酵母HOG-MAPK途径

酿酒酵母Saccharomyces cerevisiae的高渗透性甘油促分裂原活化蛋白激酶(highos-molarity glycerol mitogen-activated protein kinase,HOG-MAPK)途径是高度保守的信号转导途径,很多方面和高等真核生物MAPK途径类似。该途径在高渗应激环境下控制信号转导和基因表达,是细胞生存所必需的。现对酵母HOG-MAPK途径的信号转导以及信号传递的专一性控制、HOG-MAPK途径各组分的亚细胞定位和基因表达调控机制进行综述。     

Role of the JAK/STAT signal transduction pathway in the regulation of gene expression in CNS

Over the last 20 years the JAK/STAT signal transduction pathway has been extensively studied. An enormous amount of data on different cell signal transduction pathways is now available. The JAK/STAT signal transduction pathway is one of the intracellular signaling pathways activated by cytokines and growth factors that was first studied in the hematopoietic system, but recent data demonstrate that this signal transduction is also greatly utilized by other systems. The JAK/STAT pathway is a signaling cascade that links the activation of specific cell membrane receptors to nuclear gene expression. This review is focused on the role of JAK/STAT signal transduction pathway activation in the central nervous system (CNS).     

Genetic analysis of pathway specificity during posttranslational protein translocation across the Escherichia coli plasma membrane

In Escherichia coli, the SecB/SecA branch of the Sec pathway and the twin-arginine translocation (Tat) pathway represent two alternative possibilities for posttranslational translocation of proteins across the cytoplasmic membrane. Maintenance of pathway specificity was analyzed using a model precursor consisting of the mature part of the SecB-dependent maltose-binding protein (MalE) fused to the signal peptide of the Tat-dependent TorA protein. The TorA signal peptide selectively and specifically directed MalE into the Tat pathway. The characterization of a spontaneous TorA signal peptide mutant (TorA*), in which the two arginine residues in the c-region had been replaced by one leucine residue, showed that the TorA*-MalE mutant precursor had acquired the ability for efficiently using the SecB/SecA pathway. Despite the lack of the "Sec avoidance signal," the mutant precursor was still capable of using the Tat pathway, provided that the kinetically favored Sec pathway was blocked. These results show that the h-region of the TorA signal peptide is, in principle, sufficiently hydrophobic for Sec-dependent protein translocation, and therefore, the positively charged amino acid residues in the c-region represent a major determinant for Tat pathway specificity. Tat-dependent export of TorA-MalE was significantly slower in the presence of SecB than in its absence, showing that SecB can bind to this precursor despite the presence of the Sec avoidance signal in the c-region of the TorA signal peptide, strongly suggesting that the function of the Sec avoidance signal is not the prevention of SecB binding; rather, it must be exerted at a later step in the Sec pathway.     

The DsbA signal sequence directs efficient, cotranslational export of passenger proteins to the Escherichia coli periplasm via the signal recognition particle pathway

The Escherichia coli cytoplasmic protein thioredoxin 1 can be efficiently exported to the periplasmic space by the signal sequence of the DsbA protein (DsbAss) but not by the signal sequence of alkaline phosphatase (PhoA) or maltose binding protein (MBP). Using mutations of the signal recognition particle (SRP) pathway, we found that DsbAss directs thioredoxin 1 to the SRP export pathway. When DsbAss is fused to MBP, MBP also is directed to the SRP pathway. We show directly that the DsbAss-promoted export of MBP is largely cotranslational, in contrast to the mode of MBP export when the native signal sequence is utilized. However, both the export of thioredoxin 1 by DsbAss and the export of DsbA itself are quite sensitive to even the slight inhibition of SecA. These results suggest that SecA may be essential for both the slow posttranslational pathway and the SRP-dependent cotranslational pathway. Finally, probably because of its rapid folding in the cytoplasm, thioredoxin provides, along with gene fusion approaches, a sensitive assay system for signal sequences that utilize the SRP pathway.     

天然提取物诱导人HepG2 细胞凋亡的研究进展

细胞凋亡是机体维持内环境稳定,更好的适应生存环境采取的一种死亡过程。细胞凋亡异常与肿瘤的发生、发展存在密切的关系。细胞凋亡的信号途径主要有死亡受体介导的外源性通路、线粒体介导内源性通路、内质网信号通路及MAPK信号通路。通过作用于凋亡信号通路上一些关键基因,诱导肿瘤细胞凋亡被认为是临床抗肿瘤治疗最有成效的治疗方法之一。研究已证实多种天然提取物作用于凋亡信号途径中一些重要因子可诱导细胞凋亡,并取得较好的抑制肿瘤增殖的效果。本文是关于细胞凋亡机制及各种天然提取物作用于凋亡通路上主要基因进行抗肿瘤治疗研究进展的综述。     

Competition between Sec- and TAT-dependent protein translocation in Escherichia coli.

Recently, a new protein translocation pathway, the twin-arginine translocation (TAT) pathway, has been identified in both bacteria and chloroplasts. To study the possible competition between the TAT- and the well-characterized Sec translocon-dependent pathways in Escherichia coli, we have fused the TorA TAT-targeting signal peptide to the Sec-dependent inner membrane protein leader peptidase (Lep). We find that the soluble, periplasmic P2 domain from Lep is re-routed by the TorA signal peptide into the TAT pathway. In contrast, the full-length TorA-Lep fusion protein is not re-routed into the TAT pathway, suggesting that Sec-targeting signals in Lep can override TAT-targeting information in the TorA signal peptide. We also show that the TorA signal peptide can be converted into a Sec-targeting signal peptide by increasing the hydrophobicity of its h-region. Thus, beyond the twin-arginine motif, the overall hydrophobicity of the signal peptide plays an important role in TAT versus Sec targeting. This is consistent with statistical data showing that TAT-targeting signal peptides in general have less hydrophobic h-regions than Sec-targeting signal peptides.     

逆转肾小管上皮细胞转分化的Smad信号转导机制

肾小管上皮细胞转分化(tubular epithelial to menchymal transdifferentiation,EMT)是肾小管间质纤维化的重要病理机制之一。致纤维化细胞因子TGF-β通过几种信号转导途径调节EMT,其中TGF-β/Smads信号通路发挥核心作用。目前研究表明,Smad7、HGF、BMP-7等可通过调控Smads信号通路而逆转EMT,这为肾间质纤维化的防治提供了新的思路。该文主要介绍TGF-β/Smads信号通路在EMT发生的作用,以及Smad7、SnoN、HGF、BMP-7等分子是如何通过抑制Smads信号通路而发挥逆转EMT作用的。     

运动对线粒体介导骨骼肌细胞凋亡信号通路的影响

细胞凋亡是一种程序化的细胞死亡方式,其信号传导通路分为外源性和内源性两条主要途径,线粒体在内源性细胞凋亡途径中扮演着重要的角色.研究表明,运动可通过调节线粒体介导骨骼肌细胞凋亡的进程,而运动调节线粒体介导骨骼肌细胞凋亡信号通路影响机体细胞生物进程的机制仍有待研究.该文主要阐述了线粒体介导细胞凋亡信号传导通路及运动对其的...     

PI3K/Akt信号通路相关的生物学调控机制研究进展

PI3K/Akt信号通路是由酶联受体介导的信号转导通路,该通路不仅参与多种生长因子、细胞因子和细胞外基质等的信号转导,同时还参与细胞增殖、分化、凋亡和葡萄糖转运等多种细胞功能的调节,特别是在细胞凋亡、细胞存活以及调控细胞糖代谢等方面具有重要作用。本研究综述了PI3K-Akt信号通路的结构组成、通路活化、通信过程、调控机制及其生物学功能等方面的研究进展,为进一步研究PI3K/Akt信号通路的生物学调控作用机制提供启示。     

心肌肥厚信号通路研究进展

病理性心肌肥厚是心肌细胞受到多种因素刺激后所产生的失代偿性反应,最终可演变为心力衰竭,甚至诱发猝死。鉴于其复杂的病理过程,具体发病机制至今尚未完全阐明,但既有研究已明确有丝分裂原活化蛋白激酶信号通路、Ca~(2+)介导的信号通路、蛋白激酶信号通路、Janus激酶/信号转导子和转录激活子信号通路和MicroRNAs信号通路在调控心肌肥厚的进程中起着至关重要的作用。现就相关信号通路在心肌肥厚发生、进展及预后中所起作用的最新研究进展予以综述。     

p38激酶在肌肉发生及运动中的作用

p38通路是真核细胞转导细胞外信号到细胞内引起细胞反应的一类重要信号通路,它能够调控多种细胞内分子事件。p38是p38通路发挥生物学作用的末端激酶,它能够通过调控MyoD、Myf-5活性或表达、组蛋白修饰、染色体重塑、某些细胞分化相关mRNA的更替等方式影响肌肉分化进程。运动能够激活p38,p38可能通过NF-κB/IL-6/成肌调节因子(myogenic regulatory factor,MRF)及肌细胞专一增强因子2(muscle-specific enhancement factor2,MEF2)、过氧化物增殖物活化受体γ辅激活因子1α(peroxisome proliferator activated receptor γ coactivator-1α,PGC-1α)、葡萄糖转运蛋白4(glucose transporter 4,GLUT4)在运动介导的肌肉发生、线粒体发生、血糖摄取能力提高等几方面发挥作用。     

Competition between functional signal peptides demonstrates variation in affinity for the secretion pathway.

We have developed a system for examining the relative affinity of two different signal peptides for the protein secretion pathway in Escherichia coli. This system involves the expression of a modified alkaline phosphatase which possesses two signal peptides arranged in tandem. When both signal peptides have the wild-type sequence, cleavage after the first and cleavage after the second occur with nearly equal frequency. In both cases the remainder of the protein is transported to the periplasm. Thus both signal peptides effectively compete with each other for entrance to the secretion pathway. When the hydrophobicity of the second signal peptide is altered by small increments, we find that the more hydrophobic signal peptide is preferentially utilized. Thus, a more hydrophobic signal peptide can outcompete even an efficient wild-type signal sequence. The crossover point, for utilization of the second to the first signal peptide, is marked and occurs over a very small change in hydrophobicity. Our results suggest that the small differences in the hydrophobicity of wild-type signal peptides may have critical consequences: preproteins with the more hydrophobic signals could dominate one pathway, leaving those with only slightly less hydrophobic signals to require additional factors such as chaperonins, SecB, and other binding proteins.     

P13K—Akt—mTORC1信号途径在细胞生长增殖中的调控作用

P13K-AKT—mTORCl信号途径在细胞生长增殖中起重要调控作用,P13K-Akt—mTORl信号途径能够调节细胞周期相关蛋白基因的表达来调控细胞的增殖;同时,P13K—Akt-mTORl信号途径也能够调控细胞的生长和大小;P13K-Akt-mTORCl信号途径的异常活化与肿瘤发生紧密相关。就P13K—AKT-mTORCl信号途径在细胞生长增殖中的作用作一综述。     

WIF-1研究进展

WIF-1是Wnt信号通路上的拮抗物之一,可以阻断Wnt的经典通路和非经典通路。目前在人类多种肿瘤的研究发现WIF-1表达异常。WIF-1（Wnt inhibitory factor-1）,sFRP（Frizzled related protein）和CER（Cerberus）属于Wnt拮抗物家族,通过直接与Wnt蛋白相连从而阻止Wnt与受体蛋白复合物相连,使细胞质中的β-catenin由于磷酸化而不能积累,进而阻断了经典通路和非经典通路。WIF-1可能与中胚层的发生以及肿瘤细胞的生长分化有关。Wnt家族其他成员已经被证实与早期冠心病、Ⅱ型糖尿病、肥胖症、骨质疏松症等相关。因此了解WIF-1在通路上的更多信息,解释WIF-1调节Wnt信号通路的机理和过程,为疾病治疗和预防以及药物开发提供新的方法。     

Notch信号途径的调节

Notch信号途径是通过局部细胞间相互作用,实现细胞间通讯、胞浆内的信号转导以及核内转录,从而控制细胞的增殖、分化、凋亡、迁移及粘附等细胞的命运的途径。它在进化中非常保守,在机体的整个生长发育过程的调控中发挥着重要的作用。Notch信号途径作用过程受其他多种分子和途径的调节。本文从细胞外水平、细胞浆水平和细胞核水平分别讨论了Notch信号途径的调节。对进一步了解Notch信号途径,解释生理病理现象、控制和治疗疾病提供基础。     

双组分系统——细胞识别渗透胁迫信号的感应器

双组分系统是广泛存在于原核和真核细胞中的信号转导系统.主要由组氨酸蛋白激酶(HPK)和响应调节蛋白(RR)两个组分组成. 双组分系统信号通路一般包括信号的输入、HPK自身磷酸化、RR磷酸化、信号输出等环节.对双组分系统信号转导机制及其在渗透胁迫信号识别和传导中的作用进行了综述.     

The thylakoid delta pH-dependent pathway machinery facilitates RR-independent N-tail protein integration

The thylakoidal DeltapH-dependent and bacterial twin arginine transport systems are structurally and functionally related protein export machineries. These recently discovered systems have been shown to transport folded proteins but are not known to assemble integral membrane proteins. We determined the translocation pathway of a thylakoidal FtsH homologue, plastid fusion/protein translocation factor, which is synthesized with a chloroplast-targeting peptide, a hydrophobic signal peptide, and a hydrophobic membrane anchor. The twin arginine motif in its signal peptide and its sole integration requirement of a DeltapH suggested that plastid fusion/protein translocation factor employs the DeltapH pathway. Surprisingly, changing the twin arginine to twin lysine or deleting the signal peptide did not abrogate integration capability or characteristics. Nevertheless, three criteria argue that all three forms require the DeltapH pathway for integration. First, integration was competed by an authentic DeltapH pathway precursor. Second, antibodies to DeltapH pathway component Hcf106 specifically inhibited integration. Finally, chloroplasts from the hcf106 null mutant were unable to integrate Pftf into their thylakoids. Thus, DeltapH pathway machinery facilitates both signal peptide-directed and N-tail-mediated membrane integration and does not strictly require the twin arginine motif.     

Two frizzled planar cell polarity signals in the Drosophila wing are differentially organized by the Fat/Dachsous pathway

The regular array of distally pointing hairs on the mature Drosophila wing is evidence for the fine control of Planar Cell Polarity (PCP) during wing development. Normal wing PCP requires both the Frizzled (Fz) PCP pathway and the Fat/Dachsous (Ft/Ds) pathway, although the functional relationship between these pathways remains under debate. There is strong evidence that the Fz PCP pathway signals twice during wing development, and we have previously presented a Bidirectional-Biphasic Fz PCP signaling model which proposes that the Early and Late Fz PCP signals are in different directions and employ different isoforms of the Prickle protein. The goal of this study was to investigate the role of the Ft/Ds pathway in the context of our Fz PCP signaling model. Our results allow us to draw the following conclusions: (1) The Early Fz PCP signals are in opposing directions in the anterior and posterior wing and converge precisely at the site of the L3 wing vein. (2) Increased or decreased expression of Ft/Ds pathway genes can alter the direction of the Early Fz PCP signal without affecting the Late Fz PCP signal. (3) Lowfat, a Ft/Ds pathway regulator, is required for the normal orientation of the Early Fz PCP signal but not the Late Fz PCP signal. (4) At the time of the Early Fz PCP signal there are symmetric gradients of dachsous (ds) expression centered on the L3 wing vein, suggesting Ds activity gradients may orient the Fz signal. (5) Localized knockdown or over-expression of Ft/Ds pathway genes shows that boundaries/gradients of Ft/Ds pathway gene expression can redirect the Early Fz PCP signal specifically. (6) Altering the timing of ds knockdown during wing development can separate the role of the Ft/Ds pathway in wing morphogenesis from its role in Early Fz PCP signaling.