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。     

Mitogen and stress response pathways: MAP kinase cascades and phosphatase regulation in mammals and yeast

Evolutionarily conserved from yeast to man, mitogen-activated protein kinase (MAPK) pathways respond to a variety of disparate signals which induce differentiation, proliferation, or changes in intracellular enzyme regulation. Recent advances have identified two new mammalian MAPK relatives, JNK1 and p38, and the pathways which are responsible for their activation.     

Endoplasmic reticulum stress response in yeast and humans

Stress pathways monitor intracellular systems and deploy a range of regulatory mechanisms in response to stress. One of the best-characterized pathways, the UPR (unfolded protein response), is an intracellular signal transduction pathway that monitors ER (endoplasmic reticulum) homoeostasis. Its activation is required to alleviate the effects of ER stress and is highly conserved from yeast to human. Although metazoans have three UPR outputs, yeast cells rely exclusively on the Ire1 (inositol-requiring enzyme-1) pathway, which is conserved in all Eukaryotes. In general, the UPR program activates hundreds of genes to alleviate ER stress but it can lead to apoptosis if the system fails to restore homoeostasis. In this review, we summarize the major advances in understanding the response to ER stress in Sc (Saccharomyces cerevisiae), Sp (Schizosaccharomyces pombe) and humans. The contribution of solved protein structures to a better understanding of the UPR pathway is discussed. Finally, we cover the interplay of ER stress in the development of diseases.     

Differential regulation of glutaredoxin gene expression in response to stress conditions in the yeast Saccharomyces cerevisiae

Glutaredoxins are small heat-stable proteins that are active as glutathione-dependent oxidoreductases and are encoded by two genes, designated GRX1 and GRX2, in the yeast Saccharomyces cerevisiae. We report here that the expression of both genes is induced in response to various stress conditions including oxidative, osmotic, and heat stress and in response to stationary phase growth and growth on non-fermentable carbon sources. Furthermore, both genes are activated by the high-osmolarity glycerol pathway and negatively regulated by the Ras-protein kinase A pathway via stress-responsive STRE elements. GRX1 contains a single STRE element and is induced to significantly higher levels compared to GRX2 following heat and osmotic shock. GRX2 contains two STRE elements, and is rapidly induced in response to reactive oxygen species and upon entry into stationary phase growth. Thus, these data support the idea that the two glutaredoxin isoforms in yeast play distinct roles during normal cellular growth and in response to stress conditions.     

Biotechnological impact of stress response on wine yeast

Wine yeast deals with many stress conditions during its biotechnological use. Biomass production and its dehydration produce major oxidative stress, while hyperosmotic shock, ethanol toxicity and starvation are relevant during grape juice fermentation. Most stress response mechanisms described in laboratory strains of Saccharomyces cerevisiae are useful for understanding the molecular machinery devoted to deal with harsh conditions during industrial wine yeast uses. However, the particularities of these strains themselves, and the media and conditions employed, need to be specifically looked at when studying protection mechanisms.     

Histamine modulates the cellular stress response in yeast

The cellular stress response is a universal protective reaction to adverse environmental or microenvironmental conditions, such as heat and drugs, associated in part with the highly conserved heat shock proteins (HSPs). Histamine is a key inflammatory mediator derived from l-histidine that governs vital cellular processes beyond inflammation, while recent evidence implies additional actions in both prokaryotes and eukaryotes. This study explored the possible role of histamine in the heat shock response in yeast, an established experimental model for the pharmacological investigation of the cellular stress response. The response was evaluated by determining growth and viability of post-logarithmic phase grown yeast cultures after heat shock at 53°C for 30 min. Thermal preconditioning at 37°C for 2 h served as a positive control. The effect of histamine was investigated following long-term administration through the post-logarithmic phase of growth or short-term administration for 2 h prior to heat shock. Short-term treatment with 1 mM histamine resulted in de novo protein synthesis-dependent acquisition of thermotolerance, while lower doses or long-term administration of histamine failed to induce the heat-resistant phenotype. Preliminary investigation of HSP104, HSP70 and HSP60 expression by western blotting showed an increase of these proteins after thermal preconditioning. However, a differential HSP and tubulin expression appeared to underlie the response of yeast cells to histamine. In conclusion, histamine was capable of inducing the adaptive phenotype, while the contribution of HSPs and tubulin and the potential implications remain largely elusive.     

Differential genetic interactions of yeast stress response MAPK pathways

Genetic interaction screens have been applied with great success in several organisms to study gene function and the genetic architecture of the cell. However, most studies have been performed under optimal growth conditions even though many functional interactions are known to occur under specific cellular conditions. In this study, we have performed a large‐scale genetic interaction analysis in Saccharomyces cerevisiae involving approximately 49 × 1,200 double mutants in the presence of five different stress conditions, including osmotic, oxidative and cell wall‐altering stresses. This resulted in the generation of a differential E‐MAP (or dE‐MAP) comprising over 250,000 measurements of conditional interactions. We found an extensive number of conditional genetic interactions that recapitulate known stress‐specific functional associations. Furthermore, we have also uncovered previously unrecognized roles involving the phosphatase regulator Bud14, the histone methylation complex COMPASS and membrane trafficking complexes in modulating the cell wall integrity pathway. Finally, the osmotic stress differential genetic interactions showed enrichment for genes coding for proteins with conditional changes in phosphorylation but not for genes with conditional changes in gene expression. This suggests that conditional genetic interactions are a powerful tool to dissect the functional importance of the different response mechanisms of the cell.     

Novel insights into the osmotic stress response of yeast

Response to hyperosmolarity in the baker's yeast Saccharomyces cerevisiae has attracted a great deal of attention of molecular and cellular biologists in recent years, from both the fundamental scientific and applied viewpoint. Indeed the underlying molecular mechanisms form a clear demonstration of the intricate interplay of (environmental) signalling events, regulation of gene expression and control of metabolism that is pivotal to any living cell. In this article we briefly review the cellular response to conditions of hyperosmolarity, with focus on the high-osmolarity glycerol mitogen-activated protein kinase pathway as the major signalling route governing cellular adaptations. Special attention will be paid to the recent finding that in the yeast cell also major structural changes occur in order to ensure maintenance of cell integrity. The intriguing role of glycerol in growth of yeast under (osmotic) stress conditions is highlighted.     

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.     

Computational modeling of cardiovascular response to orthostatic stress.

The objective of this study is to develop a model of the cardiovascular system capable of simulating the short-term (< or = 5 min) transient and steady-state hemodynamic responses to head-up tilt and lower body negative pressure. The model consists of a closed-loop lumped-parameter representation of the circulation connected to set-point models of the arterial and cardiopulmonary baroreflexes. Model parameters are largely based on literature values. Model verification was performed by comparing the simulation output under baseline conditions and at different levels of orthostatic stress to sets of population-averaged hemodynamic data reported in the literature. On the basis of experimental evidence, we adjusted some model parameters to simulate experimental data. Orthostatic stress simulations are not statistically different from experimental data (two-sided test of significance with Bonferroni adjustment for multiple comparisons). Transient response characteristics of heart rate to tilt also compare well with reported data. A case study is presented on how the model is intended to be used in the future to investigate the effects of post-spaceflight orthostatic intolerance.     

Catalase modifies yeast Saccharomyces cerevisiae response towards S-nitrosoglutathione-induced stress

Abstract

Nitric oxide is known to be a messenger in animals and plants. Catalase may regulate the concentration of intracellular ^?NO. In this study, yeast Saccharomyces cerevisiae cells were treated with 1–20 mM S-nitrosoglutathione (GSNO), a nitric oxide donor, which decreased yeast survival in a concentration-dependent manner. In the wild-type strain (YPH250), 20 mM GSNO reduced survival by 32%. The strain defective in peroxisomal catalase behaved like the wild-type strain, while a mutant defective in cytosolic catalase showed 10% lower survival. Surprisingly, survival of the double catalase mutant was significantly higher than that of the other strains used. Incubation of yeast with GSNO increased the activities of both superoxide dismutase (SOD) and catalase. Pre-incubation with cycloheximide prevented the activation of catalase, but not SOD. The concentrations of oxidized glutathione increased in the wild-type strain, as well as in the mutants defective in peroxisomal catalase and an acatalasaemic strain; it failed to do this in the mutant defective in cytosolic catalase. The activity of aconitase was reduced after GSNO treatment in all strains studied, except for the mutant defective in peroxisomal catalase. The content of protein carbonyls and activities of glutathione reductase and S-nitrosoglutathione reductase were unchanged following GSNO treatment. The increase in catalase activity due to incubation with GSNO was not found in a strain defective in Yap1p, a master regulator of yeast adaptive response to oxidative stress. The obtained data demonstrate that exposure of yeast cells to the ^?NO-donor S-nitrosoglutathione induced mild oxidative/nitrosative stress and Yap1p may co-ordinate the up-regulation of antioxidant enzymes under these conditions.     

Mitophagy, mitochondrial dynamics and the general stress response in yeast

Autophagy is a fundamental cellular process promoting survival under various environmental stress conditions. Selective types of autophagy have gained much interest recently as they are involved in specific quality control mechanisms removing, for example, aggregated proteins or dysfunctional mitochondria. This is considered to counteract the development of a number of neurodegenerative disorders and aging. Here we review the role of mitophagy and mitochondrial dynamics in ensuring quality control of mitochondria. In particular, we provide possible explanations why mitophagy in yeast, in contrast with the situation in mammals, was found to be independent of mitochondrial fission. We further discuss recent findings linking these processes to nutrient sensing pathways and the general stress response in yeast. In particular, we propose a model for how the stress response protein Whi2 and the Ras/PKA (protein kinase A) signalling pathway are possibly linked and thereby regulate mitophagy.