IUBMB Life
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Geldanamycin (GA), a benzoquinone ansamycin, is one of the specific inhibitors of 90‐kDa heat shock protein and induces growth inhibition and apoptosis in certain cancer cell lines. We have investigated the mechanism of GA‐induced growth inhibition in K562 erythroleukemic cells. DNA flow‐cytometric analysis indicated that GA‐induced growth arrest was associated with G2/M phase arrest of the cell cycle. GA treatment down‐regulated the expression of cyclin B1 and inhibited phosphorylation of Cdc2 protein, both key regulatory proteins at the G2/M boundary. GA also markedly inhibited the Cdc2 kinase activity, which may be in part a result of up‐regulation of p27KIP1 by GA. The present results suggest a novel mechanism that p27KIP1 could be involved in the regulation of G2 to M phase transition.
HSP90 is one of the most abundant heat shock proteins (HSPs) in eukaryotic cells and is found in complex with several regulatory proteins such as kinases and transcription factors. Geldanamycin (GA), a benzoquinone ansamycin, specifically binds to HSP90 and disrupts the interaction of HSP90 and target proteins. Thus, GA has been used as a specific inhibitor of HSP90. In this study, we examined whether GA could affect protein synthesis and gene expression in the human erythroleukemic cell line K562. Treatment with GA, but not herbimycin A (another benzoquinone ansamycin), highly induced a 70‐kDa protein, which was revealed to be HSP70 by immunoblotting and immunoprecipitation with anti‐HSP70 antibody. The expression of HSP28 was also enhanced by GA. Furthermore, GA induced the activation of heat shock factor 1 (HSF1), but not HSF2, as determined by electromobility shift and electromobility supershift assay. In addition, similar to heat shock treatment, GA induced the phosphorylation of HSF1. Heat shock element‐binding activity and phosphorylation of HSF1 were attenuated 3 h after GA treatment. These results indicate that the functional inactivation of HSP90 by GA potentially stimulates the expression of heat shock proteins through activation of HSF1.
Các glycerophospholipid phosphatidylcholine (PC) và phosphatidylethanolamine (PE) chiếm hơn 50% tổng số loài phospholipid trong màng eukaryote và do đó đóng vai trò quan trọng trong cấu trúc và chức năng của các màng này. Trong hầu hết các tế bào eukaryote, PC và PE được tổng hợp thông qua phản ứng aminocoholphosphotransferase, sử dụng
The related disorders of obesity and diabetes are increasing to epidemic proportions. The role of neutral lipid storage and hydrolysis, and hence the adipocyte, is central to understanding this phenomenon. The adipocyte holds the major source of stored energy in the body in the form of triacylglycerols (TAG). It has been known for over 35 years that the breakdown of TAG and release of free (unesterified) fatty acids and glycerol from fat tissue can be regulated by a cAMP‐mediated process. However, beyond the initial signaling cascade, the mechanistic details of this lipolytic reaction have remained unclear. Work in recent years has revealed that both hormone‐sensitive lipase (HSL), generally thought to be the rate‐limiting enzyme, and perilipin, a lipid droplet surface protein, are required for optimal lipid storage and fatty acid release. There are multiple perilipin proteins encoded by mRNA splice variants of a single perilipin gene. The perilipin proteins are polyphosphorylated by protein kinase A and phosphorylation is necessary for translocation of HSL to the lipid droplet and enhanced lipolysis. Hence, the surface of the lipid storage droplet has emerged as a central site of regulation of lipolysis. This review will focus on adipocyte lipolysis with emphasis on hormone signal transduction, lipolytic enzymes, the lipid storage droplet, and fatty acid release from the adipocyte. IUBMB Life, 56: 379‐385, 2004
Nonalcoholic fatty liver disease (NAFLD) represents the most common chronic liver disease in western countries, being considered the hepatic manifestation of metabolic syndrome. Cumulative lines of evidence suggest that olive oil, used as primary source of fat by Mediterranean populations, may play a key role in the observed health benefits on NAFLD. In this review, we summarize the state of the art of the knowledge on the protective role of both major and minor components of olive oil on lipid metabolism during NAFLD. In particular, the biochemical mechanisms responsible for the increase or decrease in hepatic lipid content are critically analyzed, taking into account that several studies have often provided different and/or conflicting results in animal models fed on olive oil‐enriched diet. In addition, new findings that highlight the hypolipidemic and the antisteatotic actions of olive oil phenols are presented. As mitochondrial dysfunction plays a key role in the pathogenesis of NAFLD, the targeting of these organelles with olive oil phenols as a powerful therapeutic approach is also discussed. © 2015 IUBMB Life, 67(1):9–17, 2015
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease of unknown etiology characterized by degradation of cartilage and bone, accompanied by unimpeded proliferation of synoviocytes of altered phenotype. In the present study, we investigated the involvement of the glucagon‐like peptide 1 (GLP‐1) receptor on human fibroblast‐like synoviocytes (FLS) in the pathogenesis of RA using the selective GLP‐1 agonist exenatide, a licensed drug used for the treatment of type 2 diabetes. Our results indicate that exenatide may play a role in regulating tumor necrosis factor‐α‐induced mitochondrial dysfunction by increasing mitochondrial membrane potential, oxidative stress by reducing the production of reactive oxygen species, the expression of NADPH oxidase 4, expression of matrix metalloproteinase (MMP)‐3 and MMP‐13, release of proinflammatory cytokines including interleukin‐1β (IL‐1β), IL‐6, monocyte chemoattractant protein‐1, and high‐mobility group protein 1, as well as activation of the p38/nuclear factor of κ light polypeptide gene enhancer in B‐cells inhibitor, α/nuclear factor κB signaling pathway in primary human RA FLS. These positive results indicate that exenatide may have potential as a therapeutic agent for the treatment and prevention of RA. © 2019 IUBMB Life, 9999(9999):1–9, 2019
The long term use of many insecticides is continually threatened by the ability of insects to evolve resistance mechanisms that render the chemicals ineffective. Such resistance poses a serious threat to insect pest control both in the UK and worldwide. Resistance may result from either an increase in the ability of the insect to detoxify the insecticide or by changes in the target protein with which the insecticide interacts. DDT, the pyrethrins and the synthetic pyrethroids (the latter currently accounting for around 17% of the world insecticide market), act on the voltage‐gated sodium channel proteins found in insect nerve cell membranes. The correct functioning of these channels is essential for normal transmission of nerve impulses and this process is disrupted by binding of the insecticides, leading to paralysis and eventual death. Some insect pest populations have evolved modifications of the sodium channel protein which prevent the binding of the insecticide and result in the insect developing resistance. Here we review some of the work (done at Rothamsted Research and elsewhere) that has led to the identification of specific residues on the sodium channel that may constitute the DDT and pyrethroid binding sites. IUBMB Life, 59: 151‐162, 2007
Neuroglobin has been identified to protect brain neurons from apoptotic stress. Hydrogen sulphide has a role in the brain as a neuromodulator, involving NMDA receptor activation. Here we report on studies of the
Polyamines are ubiquitous small basic molecules that play multiple essential roles in mammalian physiology. Their cellular content is highly regulated and there is convincing evidence that altered metabolism is involvement in many disease states. Drugs altering polyamine levels may therefore have a variety of important targets. This review will summarize the current state of understanding of polyamine metabolism and function, the regulation of polyamine content, and heritable pathological conditions that may be derived from altered polyamine metabolism. © 2009 IUBMB IUBMB Life 61(9): 880–894, 2009
Glucose‐6‐phosphate dehydrogenase (G6PD) is the rate‐limiting enzyme of the pentose phosphate pathway. Many scientists think that the roles and regulation of G6PD in physiology and pathophysiology have been well established as the enzyme was first identified 80 years ago. And that G6PD has been extensively studied especially with respect to G6PD deficiency and its association with hemolysis, and with respect to the role G6PD plays in lipid metabolism. But there has been a growing understanding of the central importance of G6PD to cellular physiology as it is a major source of NADPH that is required by many essential cellular systems including the antioxidant pathways, nitric oxide synthase, NADPH oxidase, cytochrome p450 system, and others. Indeed G6PD is essential for cell survival. It has also become evident that G6PD is highly regulated by many signals that affect transcription, post‐translation, intracellular location, and interactions with other protein. Pathophysiologic roles for G6PD have also been identified in such disease processes as diabetes, aldosterone‐induced endothelial dysfunction, cancer, and others. It is now clear that G6PD is under complex regulatory control and of central importance to many cellular processes. In this review the biochemistry, regulatory signals, physiologic roles, and pathophysiologic roles for G6PD that have been elucidated over the past 20 years are discussed. 2012 IUBMB IUBMB Life, 2012
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