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.     

Survivin在口腔颌面部上皮性肿瘤中的研究进展

Survivin是近年发现的结构独特的凋亡抑制蛋白家族成员,具有抑制细胞凋亡、调节细胞有丝分裂的双重功能.Survivin具有肿瘤特异性,在正常成人组织中少见表达却高表达于多种肿瘤组织且与肿瘤细胞的浸润和病人的不良预后密切相关.本文对Surviviu的生物学功能及其与口腔颌面部上皮性肿瘤关系的研究进展进行综述.     

靶向Survivin基因与肿瘤

Survivin基因不仅表达于绝大多数的肿瘤细胞中,也存在于人体正常的细胞中,它具有抑制凋亡和调节有丝分裂的双重作用．临床研究表明：下调Survivin基因的表达或者抑制Survivin蛋白的功能,可以降低肿瘤细胞的生长潜力、增加凋亡的比例,而且可以增强肿瘤细胞对抗肿瘤药物和放射线的敏感性．许多抗肿瘤药物通过诱导细胞凋亡而发挥功能．但某些肿瘤表现出对它们的耐药性。导致肿瘤耐药性的一个最重要的因素就是Survivin的表达．有关细胞凋亡途径和Survivin基因表达等方面的研究可为发现和发展新型抗肿瘤药物提供新的途径．     

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。     

Survivin的研究现状与RNA干扰在基因治疗中的进展

Survivin是新近发现的凋亡抑制蛋白,在正常组织中不表达而在恶性肿瘤中高表达,与肿瘤的预后、复发、转移关系密切,具有调控细胞周期,凋亡和增殖的作用;还与对化疗的耐药性和放疗的敏感性有关;此外,与肿瘤新生血管的形成关系也十分密切.针对Survivin这些特性,应用新的基因治疗技术-RNA干扰技术降低Survivin的表达可对肿瘤组织的凋亡和增殖产生影响,由于RNA干扰技术具有的高效性,特异性,长效性,使它成为肿瘤基因治疗的重要方法,应用RNA干扰技术针对Survivin靶位降低Survivin的表达有望成为今后肿瘤基因治疗的方向.     

胰腺癌反义寡核苷酸技术治疗的新靶点-survivin

survivin对维持肿瘤细胞恶性增殖具有重要功能,是目前发现IAP家族中唯一与细胞凋亡和周期调控都相关的成员,其机理是与caspase-3、caspase-7结合而阻止细胞凋亡的发生。反义寡核苷酸具有高特异性、靶向性、无毒性等特点。以互补的形式与DNA或RNA的特异靶序列结合,抑制其转录和翻译上特定基因的表达,干扰致病蛋白质的产生,从而使肿瘤基因无法表达。存活素在胰腺癌中的表达具有一定的肿瘤特异性,可能是胰腺癌治疗的一个理想靶目标。下面就着重以survivin作为治疗靶点在肿瘤发生中的作用机制、表达和Survivin ASODN在临床应用中的应用前景作一简要综述。     

Survivin小分子抑制剂的研究进展

Survivin是凋亡抑制蛋白家族的一员,在抑制细胞凋亡、调控细胞周期、参与血管形成等方面发挥重要的生物学功能。Survivin在多种肿瘤组织中过量表达,与肿瘤不良预后和耐药性密切相关。Survivin作为一种潜在的肿瘤治疗靶点,其小分子抑制剂用于肿瘤治疗的研究为人们所关注。概述了Survivin的结构、功能及其在肿瘤组织中的特异性表达,综述了目前靶向Survivin的小分子抑制剂的研究进展。     

预热诱导心肌细胞表达Hsp70对Fas通路活化后细胞凋亡变化的研究

目的:研究Hsp70对Fas通路活化后细胞凋亡的作用及其可能机制.方法:水浴预热诱导培养新生大鼠心肌细胞Hsp70表达,Fas抗体活化Fas通路,Western blot测定Hsp70的表达,流式细胞仪检测细胞凋亡率,特异性底物测定caspase-8及caspase-3的活力.结果:预热可以使心肌细胞Hsp70表达升高,Fas抗体降低细胞凋亡率,高表达Hsp70可以降低Fas通路活化后心肌细胞凋亡率,同时相应使caspase-8及caspase-3活力升高的幅度降低.结论:Hsp70可能通过抑制caspase-8及caspase-3的活力而降低Fas通路活化后培养新生大鼠心肌细胞凋亡的发生.     

VEGF和Survivin在肾癌中的表达及其相关性研究

目的:探讨肾癌组织中血管内皮生长因子VEGF与凋亡抑制蛋白Survivin表达的相关性及其之间的关系,研究Survivin和VEGF在肾癌发生发展中的作用机制。方法:应用免疫组织化学方法检测70例肾癌组织和70例癌旁正常肾脏组织中VEGF和Survivin的表达,并将检测结果与临床病理特征进行综合分析。结果:VEGF和Survivin在肾癌中表达均高于癌旁正常肾脏组织;Survivin和VEGF在肾癌中的阳性表达率分别为75.71%(53/70)和72.86%(51/70),在癌旁肾脏组织中的表达率分别为0%(0/70)、17.14%(12/70),差异均有显著性意义(P0.05);VEGF和Survivin的表达与患者的性别、年龄、肿瘤大小、病理分级均无相关性;VEGF和Survivin表达呈正相关性。结论:VEGF和Survivin在肾癌组织中表达率较高,为肾癌的分子靶向治疗提供了新的靶点。Survivin和VEGF在RCC中的表达关系密切,测定RCC中Survivin、VEGF蛋白的表达,有助于临床判断病人预后。     

Upregulation of survivin by HIV-1 Vpr

The human survivin gene belongs to the family of inhibitor of apoptosis proteins (IAP) and is involved in apoptosis inhibition and regulation of cell division. The survivin gene is the only member of the IAP family whose expression is known to be regulated through the cell cycle. Survivin expression reaches the highest levels during the G₂/M transition and then is rapidly degraded during the G₁ phase. Here we report that the human immunodeficiency virus type 1 (HIV-1) upregulates Survivin expression via survivin promoter transactivation. Vpr, an HIV-1 accessory protein that induces cell cycle arrest in G₂/M, is necessary and sufficient for this effect. Blocking Vpr-induced G₂/M arrest leads to elimination of the survivin promoter transactivation by Vpr. Our results suggest that Survivin may be actively involved in regulating cell viability during HIV-1 infection.     

Survivin is essential for fertile egg production and female fertility in mice

Survivin is the smallest member of the inhibitor of apoptosis protein (IAP) family and acts as a bifunctional protein involved in mitosis regulation and apoptosis inhibition. To identify the physiological role of Survivin in female reproduction, we selectively disrupted Survivin expression in oocytes and granulosa cells (GCs), two major cell types in the ovary, by two different Cre-Loxp conditional knockout systems, and found that both led to defective female fertility. Survivin deletion in oocytes did not affect oocyte growth, viability and ovulation, but caused tetraploid egg production and thus female infertility. Further exploration revealed that Survivin was essential for regulating proper meiotic spindle organization, spindle assembly checkpoint activity, timely metaphase-to-anaphase transition and cytokinesis. Mutant mice with Survivin depleted in GCs showed reduced ovulation and subfertility, caused by defective follicular growth, increased follicular atresia and impaired luteinization. These findings suggest that Survivin has an important role in regulating folliculogenesis and oogenesis in the adult mouse ovary.     

Survivin and the inner centromere protein INCENP show similar cell-cycle localization and gene knockout phenotype

BACKGROUND: Survivin is a mammalian protein that carries a motif typical of the inhibitor of apoptosis (IAP)proteins, first identified in baculoviruses. Although baculoviral IAP proteins regulate cell death, the yeast Survivin homolog Bir1 is involved in cell division. To determine the function of Survivin in mammals, we analyzed the pattern of localization of Survivin protein during the cell cycle, and deleted its gene by homologous recombination in mice. RESULTS: In human cells, Survivin appeared first on centromeres bound to a novel para-polar axis during prophase/metaphase, relocated to the spindle midzone during anaphase/telophase, and disappeared at the end of telophase. In the mouse, Survivin was required for mitosis during development. Null embryos showed disrupted microtubule formation, became polyploid, and failed to survive beyond 4.5days post coitum. This phenotype, and the cell-cycle localization of Survivin, resembled closely those of INCENP. Because the yeast homolog of INCENP, Sli15, regulates the Aurora kinase homolog Ipl1p, and the yeast Survivin homolog Bir1 binds to Ndc10p, a substrate of Ipl1p, yeast Survivin, INCENP and Aurora homologs function in concert during cell division. CONCLUSIONS: In vertebrates, Survivin and INCENP have related roles in mitosis, coordinating events such as microtubule organization, cleavage-furrow formation and cytokinesis. Like their yeast homologs Bir1 and Sli15, they may also act together with the Aurora kinase.     

Participation of Survivin in mitotic and apoptotic activities of normal and tumor-derived cells

Survivin is a member of the inhibitor of apoptosis (IAP) gene family, containing a single baculovirus IAP repeat (BIR) and no RING finger, that is expressed in many human cancers. Although it has been proposed to be involved in mitotic and cytokinetic processes, its functional subcellular distribution in the cytoplasm and nucleus, and its binding to centrosomes, spindle fibers, and centromeres in relation to these processes, is not fully resolved. We have analyzed the localization of Survivin in normal (Detroit 551, IMR-90) and tumor-derived (HeLa, Saos-2) cell lines, and found that it does colocalize with centrosomes in the cytoplasm during interphase, then moves to centromeres during mitosis, and finally localizes to the midbody spindle fibers during telophase. However, Taxol, a popular microtubule stabilizing agent that is frequently used in the study of these processes, severely disrupted the localization of Survivin. Taxol treatment of cells promoted extensive relocalization of Survivin with alpha-tubulin on microtubules during either interphase or mitosis. Survivin antisense oligonucleotide markedly sensitized HeLa cells to cell death induced by agents acting at the level of cell surface receptor (Fas pathway) or at the level of mitochondria (etoposide). HeLa cell death induced by Survivin antisense oligonucleotide could be partially complemented by Deterin, the Drosophila homolog of Survivin (Jones et al. [2000] J. Biol. Chem. 275:22157-22166). Reciprocally, a chimera of the Deterin BIR domain and Survivin C-terminus could rescue Drosophila Kc cells from death induced by transfection of a human caspase-7-expressing plasmid. These results indicate common components of Survivin and Deterin antiapoptotic action in the vertebrate and invertebrate phyla.     

Adenosine-induced caspase-3 activation by tuning Bcl-X<Subscript>L</Subscript>/DIABLO/IAP expression in HuH-7 human hepatoma cells

Extracellular adenosine disrupted mitochondrial membrane potentials in HuH-7 cells, a Fas-deficient human hepatoma cell line, and the effect was inhibited by the adenosine transporter inhibitor dipyridamole or by overexpressing Bcl-X_L. Adenosine downregulated the expression of mRNAs and proteins for Bcl-X_L and inhibitor of apoptosis protein 2 (IAP2) to directly inhibit caspase-3, -7, and -9, but it otherwise upregulated the expression of mRNA and protein for DIABLO, an inhibitor of IAPs. Those adenosine effects were attenuated by dipyridamole. Caspase-3 and -8 were implicated in adenosine-induced HuH-7 cell death, and adenosine actually activated caspase-3 without caspase-9 activation. The caspase-3 activation was inhibited by overexpressing Bcl-X_L or IAP2. Taken together, the results of the present study indicate that intracellularly transported adenosine activates caspase-3 by neutralizing caspase-3 inhibition due to IAP as a result of decreased IAP2 expression and reduced IAP activity in response to increased DIABLO expression and perhaps DIABLO release from damaged mitochondria, in addition to caspase-8 activation. This represents further insight into adenosine-induced HuH-7 cell apoptotic pathway.     

Developmental and hormonal regulation of midgut remodeling in a lepidopteran insect, Heliothis virescens

Midgut tissue undergoes remodeling during metamorphosis in insects belonging to orders Lepidoptera and Diptera. We investigated the developmental and hormonal regulation of these remodeling events in lepidopteran insect, Heliothis virescens. In H. virescens, programmed cell death (PCD) of larval midgut cells as well as proliferation and differentiation of imaginal cells began at 108 h after ecdysis to the final larval instar (AEFL) and proceeded through the pupal stages. Expression patterns of pro- cell death factors (caspase-1 and ICE) and anti-cell death factor, Inhibitor of Apoptosis (IAP) were studied in midguts during last larval and pupal stages. IAP, Caspase-1 and ICE mRNAs showed peaks at 48 h AEFL, 96 h AEFL and in newly formed pupae, respectively. Immunohistochemical analysis substantiated high caspase-3 activity in midgut at 108 h AEFL. Application of methoprene, a juvenile hormone analog (JHA) blocked PCD by maintaining high levels of IAP, downregulating the expression of caspase-1, ICE and inhibiting an increase in caspase-3 protein levels in midgut tissue. Also, the differentiation of imaginal cells was impaired by methoprene treatment. These studies demonstrate that presence of JHA during final instar larvae affects both midgut remodeling and larval-pupal metamorphosis leading to larval/pupal deformities in lepidopteran insects, a mechanism that is different from that in mosquito, Ae. aegypti where JHA uncouples midgut remodeling from metamorphosis.     

Chemically synthesized human survivin does not inhibit caspase-3

Survivin is a member of the inhibitor of apoptosis protein (IAP) family that blocks cell death by inhibiting the caspase activation pathways. Overexpressed in all common human neoplasms but undetectable in most normal adult tissues, survivin confers tumor resistance to apoptosis and represents an ideal molecular target for therapeutic intervention. How survivin blocks apoptosis, however, has been a subject of intense debate, as evidenced by conflicting reports regarding whether or not survivin can directly bind and inactivate effector caspases. We chemically synthesized large amounts of highly pure human survivin of 142 amino acid residues using native chemical ligation and functionally compared synthetic survivin and a recombinant XIAP--the most intensively studied member of the IAP family. Inhibition assays showed that, while caspase-3 could be effectively inhibited by XIAP, survivin had no detectable inhibitory activity against the enzyme, even at concentrations several thousand-fold higher than XIAP. Our finding supports the premise that survivin does not directly inhibit effector caspases.     

Survivin在细胞分裂中的作用

Survivin是凋亡蛋白抑制因子家族的一个新成员,它主要在细胞周期G2/M期表达,并有两种不同的亚细胞定位。Survivin与有丝分裂细胞周期的启动有关,并在有丝分裂中的中心体装配、纺锤体检验点的监控、胞质分裂等过程中发挥作用。Survivin在减数分裂中也有一定的作用,目前研究甚少。Survivin发挥功能的首要前提是通过主要的有丝分裂激酶p34cdc2-cyclinB1使Thr34磷酸化,其表达水平受很多因素的调节。