新的凋亡抑制因子Livin

Livin是新近发现的一个凋亡抑制因子,属于抑制细胞凋亡蛋白(inhibitor of apoptosis protein,IAP)家族的新成员,主要通过抑制胱天蛋白酶-3／-7／-9(caspase-3／-7／-9)的活性来阻断细胞凋亡过程。Livin特异地表达于胚胎发育组织和大多数实体瘤,正常成人的绝大多数组织中也有表达。Livin抑制细胞凋亡,与肿瘤的发生、发展及预后相关,有望成为肿瘤治疗的新靶点。     

凋亡抑制蛋白Survivin 研究进展

存活素(Survivin)是凋亡抑制蛋白家族成员之一,具有抑制细胞凋亡和调节细胞周期的双重功能,主要表达于胚胎和发育的胎儿组织中,高表达于大多数恶性肿瘤组织,而在终末分化成熟的正常成人组织中无表达或低表达.本文就Survivin的结构、作用机制、组织分布及其在肿瘤治疗中的研究进展作一综述.     

抗凋亡因子Survivin研究进展

Survivin是在肿瘤组织及胚胎中发现的一类细胞因子,它是IAPs(inhibitorsofapoptosisprotein)家族的成员之一,具有其独特的分子结构和组织表达特异性,在细胞中参与细胞周期的调控,主要在细胞周期的G2/M期通过抑制caspase-3及caspase-7的活性发挥作用.Survivin在细胞中的活性可能受p53的调节.Survivin也是胚胎发育早期过程中调节细胞分裂分化的一类重要的因子.对Survivin的研究对于肿瘤治疗的研究及揭示胚胎早期的发育机制有重要的意义.     

凋亡抑制因子Survivin在大肠杆菌TB1中的表达纯化及鉴定

 本文旨在克隆凋亡抑制因子Survivin基因,并在大肠杆菌中进行可溶性表达与初步纯化. 采用RT-PCR法,扩增人凋亡抑制因子survivin cDNA,并克隆入原核表达载体pMAL p2X中,转化TB1大肠杆菌感受态细胞.经0.3 mmol/L IPTG诱导2 h后,收集菌体蛋白,进行SDS-PAGE、ELISA及Western 印迹鉴定. 实验获得凋亡抑制因子survivin编码区cDNA,以构建的原核表达载体pMAL-p2X survivin转化菌株后,可表达凋亡抑制因子survivin和麦芽糖结合蛋白(MBP)的融合蛋白,相对分子质量(Mr) 为58 000.并成功利用Factor Xa将融合蛋白裂解开.ELISA和Western 印迹表明,融合蛋白能与抗凋亡抑制因子survivin单克隆抗体特异性结合.获得的凋亡抑制因子survivin全长cDNA可在大肠杆菌TB1中以MBP survivin融合蛋白的形式表达,成功地将survivin目的蛋白和MBP蛋白分离,为深入研究survivin的结构和功能奠定了基础.     

凋亡抑制因子FAP-1与肿瘤的关系

在肿瘤细胞抵抗凋亡的研究中发现,FAP-1是Fas诱导凋亡的抑制因子,在多种肿瘤细胞中表达。通过对FAP-1基因、蛋白质结构等方面的研究发现,FAP-1以PDZ3结构域介导,与Fas在细胞内强结合,将Fas限制于高尔基体内,不表达于癌细胞表面,从而降低Fas的功能。另外FAP-1会通过磷酸酯酶活性的发挥、NF-κB等途径来抵抗Fas诱导的肿瘤细胞的凋亡。因此,从其作用机制出发,抑制FAP-1mRNA的表达、阻断FAP-1与Fas的结合及其信号转导通路,可以诱导肿瘤细胞的凋亡从而为肿瘤的诊治提供新途径。     

细胞凋亡抑制因子

细胞凋亡 (ａｐｏｐｔｏｓｉｓ)是一种细胞的生理性自杀行为 ,对保持周围组织的健康和正常生长具有十分重要的意义。细胞凋亡的紊乱与许多致病性疾病的发生有关 ,涉及细胞凋亡过度的疾病如ＡＩＤＳ、神经变性紊乱、局部缺血等 ;涉及到细胞凋亡程度过低而导致的疾病如癌症的发生等。因此对细胞凋亡途径具有调节作用的蛋白质引起人们的广泛关注。ＩＡＰ(ｉｎｈｉｂｉｔｏｒｏｆａｐｏｐｔｏｓｉｓ)家族蛋白最早发现于杆状病毒 ,它能抑制由病毒感染而诱导的细胞凋亡。杆状病毒在长期进化过程中 ,为适应自身的生活环境及繁殖的需要 ,获得了一些…     

凋亡抑制因子Livin的研究进展

凋亡抑制因子是一类重要的抗细胞凋亡因子,在肿瘤的发病机制中起着重要的作用.Livin是新近发现的一个IAP家族成员.在大多数成人组织中不表达或低表达,但在多种恶性肿瘤中高表达,提示该基因可能在肿瘤发生发展中起重要作用.研究其结构与功能及其作用机制对于肿瘤的发生和发展、抗肿瘤药物筛选、癌症的诊断、治疗和预后有重要意义.Livin需通过一系列的凋亡刺激物的作用来表现凋亡的抑制,其抑制凋亡的信号通路包括外在途径、内在途径和化疗药物途径等多条途径.目前对Livin抗凋亡的作用机理了解得还不是很多.本文就其相关进展进行综述.     

破骨细胞形成抑制因子研究进展

破骨细胞形成抑制因子（OPG/OCIF）是最近发现的一种参与调节骨密度的糖蛋白,是一个肿瘤坏死因子(TNF)受体超家族的新成员,其氨基酸序列中具有TNF受体结构类似区.成熟的OPG/OCIF具有7个结构域,可分为三个功能区,即：TNF受体结构区、致死结构区和肝素结合区.OPG/OCIF基因定位在8q23～24上,由5个外显子和4个内含子组成,其表达受到与骨的形成和破坏有关因子的调控：如TGF-β1、1,25(OH)₂VD₃、TNF-α等等.OPG/OCIF抑制骨的破坏和吸收机制主要是抑制破骨细胞的存活,引起破骨细胞凋亡和抑制破骨细胞形成.     

促细胞凋亡因子Bid蛋白的研究进展

Bid蛋白是Bcl-家族中促凋亡类的蛋白。它具有可被caspase8酶切高控、高效地诱民细胞色素c从线粒体泄漏到胞浆中的功能,从而在细胞凋亡中起着重要的作用,因而倍受人们的重视。Bid蛋白的功能被发现以来,短短几年间,人们从分子生物学、细胞学、结构分析以及利用脂质体模型膜体系等各方面对Bid蛋白进行研究,取得了很大的进展。     

杆状病毒凋亡抑制基因的研究进展

杆状病毒(bacu lovirus)感染昆虫细胞能引起细胞凋亡,但在长期进化过程中,杆状病毒可通过自身编码凋亡抑制基因的表达,抑制细胞凋亡以利于自己的增殖。目前在杆状病毒基因组中已发现两种不同类型的细胞凋亡抑制基因p35/p49和iap,这两类凋亡抑制基因分别作用于细胞凋亡途径的不同位点,以抑制细胞的凋亡。近年来人们对这两种基因的蛋白结构及作用机制等方面进行了大量的研究,这些为今后研究昆虫细胞凋亡,扩大杆状病毒宿主范围等方面奠定了基础。     

Survivin: A target from brain cancer to neurodegenerative disease

Apoptosis is an important contributing factor during neuronal death in a variety of neurodegenerative disorders, including multiple sclerosis, Parkinson’s disease and sciatic nerve injury. Whereas several clinical and preclinical studies have focused on the neuroprotective effects of caspase inhibitors, their clinical benefits are still unclear. Here, we discuss novel alternative strategies to protect neuronal cells from apoptotic death using members of the inhibitors of apoptosis (IAP) family. We specifically review the different roles of survivin, which is an important member of the IAP family that serves a dual role in the inhibition of apoptosis as well as a vital role in mitosis and cell division. Due to the various roles of survivin during cell division and apoptosis, targeting this protein illustrates a new therapeutic window for the treatment of neurodegenerative diseases.     

Anti-apoptosis engineering

An increased understanding of apoptosis makes anti-apoptosis engineering possible, which is an approach used to inhibit apoptosis for the purpose of therapeutic, or industrial applications in the treatment of the diseases associated with increased apoptosis, or to improve the productivity of animal cell cultures, respectively. Some known anti-apoptotic proteins are the Bcl-2 family, IAP (inhibitor of apoptosis) and Hsps (heat shock proteins), with which anti-apoptosis engineering has progressed. This article reviews anti-apoptosis engineering using known anti-apoptotic compounds, and introduces a 30 K protein, isolated from silkworm hemolymph, as a novel anti-apoptotic protein, that shows no homology with other known anti-apoptotic proteins. The regulation of apoptosis, using anti-apoptotic proteins and genes originating from the silkworm,Bombyx mori, may provide a new strategy in this field.     

Prognostic significance of X-linked inhibitor of apoptosis protein in solid tumors: A systematic review and meta-analysis

X-linked inhibitor of apoptosis protein (XIAP) is aberrantly expressed in solid tumors. Considering conflicting data, we conducted this meta-analysis to investigate its prognostic role. Electronic databases were searched to collect studies about associations between XIAP expressions and survival outcomes. Hazard ratio (HR), odds ratio (OR), and 95% confidence interval (CI) were utilized as effect size estimates. A total of 3,794 patients from 21 published studies were included. The results revealed that high XIAP expressions correlated with age (OR = 2.02; 95% CI, 1.07–3.84), lymph node metastasis (OR = 1.69; 95% CI, 1.02–2.77), histological grade (OR = 2.04; 95% CI, 1.01–4.11), and tumor stage (OR = 2.18; 95% CI, 1.20–3.96). The combined HR revealed that high XIAP expressions associated with poor overall survival (OS) (HR = 1.60; 95% CI, 1.22–2.10). Our study suggested high XIAP expressions may be indicative of poor prognosis in solid tumors.     

Survivin a pivotal antiapoptotic protein in rheumatoid arthritis

Rheumatoid arthritis (RA) is an autoimmune disease, pathologically characterized by lymphocyte infiltration of the synovial membrane that leads to chronic inflammation and progressive joint damage. RA develops as a result of increased cell infiltration and cell proliferation as well as impaired cell death. Activated cells in joints including lymphocytes and fibroblast-like synoviocytes (FLS) survive for a long time as a consequence of compromised apoptosis, but the mechanism underlying cell survival in synovium remains to be firmly established. Inhibition of apoptosis by survivin, as a critical antiapoptotic protein, contributes to both the persistence of autoreactive T lymphocytes and tumor-like phenotype of FLS in RA. In addition to the antiapoptotic role, survivin also has prognostic relevance in RA prodromal phase. Hence, this review provides an overview of the current knowledge regarding the involvement of survivin protein in the pathogenesis of RA.     

Inhibitor of apoptosis proteins and apoptosis

Apoptosis is a physiological cell death process that plays a critical role in development, homeostasis, and immune defense of multicellular animals. Inhibitor of apoptosis proteins (IAPs) constitute a family of proteins that possess between one and three baculovirus IAP repeats. Some of them also have a really interesting new gene finger domain, and can prevent cell death by binding and inhibiting active caspases, but are regulated by IAP antagonists. Some evidence also indicates that IAP can modulate the cell cycle and signal transduction. The three main factors, IAPs, IAP antagonists, and caspases, are involved in regulating the progress of apoptosis in many species. Many studies and assumptions have been focused on the anfractuous interactions between these three main factors to explore their real functional model in order to develop potential anticancer drugs. In this review, we describe the classification, molecular structures, and properties of IAPs and discuss the mechanisms of apoptosis. We also discuss the promising significance of clinical applications of IAPs in the diagnosis and treatment of malignancy.     

Interaction of Beclin 1 with survivin regulates sensitivity of human glioma cells to TRAIL-induced apoptosis

We reported a novel interaction between Beclin 1, a key regulator of autophagy, and survivin, a member of the inhibitor of apoptosis protein family. We found that knock-down of Beclin 1 down-regulated survivin protein, and the turnover rate of survivin was increased when Beclin 1 expression was silenced. Knock-down of Beclin 1 sensitized glioma cells to TRAIL-induced apoptosis, and introduction of survivin antagonized the sensitizing effect, suggesting that down-regulation of survivin mediates the enhanced sensitivity to TRAIL-induced apoptosis. These results demonstrate a novel interaction between Beclin 1 and survivin, and may provide a potential mechanism underlying the cross-talk between autophagy and apoptosis.

Structured summary

MINT-7969366: Beclin-1 (uniprotkb:Q14457) physically interacts (MI:0915) with survivin (uniprotkb:O15392) by anti tag coimmunoprecipitation (MI:0007)MINT-7968986, MINT-7969161: survivin (uniprotkb:O15392) physically interacts (MI:0915) with Beclin-1 (uniprotkb:Q14457) by anti bait coimmunoprecipitation (MI:0006)     

Molecular circuits of apoptosis regulation and cell division control: the survivin paradigm

The coupling of cell proliferation to cell death is thought to function as a pivotal crossroad, essential to preserve normal homeostasis and to eliminate dangerous cells before they divide. Survivin is a prototype molecule at this crossroad, intercalated in protection against mitochondrial cell death and orchestrating various aspects of cell division. Dramatically exploited in cancer and an unfavorable gene signature for disease outcome, the survivin pathway has now provided tangible opportunities for targeted, rational cancer therapy.     

Crystal structure of the BIR1 domain of XIAP in two crystal forms

X-linked inhibitor of apoptosis (XIAP) is a potent negative regulator of apoptosis. It also plays a role in BMP signaling, TGF-beta signaling, and copper homeostasis. Previous structural studies have shown that the baculoviral IAP repeat (BIR2 and BIR3) domains of XIAP interact with the IAP-binding-motifs (IBM) in several apoptosis proteins such as Smac and caspase-9 via the conserved IBM-binding groove. Here, we report the crystal structure in two crystal forms of the BIR1 domain of XIAP, which does not possess this IBM-binding groove and cannot interact with Smac or caspase-9. Instead, the BIR1 domain forms a conserved dimer through the region corresponding to the IBM-binding groove. Structural and sequence analyses suggest that this dimerization of BIR1 in XIAP may be conserved in other IAP family members such as cIAP1 and cIAP2 and may be important for the action of XIAP in TGF-beta and BMP signaling and the action of cIAP1 and cIAP2 in TNF receptor signaling.     

Oncogenic c-H-ras deregulates survivin expression: an improvement for survival

Survivin protein accomplishes two basic functions: cell cycle regulation and control of apoptosis. It is only expressed in G2/M phase and it influences rescue pathways in apoptosis-induced cells. Overexpression of constitutive active c-H-ras in HeLa, or induction of c-H-ras in a stable HeLaDiR cell line, led to sustained survivin expression in all cell cycle phases and even protected cells from drug induced apoptosis. siRNA-mediated silencing of survivin reversed this protection. Here we link the anti-apoptotic property of survivin to its cell cycle (in)dependent regulation via the activity of oncogenic c-H-ras.