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161.
The p66shc adaptor protein controls oxidative stress response and life span in mammals 总被引:44,自引:0,他引:44
Migliaccio E Giorgio M Mele S Pelicci G Reboldi P Pandolfi PP Lanfrancone L Pelicci PG 《Nature》1999,402(6759):309-313
Gene mutations in invertebrates have been identified that extend life span and enhance resistance to environmental stresses such as ultraviolet light or reactive oxygen species. In mammals, the mechanisms that regulate stress response are poorly understood and no genes are known to increase individual life span. Here we report that targeted mutation of the mouse p66shc gene induces stress resistance and prolongs life span. p66shc is a splice variant of p52shc/p46shc (ref. 2), a cytoplasmic signal transducer involved in the transmission of mitogenic signals from activated receptors to Ras. We show that: (1) p66shc is serine phosphorylated upon treatment with hydrogen peroxide (H2O2) or irradiation with ultraviolet light; (2) ablation of p66shc enhances cellular resistance to apoptosis induced by H2O2 or ultraviolet light; (3) a serine-phosphorylation defective mutant of p66shc cannot restore the normal stress response in p66shc-/- cells; (4) the p53 and p21 stress response is impaired in p66shc-/- cells; (5) p66shc-/- mice have increased resistance to paraquat and a 30% increase in life span. We propose that p66shc is part of a signal transduction pathway that regulates stress apoptotic responses and life span in mammals. 相似文献
162.
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165.
de Wit PJ 《Cellular and molecular life sciences : CMLS》2007,64(21):2726-2732
Plants have an innate immunity system to defend themselves against pathogens. With the primary immune system, plants recognize
microbe-associated molecular patterns (MAMPs) of potential pathogens through pattern recognition receptors (PRRs) that mediate
a basal defense response. Plant pathogens suppress this basal defense response by means of effectors that enable them to cause
disease. With the secondary immune system, plants have gained the ability to recognize effector-induced perturbations of host
targets through resistance proteins (RPs) that mediate a strong local defense response that stops pathogen growth. Both primary
and secondary immune responses in plants depend on germ line-encoded PRRs and RPs. During induction of local immune responses,
systemic immune responses also become activated, which predispose plants to become more resistant to subsequent pathogen attacks.
This review gives an update on recent findings that have enhanced our understanding of plant innate immunity and the arms
race between plants and their pathogens.
Received 24 June 2007; received after revision 18 July 2007; accepted 15 August 2007 相似文献
166.
Komen JC Distelmaier F Koopman WJ Wanders RJ Smeitink J Willems PH 《Cellular and molecular life sciences : CMLS》2007,64(24):3271-3281
Refsum disease is a rare, inherited neurodegenerative disorder characterized by accumulation of the dietary branched-chain
fatty acid phytanic acid in plasma and tissues caused by a defect in the alphaoxidation pathway. The accumulation of phytanic
acid is believed to be the main pathophysiological cause of the disease. However, the exact mechanism(s) by which phytanic
acid exerts its toxicity have not been resolved. In this study, the effect of phytanic acid on mitochondrial respiration was
investigated. The results show that in digitonin-permeabilized fibroblasts, phytanic acid decreases ATP synthesis, whereas
substrate oxidation per se is not affected. Importantly, studies in intact fibroblasts revealed that phytanic acid decreases both the mitochondrial
membrane potential and NAD(P)H autofluorescence. Taken together, the results described here show that unesterified phytanic
acid exerts its toxic effect mainly through its protonophoric action, at least in human skin fibroblasts.
Received 4 August 2007; received after revision 26 September 2007; accepted 10 October 2007
J. C. Komen, F. Distelmaier: These authors contributed equally to this work. 相似文献
167.
Dhar-Chowdhury P Malester B Rajacic P Coetzee WA 《Cellular and molecular life sciences : CMLS》2007,64(23):3069-3083
Glycolysis is an evolutionary conserved metabolic pathway that provides small amounts of energy in the form of ATP when compared
to other pathways such as oxidative phosphorylation or fatty acid oxidation. The ATP levels inside metabolically active cells
are not constant and the local ATP level will depend on the site of production as well as the respective rates of ATP production,
diffusion and consumption. Membrane ion transporters (pumps, exchangers and channels) are located at sites distal to the major
sources of ATP formation (the mitochondria). We review evidence that the glycolytic complex is associated with membranes;
both at the plasmalemma and with membranes of the endo/sarcoplasmic reticular network. We examine the evidence for the concept
that many of the ion transporters are regulated preferentially by the glycolytic process. These include the Na+/K+-ATPase, the H+-ATPase, various types of Ca2+-ATPases, the Na+/H+ exchanger, the ATP-sensitive K+ channel, cation channels, Na+ channels, Ca2+ channels and other channels involved in intracellular Ca2+ homeostasis. Regulation of these pumps, exchangers and ion channels by the glycolytic process has important consequences
in a variety of physiological and pathophysiological processes, and a better understanding of this mode of regulation may
have important consequences for developing future strategies in combating disease and developing novel therapeutic approaches.
Received 20 July 2007; received after revision 30 July 2007; accepted 17 August 2007 相似文献
168.
Hellgren M Strömberg P Gallego O Martras S Farrés J Persson B Parés X Höög JO 《Cellular and molecular life sciences : CMLS》2007,64(4):498-505
The metabolism of all-trans- and 9-cis-retinol/ retinaldehyde has been investigated with focus on the activities of human, mouse and rat alcohol dehydrogenase 2
(ADH2), an intriguing enzyme with apparently different functions in human and rodents. Kinetic constants were determined with
an HPLC method and a structural approach was implemented by in silico substrate dockings. For human ADH2, the determined Km values ranged from 0.05 to 0.3 μM and kcat values from 2.3 to 17.6 min−1, while the catalytic efficiency for 9-cis-retinol showed the highest value for any substrate. In contrast, poor activities
were detected for the rodent enzymes. A mouse ADH2 mutant (ADH2Pro47His) was studied that resembles the human ADH2 setup.
This mutation increased the retinoid activity up to 100-fold. The Km values of human ADH2 are the lowest among all known human retinol dehydrogenases, which clearly support a role in hepatic
retinol oxidation at physiological concentrations.
Received 12 October 2006; received after revision 6 December 2006; accepted 8 January 2007 相似文献
169.
Genetic studies of diseases 总被引:1,自引:0,他引:1
The biological system is a complex physicochemical system consisting of numerous dynamic networks of biochemical reactions and signaling interactions between cellular components. This complexity makes it virtually unanalyzable by traditional methods. Hence, biological networks have been developed as a platform for integrating information from high- to low-throughput experiments for analysis of biological systems. The network analysis approach is vital for successful quantitative modeling of biological systems. The numerous online pathway databases vary widely in coverage and representation of biological processes. An integrated network-based information system for querying, visualization and analysis promised successful integration of data on a large scale. Such integrated systems will greatly facilitate the understanding of biological interactions and experimental verification. 相似文献
170.