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Damaged Proteins (damaged + protein)
Selected AbstractsThe ubiquitin-proteasome system and its role in ethanol-induced disordersADDICTION BIOLOGY, Issue 1 2002Terrence M. Donohue Jr The levels of these proteins are controlled by their rates of degradation. Similarly, protein catabolism plays a crucial role in prolonging cellular life by destroying damaged proteins that are potentially cytotoxic. A major player in these catabolic reactions is the ubiquitin-proteasome system, a novel proteolytic system that has become the primary proteolytic pathway in eukaryotic cells. Ubiquitin-mediated proteolysis is now regarded as the major pathway by which most intracellular proteins are destroyed. Equally important, from a toxicological standpoint, is that the ubiquitin-proteasome system is also widely considered to be a cellular defense mechanism, since it is involved in the removal of damaged proteins generated by adduct formation and oxidative stress. This review describes the history and the components of the ubiquitin-proteasome system, its regulation and its role in pathological states, with the major emphasis on ethanol-induced organ injury. The available literature cited here deals mainly with the effects of ethanol consumption on the ubiquitin-proteasome pathway in the liver. However, since this proteolytic system is an essential pathway in all cells it is an attractive experimental model and therapeutic target in extrahepatic organs such as the brain and heart that are also affected by excessive alcohol consumption. [source] Early transcriptional response of Saccharomyces cerevisiae to stress imposed by the herbicide 2,4-dichlorophenoxyacetic acidFEMS YEAST RESEARCH, Issue 2 2006Miguel Cacho Teixeira Abstract The global gene transcription pattern of the eukaryotic experimental model Saccharomyces cerevisiae in response to sudden aggression with the widely used herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) was analysed. Under acute stress, 14% of the yeast transcripts suffered a greater than twofold change. The yeastract database was used to predict the transcription factors mediating the response registered in this microarray analysis. Most of the up-regulated genes in response to 2,4-D are known targets of Msn2p, Msn4p, Yap1p, Pdr1p, Pdr3p, Stp1p, Stp2p and Rpn4p. The major regulator of ribosomal protein genes, Sfp1p, is known to control 60% of the down-regulated genes, in particular many involved in the transcriptional and translational machinery and in cell division. The yeast response to the herbicide includes the increased expression of genes involved in the oxidative stress response, the recovery or degradation of damaged proteins, cell wall remodelling and multiple drug resistance. Although the protective role of TPO1 and PDR5 genes was confirmed, the majority of the responsive genes encoding multidrug resistance do not confer resistance to 2,4-D. The increased expression of genes involved in alternative carbon and nitrogen source metabolism, fatty acid ,-oxidation and autophagy was also registered, suggesting that acute herbicide stress leads to nutrient limitation. [source] Proteasome activation as a novel antiaging strategyIUBMB LIFE, Issue 10 2008Niki Chondrogianni Abstract Homeostasis is a key feature of cellular lifespan. Maintenance of cellular homeostasis influences the rate of aging and is determined by several factors, including efficient proteolysis of damaged proteins. Protein degradation is predominately catalyzed by the proteasome. Specifically, the proteasome is responsible for cell clearance of abnormal, denatured or in general damaged proteins as well as for the regulated degradation of short-lived proteins. As proteasome has an impaired function during aging, emphasis has been given recently in identifying ways of its activation. A number of studies have shown that the proteasome can be activated by genetic manipulations as well as by factors that affect its conformation and stability. Importantly the developed proteasome activated cell lines exhibit an extended lifespan. This review article discusses in details the various factors that are involved in proteasome biosynthesis and assembly and how they contribute to its activation. Finally as few natural compounds have been identified having proteasome activation properties, we discuss the advantages of this novel antiaging strategy. © 2008 IUBMB IUBMB Life, 60(10): 651,655, 2008 [source] Protein modification and replicative senescence of WI-38 human embryonic fibroblastsAGING CELL, Issue 2 2010Emad K. Ahmed Summary Oxidized proteins as well as proteins modified by the lipid peroxidation product 4-hydroxy-2-nonenal (HNE) and by glycation (AGE) have been shown to accumulate with aging in vivo and during replicative senescence in vitro. To better understand the mechanisms by which these damaged proteins build up and potentially affect cellular function during replicative senescence of WI-38 fibroblasts, proteins targeted by these modifications have been identified using a bidimensional gel electrophoresis-based proteomic approach coupled with immunodetection of HNE-, AGE-modified and carbonylated proteins. Thirty-seven proteins targeted for either one of these modifications were identified by mass spectrometry and are involved in different cellular functions such as protein quality control, energy metabolism and cytoskeleton. Almost half of the identified proteins were found to be mitochondrial, which reflects a preferential accumulation of damaged proteins within the mitochondria during cellular senescence. Accumulation of AGE-modified proteins could be explained by the senescence-associated decreased activity of glyoxalase-I, the major enzyme involved in the detoxification of the glycating agents methylglyoxal and glyoxal, in both cytosol and mitochondria. This finding suggests a role of detoxification systems in the age-related build-up of damaged proteins. Moreover, the oxidized protein repair system methionine sulfoxide reductase was more affected in the mitochondria than in the cytosol during cellular senescence. Finally, in contrast to the proteasome, the activity of which is decreased in senescent fibroblasts, the mitochondrial matrix ATP-stimulated Lon-like proteolytic activity is increased in senescent cells but does not seem to be sufficient to cope with the increased load of modified mitochondrial proteins. [source] Down-regulation of protein l -isoaspartyl methyltransferase in human epileptic hippocampus contributes to generation of damaged tubulinJOURNAL OF NEUROCHEMISTRY, Issue 3 2002Julie Lanthier Abstract Protein l -isoaspartyl methyltransferase (PIMT) repairs the damaged proteins which have accumulated abnormal aspartyl residues during cell aging. Gene targeting has elucidated a physiological role for PIMT by showing that mice lacking PIMT died prematurely from fatal epileptic seizures. Here we investigated the role of PIMT in human mesial temporal lobe epilepsy. Using surgical specimens of hippocampus and neocortex from controls and epileptic patients, we showed that PIMT activity and expression were 50% lower in epileptic hippocampus than in controls but were unchanged in neocortex. Although the protein was down-regulated, PIMT mRNA expression was unchanged in epileptic hippocampus, suggesting post-translational regulation of the PIMT level. Moreover, several proteins with abnormal aspartyl residues accumulate in epileptic hippocampus. Microtubules component ,-tubulin, one of the major PIMT substrates, had an increased amount (two-fold) of l -isoaspartyl residues in the epileptic hippocampus. These results demonstrate that the down-regulation of PIMT in epileptic hippocampus leads to a significant accumulation of damaged tubulin that could contribute to neuron dysfunction in human mesial temporal lobe epilepsy. [source] Insights into yeast adaptive response to the agricultural fungicide mancozeb: A toxicoproteomics approachPROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 3 2009Pedro M. Santos Abstract Toxicogenomics has the potential to elucidate gene,environment interactions to identify genes that are affected by a particular chemical at the early stages of the toxicological response and to establish parallelisms between different organisms. The fungicide mancozeb, widely used in agriculture, is an ethylene-bis-dithiocarbamate complex with manganese and zinc. Exposure to this pesticide has been linked to the development of idiopathic Parkinson's disease and cancer. Given that many signalling pathways and their molecular components are substantially conserved among eukaryotic organisms, we used Saccharomyces cerevisiae to get insights into the molecular mechanisms of mancozeb toxicity and adaptation based on expression proteomics. The early global response to mancozeb was analysed by quantitative proteomics using 2-DE. The target genes (e.g. TSA1, TSA2, SOD1, SOD2, AHP1, GRE2, GRX1, CYS3, PRE3, PRE6, PRE8, PRE9, EFT1, RPS5, TIF11, HSP31, HSP26, HSP104, HSP60, HSP70 -family) and the putative main transcription activators (e.g. Yap1, Msn2/Msn4, Met4, Hsf1, Aft1, Pdr1, Skn7, Rpn4p, Gcn4) of the complex mancozeb-induced expression changes are related with yeast response to stress, in particular to oxidative stress, protein translation initiation and protein folding, disassembling of protein aggregates and degradation of damaged proteins. Our results also suggest that this study provided powerful indications that may be useful to expand the knowledge obtained in yeast not only to the global response to mancozeb toxicity in phytopathogenic fungi but also to humans. [source] 2231: Age-related modifications in RPE cellsACTA OPHTHALMOLOGICA, Issue 2010E MANNERMAA Age-related macular degeneration (AMD) is a multi-factorial polygenetic aging disease. It has been shown that RPE dysfunction predisposes neural retinal dysfunction and the development of choroidal neovascularization. The pathogenesis of age-related macular degeneration (AMD) essentially involves chronic oxidative stress, increased accumulation of lipofuscin in retinal pigment epithelial (RPE) cells and extracellular drusen formation, as well as the presence of chronic inflammation. The capacity to prevent the accumulation of cellular cytotoxic protein aggregates is decreased in senescent cells which may evoke lipofuscin accumulation into lysosomes in postmitotic RPE cells. This presence of lipofuscin decreases lysosomal enzyme activity and impairs autophagic clearance of damaged proteins which should be removed from cells. Proteasomes are another crucial proteolytic machine which degrades especially cellular proteins damaged by oxidative stress. The cross-talk between lysosomes, autophagy and proteasomes in RPE cell protein aggregation, their role as a possible therapeutic target and their involvement in the pathogenesis of AMD is discussed. In addition, age related changes in Bruch's membrane and choroidal blood flow may take part in the pathogenesis of AMD. This will be also discussed. [source] | ||||||||||