钙依赖性粘附素及其信号转导

钙依赖性粘附素介导的粘附连接在决定和维持发育及成年机体的组织结构中起着重要作用。钙依赖性粘附素结合的特异性取决于其细胞外段,但完整的生理性粘附还需其胞质尾段与胞质相关蛋白以及细胞骨架的相互作用和联系。粘附连接的调节涉及到钙依赖性粘附素基因表达、聚集和磷酸化以及缝隙连接通讯等;此外,钙依赖性粘附素－连环素复合体还参与信号转导过程,从而影响组织的结构和功能。     

钙/钙调蛋白依赖性丝氨酸蛋白激酶的结构和功能

钙/钙调蛋白依赖性丝氨酸蛋白激酶(calcium/calmodulin-dependent serine protein kinase, CASK)属于膜相关鸟苷酸激酶(membrane associated guanylate kinase, MAGUK)家族.CASK具有多个不同蛋白质结合结构域,在细胞膜的特定区域,与其他蛋白质形成多种蛋白质复合体,参与组成细胞骨架.它通过衔接细胞外信号蛋白和细胞内骨架蛋白,协助功能蛋白质的转运和定位,以及细胞内的信号传递.此外CASK还可以进入细胞核影响基因转录调控,以及作用在神经突触膜上参与神经递质的释放.     

钙/钙调蛋白依赖性丝氨酸蛋白激酶的结构和功能

钙/钙调蛋白依赖性丝氨酸蛋白激酶(calcium/calmodulin-dependent serine protein kinase, CASK)属于膜相关鸟苷酸激酶（membrane associated guanylate kinase, MAGUK）家族.CASK具有多个不同蛋白质结合结构域，在细胞膜的特定区域，与其他蛋白质形成多种蛋白质复合体，参与组成细胞骨架.它通过衔接细胞外信号蛋白和细胞内骨架蛋白，协助功能蛋白质的转运和定位，以及细胞内的信号传递.此外CASK还可以进入细胞核影响基因转录调控，以及作用在神经突触膜上参与神经递质的释放.     

T-钙粘附素在肿瘤发生发展中的作用

T-钙粘附素是钙粘附素家族中的一个特殊成员,缺乏跨膜区和胞浆区,是通过糖基磷脂酰肌醇附着于细胞膜上．T-钙粘附素的异常表达参与到多种肿瘤的发生发展过程中,如肿瘤细胞的凋亡、增殖、侵袭和转移等过程．T-钙粘附素还可能参与肿瘤新生血管的形成和胞内外的信号传导过程．本文就T 钙粘附素在肿瘤发生发展过程中的作用及分子机制作一综述,该蛋白有可能成为肿瘤治疗的新靶点.     

TGF-β1对人正常胎盘滋养层细胞表达E-钙粘素的调节

E-钙粘素是在胚胎发育中最早表达的分子之一,它可以与Catenin家族成员形成钙粘素/Catenin复合物参与多种细胞功能,对于胚胎植入和胎盘发生具有重要作用.通过RT-PCR、免疫组织化学、细胞粘附分析等方法,在人正常妊娠和输卵管妊娠母胎界面上,发现E-钙粘素主要定位于绒毛细胞滋养层细胞和滋养层细胞柱,从滋养层细胞柱近端向远端,其蛋白质水平逐渐降低.正常胎盘组织中E-钙粘素水平在妊娠早期较高,妊娠中期直至分娩期均维持低水平.在体外培养的人正常胎盘细胞滋养层细胞系(NPC细胞)中,转化生长因子β(TGFβ1)显著上调E-钙粘素蛋白和mRNA的表达,并呈现时间和剂量依赖性,同时,TGFβ1促进NPC细胞之间的粘附.上述结果表明,胎盘中存在E-钙粘素的旁分泌调节机制,E-钙粘素可通过调节滋养层细胞粘附而参与细胞侵润的有节制调控.     

Ca2+和突触细胞融合

神经突触传递对于神经系统功能的实现具有十分重要的意义,而神经突触传递涉及到突触囊泡膜和突触前膜的融合,3种膜蛋白SNARE特异性识别并形成复合物,从而介导了神经递质的释放。Ca^2 通过其感受器突触结合蛋白而调节了突触细胞的融合过程,也最终影响了神经元的胞吐作用。     

神经可塑性与认知功能关系研究进展

认知是神经中枢的高级智能活动,其神经生理特性是中枢神经之高度可塑性,涵盖神经网络、神经再生及突触连接等层次的可塑性调节变化。因突触可塑性是神经元之间信息传递之中心枢纽,亦为神经可塑性之主要部位。故本文主要从与突触可塑性相关的LTP、突触素、相关神经递质及临床相关疾病等方面阐述突触可塑性对认知功能的影响。     

蛋白磷酸化去磷酸化与突触囊泡循环

神经递质合成酶、胞吐相关蛋白、神经递质受体,以及离子通道等蛋白的磷酸化和去磷酸化对神经系统的功能具有重要作用。神经递质的释放往往伴随众多蛋白的磷酸化或去磷酸化过程,包括突触蛋白磷酸化引起突触囊泡从细胞骨架上解离、突触囊泡通过复合体SNARE和Ca2 的介导与突触前膜发生锚靠、融合和神经递质释放,以及以网格蛋白依赖的形式实现突触囊泡从突触前膜上内陷、出芽和缢缩后,从膜上裂解到胞浆中重新形成突触囊泡。因此,蛋白磷酸化和去磷酸化对于神经系统完成神经信号传递具有重要的意义。     

Calsyntenins家族在学习记忆和阿尔茨海默病发病中的作用研究

钙结合蛋白家族(calsyntenins,CLSTNs)属于细胞黏附分子钙黏素超家族,包括CLSTN1、CLSTN2和CLSTN3三个成员,主要表达于锥体神经元突触后膜和转运囊泡中,参与调控线虫和人的学习记忆。CLSTNs能将细胞外水解信号和细胞内Ca~(2+)激活信号相关联,还是一个调控多个膜结合细胞器转运的胞内运输蛋白。现分析CLSTNs激活Ca~(2+)信号途径和参与胞内转运的功能,归纳CLSTNs调控学习记忆、突触发育和突触传递的作用,以及在阿尔茨海默病(Alzheimer’s disease,AD)发病中的作用,为理解CLSTNs的细胞生物学功能提供线索。     

粘附分子与信号传导

跨膜信号传导是基本的生命现象。粘附分子,尤其是整合素（integrins）,是信号传导中重要的跨膜分子。细胞通过整合素等与配体结合,进行胞内外信息交流,调节细胞与细胞、细胞与基质的粘附以及细胞形态和功能,从而发挥细胞的正常功能。     

Context-dependent regulation of Musashi-mediated mRNA translation and cell cycle regulation

Musashi-mediated mRNA translational control has been implicated in the promotion of physiological and pathological stem cell proliferation. During self-renewal of mammalian stem cells, Musashi has been proposed to act to repress the translation of mRNAs encoding inhibitors of cell cycle progression. By contrast, in maturing Xenopus oocytes Musashi activates translation of target mRNAs that encode proteins promoting cell cycle progression. The mechanisms directing Musashi to differentially control mRNA translation in mammalian stem cells and Xenopus oocytes is unknown. In this study, we demonstrate that the mechanisms defining Musashi function lie within the cellular context. Specifically, we show that murine Musashi acts as an activator of translation in maturing Xenopus oocytes while Xenopus Musashi functions as a repressor of target mRNA translation in mammalian cells. We further demonstrate that within the context of a primary mammalian neural stem/progenitor cell, Musashi can be converted from a repressor of mRNA translation to an activator of translation in response to extracellular stimuli. We present current models of Musashi-mediated mRNA translational control and discuss possible mechanisms for regulating Musashi function. An understanding of these mechanisms presents exciting possibilities for development of therapeutic targets to control physiological and pathological stem cell proliferation.Key words: musashi, stem cell, oocyte, mRNA translation, proliferation, differentiation, cell cycle     

Combinatorial network of transcriptional regulation and microRNA regulation in human cancer

Background

In order to reduce time and efforts to develop microbial strains with better capability of producing desired bioproducts, genome-scale metabolic simulations have proven useful in identifying gene knockout and amplification targets. Constraints-based flux analysis has successfully been employed for such simulation, but is limited in its ability to properly describe the complex nature of biological systems. Gene knockout simulations are relatively straightforward to implement, simply by constraining the flux values of the target reaction to zero, but the identification of reliable gene amplification targets is rather difficult. Here, we report a new algorithm which incorporates physiological data into a model to improve the model??s prediction capabilities and to capitalize on the relationships between genes and metabolic fluxes.

Results

We developed an algorithm, flux variability scanning based on enforced objective flux (FVSEOF) with grouping reaction (GR) constraints, in an effort to identify gene amplification targets by considering reactions that co-carry flux values based on physiological omics data via ??GR constraints??. This method scans changes in the variabilities of metabolic fluxes in response to an artificially enforced objective flux of product formation. The gene amplification targets predicted using this method were validated by comparing the predicted effects with the previous experimental results obtained for the production of shikimic acid and putrescine in Escherichia coli. Moreover, new gene amplification targets for further enhancing putrescine production were validated through experiments involving the overexpression of each identified targeted gene under condition-controlled batch cultivation.

Conclusions

FVSEOF with GR constraints allows identification of gene amplification targets for metabolic engineering of microbial strains in order to enhance the production of desired bioproducts. The algorithm was validated through the experiments on the enhanced production of putrescine in E. coli, in addition to the comparison with the previously reported experimental data. The FVSEOF strategy with GR constraints will be generally useful for developing industrially important microbial strains having enhanced capabilities of producing chemicals of interest.     

Context-dependent regulation of Musashi-mediated mRNA translation and cell cycle regulation.

Musashi-mediated mRNA translational control has been implicated in the promotion of physiological and pathological stem cell proliferation. During self-renewal of mammalian stem cells, Musashi has been proposed to act to repress the translation of mRNAs encoding inhibitors of cell cycle progression. By contrast, in maturing Xenopus oocytes Musashi activates translation of target mRNAs that encode proteins promoting cell cycle progression. The mechanisms directing Musashi to differentially control mRNA translation in mammalian stem cells and Xenopus oocytes is unknown. In this study, we demonstrate that the mechanisms defining Musashi function lie within the cellular context. Specifically, we show that murine Musashi acts as an activator of translation in maturing Xenopus oocytes while Xenopus Musashi functions as a repressor of target mRNA translation in mammalian cells. We further demonstrate that within the context of a primary mammalian neural stem/progenitor cell, Musashi can be converted from a repressor of mRNA translation to an activator of translation in response to extracellular stimuli. We present current models of Musashi-mediated mRNA translational control and discuss possible mechanisms for regulating Musashi function. An understanding of these mechanisms presents exciting possibilities for development of therapeutic targets to control physiological and pathological stem cell proliferation.