Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The primary intracellular protein degradation systems, including the ubiquitin-proteasome and the lysosome pathways, have been emerging as central regulators of viral infectivity, inflammation, and viral pathogenicity. Viral myocarditis is an inflammatory disease of the myocardium caused by virus infection in the heart. The disease progression of viral myocarditis occurs in three distinct stages: acute viral infection, immune cell infiltration, and cardiac remodelling. Growing evidence suggests a crucial role for host proteolytic machineries in the regulation of the pathogenesis and progression of viral myocarditis in all three stages. Cardiotropic viruses evolve different strategies to subvert host protein degradation systems to achieve successful viral replication. In addition, these proteolytic systems play important roles in the activation of innate and adaptive immune responses during viral infection. Recent evidence also suggests a key role for the ubiquitin-proteasome and lysosome systems as the primary effectors of protein quality control in the regulation of cardiac remodelling. This review summarizes the recent advances in understanding the direct interaction between cardiotropic viruses and host proteolytic systems, with an emphasis on coxsackievirus B3, one of the primary aetiological agents causing viral myocarditis, and highlights possible roles of the host degradation systems in the pathogenesis of viral myocarditis and its progression to dilated cardiomyopathy.
Cardiovasc Res 2010 Jan 15
PMID:Protein degradation systems in viral myocarditis leading to dilated cardiomyopathy. 1957 74

Degradation of poly-ubiquitinated proteins by the 26S-proteasome complex represents a crucial quantitative control mechanism. The ubiquitin-proteasome system (UPS) plays a pivotal role in the complex molecular network regulating the progression both between and within each cell-cycle phase. Two major complexes are involved: the SKP1-CUL1-F-box-protein complex (SCF) and the anaphase-promoting complex/cyclosome (APC/C). Notwithstanding structural similarities, SCF and APC/C display different cellular functions and mechanisms of action. SCF modulates all cell-cycle stages and plays a prominent role at G1/S transition mainly through three regulatory subunits: Skp2, Fbw7, and beta-TRCP. APC/C, regulated by Cdc20 or Cdh1 subunits, has a crucial role in mitosis. In this review, we will describe how the endothelial cell cycle is regulated by the UPS. We will illustrate the principal SCF- and APC/C-dependent molecular mechanisms that modulate cell growth, allowing a unidirectional cell-cycle progression. Then, we will focus our attention on UPS modulation by oxidative stress, a pathogenic stimulus that causes endothelial dysfunction and is involved in numerous cardiovascular diseases.
Cardiovasc Res 2010 Jan 15
PMID:Regulation of the endothelial cell cycle by the ubiquitin-proteasome system. 1961 22

Cardiomyopathies represent an important cause of cardiovascular morbidity and mortality due to heart failure, arrhythmias, and sudden death. Most forms of hypertrophic cardiomyopathy (HCM) are familial with an autosomal-dominant mode of inheritance. Over the last 20 years, the genetic basis of the disease has been largely unravelled. HCM is considered as a sarcomeropathy involving mutations in sarcomeric proteins, most often beta-myosin heavy chain and cardiac myosin-binding protein C. 'Missense' mutations, more common in the former, are associated with dysfunctional proteins stably integrated into the sarcomere. 'Nonsense' and frameshift mutations, more common in the latter, are associated with low mRNA and protein levels derived from the diseased allele, leading to haploinsufficiency of the remaining healthy allele. The two quality control systems responsible for the removal of the affected mRNAs and proteins are the nonsense-mediated mRNA decay (NMD) and the ubiquitin-proteasome system (UPS), respectively. This review discusses clinical and genetic aspects of HCM and the role of NMD and UPS in the regulation of mutant proteins, evidence for impairment of UPS as a pathogenic factor, as well as potential therapies for HCM.
Cardiovasc Res 2010 Jan 15
PMID:The ubiquitin-proteasome system and nonsense-mediated mRNA decay in hypertrophic cardiomyopathy. 1961 24

Unfolded and misfolded proteins are inherently toxic to cells and have to be quickly and efficiently eliminated before they intoxicate the intracellular environment. This is of particular importance during proteotoxic stress when, as a consequence of intrinsic or extrinsic factors, the levels of misfolded proteins are transiently or persistently elevated. To meet this demand, metazoan cells have developed specific protein quality control mechanisms that allow the identification and proper handling of non-native proteins. An important defence mechanism is the specific destruction of these proteins by the ubiquitin-proteasome system (UPS). A number of studies have shown that various proteotoxic stress conditions can cause functional impairment of the UPS resulting in cellular dysfunction and apoptosis. In this review, we will summarize our current understanding of proteotoxic stress-induced dysfunction of the UPS and some of its implications for human pathologies.
Cardiovasc Res 2010 Jan 15
PMID:Stressing the ubiquitin-proteasome system. 1963 14

The cardiac proteasome is a complex, heterogeneous, and dynamic organelle. Its function is regulated by its molecular organization, post-translational modifications, and associated partner proteins. Pressure overload, ischaemic heart disease, or genetic mutations in contractile proteins can cause heart failure, during which misfolded protein levels are elevated. At the same time, numerous interconnected signal transduction pathways are activated that may modulate any of the three proteasomal regulatory mechanisms mentioned above, resulting in functional changes in cardiac proteasomes. Many lines of evidence support the important role of the ubiquitin-proteasome system (UPS) in the development of heart diseases. Many researchers have focused on the UPS, applying new drug discovery methods not only in the field of cancer research but also in cardiovascular fields such as cardiac hypertrophy and ischaemic heart diseases. More understanding of UPS in the pathophysiology of heart diseases will lead to new routes for therapy.
Cardiovasc Res 2010 Jan 15
PMID:Functional alterations of cardiac proteasomes under physiological and pathological conditions. 1968 34

Protein quality control (PQC) depends on elegant collaboration between molecular chaperones and targeted proteolysis in the cell. The latter is primarily carried out by the ubiquitin-proteasome system, but recent advances in this area of research suggest a supplementary role for the autophagy-lysosomal pathway in PQC-related proteolysis. The (patho)physiological significance of PQC in the heart is best illustrated in cardiac proteinopathy, which belongs to a family of cardiac diseases caused by expression of aggregation-prone proteins in cardiomyocytes. Cardiac proteasome functional insufficiency (PFI) is best studied in desmin-related cardiomyopathy, a bona fide cardiac proteinopathy. Emerging evidence suggests that many common forms of cardiomyopathy may belong to proteinopathy. This review focuses on examining current evidence, as it relates to the hypothesis that PFI impairs PQC in cardiomyocytes and contributes to the progression of cardiac proteinopathies to heart failure.
Cardiovasc Res 2010 Jan 15
PMID:The ubiquitin-proteasome system in cardiac proteinopathy: a quality control perspective. 1969 71

The ubiquitin-proteasome system (UPS) plays a central role in protein degradation and regulates a variety of critical cellular processes. During recent years, the cardiac UPS has become increasingly recognized as a key regulator of cardiac function under both physiological and pathological conditions. Numerous studies have demonstrated that altered UPS function is involved in the pathogenesis of cardiac disease including myocardial ischaemia or infarction. The expression and activity of the E3 ubiquitin ligases, which confer substrate specificity in the UPS pathway, affect the apoptosis and severity of disease in myocardial ischaemia and reperfusion. Although impaired proteasome function is commonly associated with myocardial ischaemic injury, recent evidence also supports a cardioprotective role for proteasome inhibitors in myocardial ischaemia. We will review these studies and data, discuss controversies regarding the UPS alterations and use of proteasome inhibitors in myocardial ischaemia, and attempt to identify strategies that may enhance their clinical application.
Cardiovasc Res 2010 Jan 15
PMID:Proteasome inhibition during myocardial infarction. 1974 47

The ubiquitin-proteasome system (UPS) has been recognized as a key regulatory pathway in cardiovascular diseases. Although the role of this system in the pathogenesis of endothelial dysfunction remains largely unknown, available data suggest that proteasome activity is modified by mediators and processes--e.g. nitric oxide and oxidative stress--involved in the regulation of endothelial function. In addition, there is some evidence that the UPS itself modulates the activity of endothelial nitric oxide synthase, the key enzyme of vascular homeostasis, interacts with other vasoactive mediators involved in regulation of endothelial function, influences oxidative stress response in the vasculature, and thereby contributes to regulation of endothelial (dys)function. This review discusses the potential implications of the UPS in endothelial dysfunction.
Cardiovasc Res 2010 Jan 15
PMID:The ubiquitin-proteasome pathway and endothelial (dys)function. 1976 93

The ubiquitin-proteasome system (UPS) represents the major pathway for degradation of intracellular proteins. This article reviews the major components and configurations of the UPS including the 26S proteasome and 11S activated proteasome relevant to myocardial ischaemia. We then present the evidence that the UPS is dysfunctional during myocardial ischaemia as well as potential consequences of this, including dysregulation of target substrates, many of them active signalling proteins, and accumulation of oxidized proteins. As part of this discussion, potential mechanisms, including ATP depletion, inhibition by insoluble protein aggregates, and oxidation of proteasome and regulatory particle subunits, are discussed. Finally, the evidence suggesting a role for the UPS in ischaemic preconditioning is presented. Much of this is inferential but clearly indicates the need for additional research.
Cardiovasc Res 2010 Jan 15
PMID:The ubiquitin-proteasome system in myocardial ischaemia and preconditioning. 1979 65

Protein metabolism is a central element of every living cell. The ubiquitin-proteasome system (UPS) is an integral part of the protein metabolism machinery mediating post-transcriptional processing and degradation of the majority of intracellular proteins. Over the past few years, remarkable progress has been made in our understanding of the role of the UPS in vascular biology and pathobiology, particularly atherosclerosis. This review reflects on the recent developments from the effects on endothelial cells and the initial stage of atherosclerosis to the effects on vascular smooth muscle and the progression stage of atherosclerosis and finally to the effects on cell viability and the complication stage of atherosclerosis. It will conclude with the integration of the available information in a synoptic view of the involvement of the UPS in atherosclerosis.
Cardiovasc Res 2010 Jan 15
PMID:On to the road to degradation: atherosclerosis and the proteasome. 1981 65


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