca²⁺ ion dependent homeostasis regulation. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 39, No. 12, pp. 3–8, December, 2005.     

Molecular mechanisms of apoptosis induced by cytotoxic chemicals

The purpose of this review article is to discuss established molecular mechanisms of apoptosis and their relevance to cell death induced by environmental toxicants. Apoptosis is a highly regulated form of cell death distinguished by the activation of a family of cysteine-aspartate proteases (caspases) that cleave various proteins resulting in morphological and biochemical changes characteristic of this form of cell death. Abundant evidence supports a role for mitochondria in regulating apoptosis. Specifically, it seems that a number of death stimuli target these organelles and stimulate, by an unknown mechanism, the release of several proteins, including cytochrome c. Once released into the cytosol, cytochrome c binds to its adaptor molecule, Apaf-1, which oligomerizes and then activates pro-caspase-9. Caspase-9 can signal downstream and activate pro-caspase-3 and -7. The release of cytochrome c can be influenced by different Bcl-2 family member proteins, including, but not limited to, Bax, Bid, Bcl-2, and Bcl-X(L). Bax and Bid potentiate cytochrome c release, whereas Bcl-2 and Bcl-X(L) antagonize this event. Although toxicologists have traditionally associated cell death with necrosis, emerging evidence suggests that different types of environmental contaminants exert their toxicity, at least in part, by triggering apoptosis. The mechanism responsible for eliciting the pro-apoptotic effect of a given chemical is often unknown, although in many instances mitochondria appear to be key participants. This review describes our current understanding of the role of apoptosis in environmental toxicant-induced cell death, using dioxin, metals (cadmium and methylmercury), organotin compounds, dithiocarbamates, and benzene as specific examples. Finally, we conclude with a critical discussion of the current knowledge in this area and provide recommendations for future directions.     

Anticancer drugs of tomorrow: apoptotic pathways as targets for drug design

Apoptosis or programmed cell death is a set of ordered events that enables the selective removal of cells from tissue and is essential for homeostasis and proper function of multicellular organisms. Components of this signaling network, which include ligands, such as CD95, tumor necrosis factor (TNF) and TNF-related apoptosis-inducing ligand, as well as downstream molecules, such as caspases, Bcl-2 family members, and inhibitor-of-apoptosis proteins, which trigger and regulate apoptosis, are crucial targets for conventional drug development and gene therapy of cancer and other diseases. Here, we focus on apoptotic pathways and propose new potential molecular targets that could prove effective in controlling cell death in the clinical setting.