c-Abl与应激损伤调控

非受体酪氨酸激酶c-Abl广泛表达于人和哺乳动物等的细胞中并受到严格调控,通过蛋白之间相互作用、与DNA相互作用及其酪氨酸激酶活性在一系列的重要生命活动中发挥调节作用。在应激损伤反应如DNA损伤反应中．c-Abl的Ser^465被ATM和DNA-PK磷酸化而激活,通过与Rad51、p53和p73等分子的相互作用参与DNA重组修复、细胞周期和细胞凋亡等的调控,不同信号途径之间的平衡决定细胞的生存和死亡。     

Structural basis and regulation of the reductive stress response

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RNA-dependent regulation of the cell wall stress response

Stress response requires the precise modulation of gene expression in response to changes in growth conditions. This report demonstrates that selective nuclear mRNA degradation is required for both the cell wall stress response and the regulation of the cell wall integrity checkpoint. More specifically, the deletion of the yeast nuclear dsRNA-specific ribonuclease III (Rnt1p) increased the expression of the mRNAs associated with both the morphogenesis checkpoint and the cell wall integrity pathway, leading to an attenuation of the stress response. The over-expression of selected Rnt1p substrates, including the stress associated morphogenesis protein kinase Hsl1p, in wild-type cells mimicked the effect of RNT1 deletion on cell wall integrity, and their mRNAs were directly cleaved by the recombinant enzyme in vitro. The data supports a model for gene regulation in which nuclear mRNA degradation optimizes the cell response to stress and links it to the cell cycle.     

Dynamics and regulation of the stress response: meeting report on the stress response and molecular chaperones from Kyoto

No Abstract Available     

Physiological function as regulation of large transcriptional programs: the cellular response to genotoxic stress

The responses to ionizing radiation and other genotoxic environmental stresses are complex and are regulated by a number of overlapping molecular pathways. One such stress signaling pathway involves p53, which regulates the expression of over 100 genes already identified. It is also becoming increasingly apparent that the pattern of stress gene expression has some cell type specificity. It may be possible to exploit these differences in stress gene responsiveness as molecular markers through the use of a combined informatics and functional genomics approach. The techniques of microarray analysis potentially offer the opportunity to monitor changes in gene expression across the entire set of expressed genes in a cell or organism. As an initial step in the development of a functional genomics approach to stress gene analysis, we have recently demonstrated the utility of cDNA microarray hybridization to measure radiation-stress gene responses and identified a number of previously unknown radiation-regulated genes. The responses of some of these genes to DNA-damaging agents vary widely in cell lines from different tissues of origin and different genetic backgrounds. While this again highlights the importance of a cellular context to genotoxic stress responses, it also raises the prospect of expression-profiling of cell lines, tissues, and tumors. Such profiles may have a predictive value if they can define regions of ‘expression space’ that correlate with important endpoints, such as response to cancer therapy regimens, or identification of exposures to environmental toxins.     

Bistability in feedback circuits as a byproduct of evolution of evolvability

Noisy bistable dynamics in gene regulation can underlie stochastic switching and is demonstrated to be beneficial under fluctuating environments. It is not known, however, if fluctuating selection alone can result in bistable dynamics. Using a stochastic model of simple feedback networks, we apply fluctuating selection on gene expression and run in silico evolutionary simulations. We find that independent of the specific nature of the environment–fitness relationship, the main outcome of fluctuating selection is the evolution of increased evolvability in the network; system parameters evolve toward a nonlinear regime where phenotypic diversity is increased and small changes in genotype cause large changes in expression level. In the presence of noise, the evolution of increased nonlinearity results in the emergence and maintenance of bistability. Our results provide the first direct evidence that bistability and stochastic switching in a gene regulatory network can emerge as a mechanism to cope with fluctuating environments. They strongly suggest that such emergence occurs as a byproduct of evolution of evolvability and exploitation of noise by evolution.     

Ribosome stalling is a signal for metabolic regulation by the ribotoxic stress response

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Radiation adaptive response as a stress reaction of a cell

The published data on the primary changes that occur in human peripheral blood lymphocytes after small dose irradiation in vitro (SDI), as well as relation between these changes and the adaptive response mechanism (increase of radioresistance of lymphocytes after SDI) have been analyzed. The author has come to a conclusion in favor of the absence among the revealed primary changes of any traces of a specific inducible mechanism that protects a cell from exterior influences and elevates cell radioresistance. The changes in cell radioresistance following the SDI comprise only an insignificant part of all the changed characteristics. There are large numbers of mechanisms by which radioresistance changes and they are poorly studied at that. The author speculates that the adaptive response isn't a specific radiobiological protective phenomenon, but it is rather a type of the cell stress reaction that is evoked by external influences. Signals that trigger transition to a state of stress, as well as the signals to implement adaptive functions, thus restoring the normal state, can be represented, for example, by increased concentrations of reactive oxygen species, and most likely by as yet unknown metabolic changes. An irradiated cell transfers into the state of stress and mobilizes all possible ways to increase resistance to any damaging effects, radiation including. What particular way of increasing radioresistance will be used depends on the genotype, experiment conditions, etc. The consequences of stress could cause more rapid cell division, malignant transformations and increased stability of malignization, hormesis and many other things.     

Gynandromorphs as indicators of modularity and evolvability in ants

Gynandromorphs, individuals that display a mosaic of male and female tissues or cell populations, have been extensively documented in solitary and social insects for over 100 years. Yet the evolutionary significance of gynandromorphs has remained obscure. Here we describe our discovery of a gynandromorph in the hyperdiverse ant genus Pheidole whose pattern of bilateral head mosaicism occurs repeatedly across a wide range of ant species. Based on our findings, we propose that gynandromorphs and other mosaic forms may provide new insights into the modularity and evolvability of morphological traits.     

Gender specificity in the neural regulation of the response to stress

Pronounced gender-related differences are observable in the regulation of the limbic-hypothalamic-pituitary-adrenal (LHPA) activity under basal and stress-related conditions, and by circulating glucocorticoid levels. This article reviews recent studies that have unequivocally demonstrated that these differences emerge from the organizational effects of gonadal steroids during early brain development. Although largely masked by the dominating role of glucocorticoids in maintaining feedback thresholds, gonadal steroids continue to exert gender-specific activational effects on the LHPA axis through adulthood. The importance of these modulatory effects of gonadal steroids may be reflected in gender differences in the incidence of psychopathologies that are accompanied by symptoms of LHPA dysregulation. One goal of this review is to highlight the need for further investigations into the (still elusive) cellular and molecular mechanisms underlying the activational effects of sex steroids, which may provide leads for neuroprotective hormone replacement strategies.     

Differential mechanisms for regulation of the stress response across latitudinal gradients

We examined plasticity of the stress response among three populations of the white-crowned sparrow (Zonotrichia leucophrys). These populations breed at different elevations and latitudes and thus have breeding seasons that differ markedly in length. We hypothesize that in populations where birds raise only one or rarely two broods in a season, the fitness costs of abandoning a nest are substantially larger than in closely related populations that raise up to three broods per season. Thus individuals with short breeding seasons should be less responsive to stressors and therefore less likely to abandon their young. In our study, baseline and handling-induced corticosterone levels were similar among populations, but corticosteroid-binding globulins differed, leading to a direct relationship between stress-induced free corticosteroid levels and length of breeding season. There were also population-specific differences in intracellular low-affinity (glucocorticoid-like) receptors in both liver and brain tissue. Although investigations of population-based differences in glucocorticoid secretion are common, this is the first study to demonstrate population-level differences in binding globulins. These differences could lead to dramatically different physiological and behavioral responses to stress.     

MDMX regulation of p53 response to ribosomal stress

Ribosomal stress such as disruption of rRNA biogenesis activates p53 by release of ribosomal proteins from the nucleoli, which bind to MDM2 and inhibit p53 degradation. We found that p53 activation by ribosomal stress requires degradation of MDMX in an MDM2-dependent fashion. Tumor cells overexpressing MDMX are less sensitive to actinomycin D-induced growth arrest due to formation of inactive p53-MDMX complexes. Knockdown of MDMX increases sensitivity to actinomycin D, whereas MDMX overexpression abrogates p53 activation and prevents growth arrest. Furthermore, MDMX expression promotes resistance to the chemotherapeutic agent 5-fluorouracil (5-FU), which at low concentrations activates p53 by inducing ribosomal stress without significant DNA damage signaling. Knockdown of MDMX abrogates HCT116 tumor xenograft formation in nude mice. MDMX overexpression does not accelerate tumor growth but increases resistance to 5-FU treatment in vivo. Therefore, MDMX is an important regulator of p53 response to ribosomal stress and RNA-targeting chemotherapy agents.     

Redox regulation of cellular stress response in neurodegenerative disorders

There is increasing evidence that reactive oxygen species (ROS) are not only toxic but play an important role in cellular signaling and in the regulation of gene expression. A number of biochemical and physiologic stimuli, such as perturbation in redox status, expression of misfolded proteins, altered glyc(osyl)ation and glucose deprivation, overloading of products of polyunsaturated fatty acid peroxidation (Hydroxynonenals, HNE) or cholesterol oxidation and decomposition, can disrupt redox homeostasis, impose stress and subsequently lead to accumulation of unfolded or misfolded proteins in brain cells. Alzheimer's (AD), Parkinson's (PD), Huntington's disease (HD), Amyothrophic lateral sclerosis (ALS) and Friedreich ataxia (FRDA) are major neurological disorders associated with production of abnormal proteins and, as such, belong to the so called "protein conformational diseases". The Central Nervous System has evolved highly specific signaling pathways called the unfolded protein response to cope with the accumulation of unfolded or misfolded proteins. Recent discoveries of the mechanisms of cellular stress signaling have led to major new insights into the diverse processes that are regulated by cellular stress response. Thus, the pathogenic dysfunctional aggregation of proteins in non-native conformations is associated with metabolic derangements and excessive production of ROS. The brain response to detect and control metabolic or oxidative stress is accomplished by a complex network of "longevity assurance processes" integrated to the expression of genes termed vitagenes. Heat shock proteins are a highly conserved system responsible for the preservation and repair of correct protein conformation. Heme oxygenase-1, a inducible and redox-regulated enzyme, is currently considered as having an important role in cellular antioxidant defense. A neuroprotective effect, due to its heme degrading activity, and tissue-specific antioxidant effects due to its products CO and biliverdin, this latter being further reduced by biliverdin reductase in bilirubin is an emerging concept. There is a current interest in dietary compounds that can inhibit, retard or reverse the multi-stage pathophysiology of Alzheimer disease, with a chronic inflammatory response, brain injury and beta-amyloid associated pathology. Curcumin and ferulic acid, two powerful antioxidants, the first from the curry spice turmeric and the second a major constituent of fruit and vegetables, have emerged as strong inducers of the heat shock response. Food supplementation with curcumin and ferulic acid is considered a nutritional approach to reduce oxidative damage and amyloid pathology in Alzheimer disease. This review summarizes the complex regulation of cellular stress signaling and its relevance to human physiology and disease.     

植物应对干旱胁迫的气孔调节

气孔是植物控制叶片与大气之间碳、水交换的重要门户,植物的生长和生存都依赖于叶片气孔对碳获取和水散失的调控.因此,气孔调节机理研究与气孔导度模型研发是精确模拟陆地生态系统碳、水循环过程不可或缺的内容.近年来,随着气候变化的加剧,干旱事件愈发频繁,对植物的存活、生长和分布产生深刻影响.为了深入理解植物碳-水耦合机理过程、预测全球变化下植物及群落的动态,开展植物应对干旱胁迫的气孔调节研究尤为重要.本文综述了植物在干旱胁迫条件下气孔调节机制和模型研究进展.首先阐述了植物气孔对干旱胁迫的主动调节与被动调节,讨论了气孔调节的演化过程,包括蕨类和石松类植物的被动水力调节、被子植物的主动调节和裸子植物的双重调节机制,认为裸子植物的气孔调节方式是植物进化过程中介于蕨类、石松类植物和被子植物之间的一种重要过渡类型.然后分析了气孔调节与水力调节的关系,讨论了“植物水势和气孔导度解耦”问题中存在的争议.之后介绍了基于水分利用效率假说和最大碳增益假说所建立的气孔导度优化模型的应用,并指出后者有更强的预测能力和应用前景.最后,为了有效减少植被对气候变化响应预测中的不确定性,提出了2个亟待开展的研究问题:将植物叶片的气孔调节功能研究由个体扩展到生态系统甚至更大尺度,改进陆地生态系统碳水循环机理模型;量化气孔调节的主动水力反馈过程,修正植物气孔功能水力模型.     

Independent regulation of prostaglandin production and the stress response in human fibroblasts.

The stress, or heat shock response of eukaryotic cells is characterized by dramatic changes in the metabolism of responding cells, most notably the increased synthesis of a group of proteins known as heat shock proteins. In this study, we examined the relationship of prostaglandin synthesis/release to the stress response. Stress protein synthesis was induced with sodium arsenite, and prostaglandin E2 and prostacyclin (measured as 6-keto PGF1 alpha) levels were determined by enzyme immunoassay. The stress response was monitored by the incorporation of [35S]methionine and separation of protein by one-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Prostaglandin synthesis and the stress response were both induced by sodium arsenite. However, aspirin, a cyclooxygenase inhibitor, inhibited arsenite-induced prostaglandin synthesis but did not inhibit stress protein synthesis. Conversely, the calcium ionophore A23187 also stimulated prostaglandin synthesis, but did not induce the stress response. The results of this study indicate that sodium arsenite, a stress response inducer, stimulates prostaglandin production, but this appears to be a correlative rather than causative occurrence in the stress response. Determination of the cytotoxicity of arsenite indicated a high correlation of stimulation of prostaglandin release with cytotoxicity.