Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.25.1 (proteasome)
28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

G protein-coupled receptor kinases (GRKs) are key modulators of G protein-coupled receptor signalling. Increasing evidence points to the occurrence of complex mechanisms able to modulate the subcellular localization, activity and expression levels of GRKs, revealing new functional interactions of these kinases with different cellular proteins and transduction cascades. GRK activity and subcellular targeting is tightly regulated by interaction with receptor domains, G protein subunits, lipids, anchoring proteins, caveolin and calcium-sensing proteins. In addition, GRK phosphorylation by several other kinases has recently been shown to modulate its functionality, thus putting forward new feedback mechanisms connecting different signalling pathways to G protein-coupled receptors (GPCR) regulation. On the other hand, the mechanisms governing GRK expression at both transcriptional and protein stability levels are just beginning to be unveiled. Namely, GRK2 has been shown to be rapidly degraded by the proteasome pathway in a process dependent on beta-arrestin and c-Src function, and also to be proteolyzed by m-calpain. A better knowledge of GRK regulatory mechanisms would contribute to greater understanding of GRK physiological function and also its reported alterations in different pathological situations, such as congestive heart failure, hypertension or inflammation.
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PMID:Mechanisms of regulation of the expression and function of G protein-coupled receptor kinases. 1449 40

Protein misfolding and aberrant aggregation are associated with many severe disorders, such as neural degenerative diseases, desmin-related myopathy (DRM), and congestive heart failure. Intrasarcoplasmic amyloidosis and increased ubiquitinated proteins are observed in human failing hearts. The pathogenic roles of these derangements in the heart remain unknown. The ubiquitin-proteasome system (UPS) plays a central role in intracellular proteolysis and regulates critical cellular processes. In cultured cells, aberrant aggregation by a mutant (MT) or misfolded protein impairs the UPS. However, this has not been demonstrated in intact animals, and it is unclear how the UPS is impaired. Cross-breeding UPS reporter mice with a transgenic mouse model of DRM featured by aberrant protein aggregation in cardiomyocytes, we found that overexpression of MT-desmin but not normal desmin protein impairs UPS proteolytic function in the heart. The primary defect does not appear to be in the ubiquitination or the proteolytic activity of the 20S proteasome, because ubiquitinated proteins and the peptidase activities of 20S proteasomes were significantly increased rather than decreased in the DRM heart. Therefore, the defect resides apparently in the entry of ubiquitinated proteins into the 20S proteasome. Consistent with this notion, key components (Rpt3 and Rpt5) of 19S proteasomes were markedly decreased, while major components of 20S proteasomes were increased. Additional experiments with HEK cells suggest that proteasomal malfunction observed in MT-desmin hearts is not secondary to cardiac malfunction or to disruption of desmin filaments. Thus, UPS impairment may represent an important pathogenic mechanism underlying cardiac disorders with abnormal protein aggregation.
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PMID:Impairment of the ubiquitin-proteasome system in desminopathy mouse hearts. 1637 26

The ubiquitin-proteasome system (UPS) is the major nonlysosomal pathway for intracellular protein degradation, generally requiring a covalent linkage of one or more chains of polyubiquitins to the protein intended for degradation. It has become clear that the UPS plays major roles in regulating many cellular processes, including the cell cycle, immune responses, apoptosis, cell signaling, and protein turnover under normal and pathological conditions, as well as in protein quality control by removal of damaged, oxidized, and/or misfolded proteins. This review will present an overview of the structure, biochemistry, and physiology of the UPS with emphasis on its role in the heart, if known. In addition, evidence will be presented supporting the role of certain muscle-specific ubiquitin protein ligases, key regulatory components of the UPS, in regulation of sarcomere protein turnover and cardiomyocyte size and how this might play a role in induction of the hypertrophic phenotype. Moreover, this review will present the evidence suggesting that proteasomal dysfunction may play a role in cardiac pathologies such as myocardial ischemia, congestive heart failure, and myofilament-related and idiopathic-dilated cardiomyopathies, as well as cardiomyocyte loss in the aging heart. Finally, certain pitfalls of proteasome studies will be described with the intent of providing investigators with enough information to avoid these problems. This review should provide current investigators in the field with an up-to-date analysis of the literature and at the same time provide an impetus for new investigators to enter this important and rapidly changing area of research.
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PMID:The ubiquitin-proteasome system in cardiac physiology and pathology. 1650 Oct 26

Many elements contribute to congestive heart failure: changes in perfusion, hemodynamic stresses, alterations in calcium metabolism, and dysregulation of cell signaling pathways. Intervention in these processes forms the basis for current heart failure therapies. Nevertheless, heart failure is primarily a disease of wear and tear; despite everything we know about cardiac physiology and the clinical manifestations of heart failure, only in rare instances does therapy for heart failure normalize cardiac function. Proteins are especially prone to the forces of wear and tear in the heart because they are the primary mechanisms for stress sensing and force generation. Recent evidence supports a role for protein damage and impaired clearance of damaged proteins in the pathophysiology of human heart failure syndromes. The process of monitoring and protecting cardiac cells from accumulation of damaged proteins is known as protein quality control, and the molecular chaperone and ubiquitin-proteasome systems are the primary effectors of this process. Insights from protein quality-control strategies may lead to new concepts about prevention and treatment of human heart failure. This review provides a general overview of these pathways and their known and postulated roles in human heart failure syndromes, with a focus on providing a clinically oriented understanding of these fundamental mechanisms.
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PMID:The bitter end: the ubiquitin-proteasome system and cardiac dysfunction. 1737 87

Diaphragm weakness commonly occurs in patients with congestive heart failure (CHF) and is an independent predictor of mortality. However, the pathophysiology of diaphragm weakness is poorly understood. We hypothesized that CHF induces diaphragm weakness at the single-fiber level by decreasing myosin content. In addition, we hypothesized that myofibrillar Ca(2+) sensitivity is decreased and cross-bridge kinetics are slower in CHF diaphragm fibers. Finally, we hypothesized that loss of myosin in CHF diaphragm weakness is associated with increased proteolytic activities of caspase-3 and the proteasome. In skinned diaphragm single fibers of rats with CHF, induced by left coronary artery ligation, maximum force generation was reduced by approximately 35% (P < 0.01) compared with sham-operated animals for slow, 2a, and 2x fibers. In these CHF diaphragm fibers, myosin heavy chain content per half-sarcomere was concomitantly decreased (P < 0.01). Ca(2+) sensitivity of force generation and the rate constant of tension redevelopment were significantly reduced in CHF diaphragm fibers compared with sham-operated animals for all fiber types. The cleavage activity of the proteolytic enzyme caspase-3 and the proteasome were approximately 30% (P < 0.05) and approximately 60% (P < 0.05) higher, respectively, in diaphragm homogenates from CHF rats than from sham-operated rats. The present study demonstrates diaphragm weakness at the single-fiber level in a myocardial infarct model of CHF. The reduced maximal force generation can be explained by a loss of myosin content in all fiber types and is associated with activation of caspase-3 and the proteasome. Furthermore, CHF decreases myofibrillar Ca(2+) sensitivity and slows cross-bridge cycling kinetics in diaphragm fibers.
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PMID:Diaphragm single-fiber weakness and loss of myosin in congestive heart failure rats. 1744 57

We have reviewed the impact of the ubiquitin proteasome system (UPS) on atherosclerosis progression of diabetic patients. A puzzle of many pieces of evidence suggests that UPS, in addition to its role in the removal of damaged proteins, is involved in a number of biological processes including inflammation, proliferation and apoptosis, all of which constitute important characteristics of atherosclerosis. From what can be gathered from the very few studies on the UPS in diabetic cardiovascular diseases published so far, the system seems to be functionally active to a different extent in the initiation, progression, and complication stage of atherosclerosis in the diabetic people. Further evidence for this theory, however, has to be given, for instance by specifically targeted antagonism of the UPS. Nonetheless, this hypothesis may help us understand why diverse therapeutic interventions, which have in common the ability to reduce ubiquitin-proteasome activity, can impede or delay the onset of diabetes and cardiovascular diseases (CVD). People with type 2 diabetes are disproportionately affected by CVD, compared with those without diabetes 1. The prevalence, incidence, and mortality from all forms of CVD (myocardial infarction, cerebro-vascular disease and congestive heart failure) are strikingly increased in persons with diabetes compared with those withoutdiabetes 2. Furthermore, diabetic patients have not benefited by the advances in the management of obesity, dyslipidemia, and hypertension that have resulted in a decrease in mortality for coronary heart disease (CHD) patients without diabetes 3. Nevertheless, these risk factors do not fully explain the excess risk for CHD associated with diabetes 45. Thus, the determinants of progression of atherosclerosis in persons with diabetes must be elucidated. Beyond the major risk factors, several studies have demonstrated that such factors, strictly related to diabetes, as insulin-resistance, post-prandial hyperglycemia and chronic hyperglycemia play a role in the atherosclerotic process and may require intervention 67. Moreover, it is important to recognize that these risk factors frequently "cluster" inindividual patients and possibly interact with each other, favouring the atherosclerosis progression toward plaque instability. Thus, a fundamental question is, "which is the common soil hypothesis that may unifying the burden of all these factors on atherosclerosis of diabetic patients? Because evidences suggest that insulin-resistance, diabetes and CHD share in common a deregulation of ubiquitin-proteasome system (UPS), the major pathway for nonlysosomal intracellular protein degradation in eucaryotic cells 89, in this review ubiquitin-proteasome deregulation is proposed as the common persistent pathogenic factor mediating the initial stage of the atherosclerosis as well as the progression to complicated plaque in diabetic patients.
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PMID:The possible role of the ubiquitin proteasome system in the development of atherosclerosis in diabetes. 1797 Dec 5

In congestive heart failure (CHF), diaphragm weakness is known to occur and is associated with myosin loss and activation of the ubiquitin-proteasome pathway. The effect of modulating proteasome activity on myosin loss and diaphragm function is unknown. The present study investigated the effect of in vivo proteasome inhibition on myosin loss and diaphragm function in CHF rats. Coronary artery ligation was used as an animal model for CHF. Sham-operated rats served as controls. Animals were treated with the proteasome inhibitor bortezomib (intravenously) or received saline (0.9%) injections. Force generating capacity, cross-bridge cycling kinetics, and myosin content were measured in diaphragm single fibers. Proteasome activity, caspase-3 activity, and MuRF-1 and MAFbx mRNA levels were determined in diaphragm homogenates. Proteasome activities in the diaphragm were significantly reduced by bortezomib. Bortezomib treatment significantly improved diaphragm single fiber force generating capacity (approximately 30-40%) and cross-bridge cycling kinetics (approximately 20%) in CHF. Myosin content was approximately 30% higher in diaphragm fibers from bortezomib-treated CHF rats than saline. Caspase-3 activity was decreased in diaphragm homogenates from bortezomib-treated rats. CHF increased MuRF-1 and MAFbx mRNA expression in the diaphragm, and bortezomib treatment diminished this rise. The present study demonstrates that treatment with a clinically used proteasome inhibitor improves diaphragm function by restoring myosin content in CHF.
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PMID:Proteasome inhibition improves diaphragm function in congestive heart failure rats. 1842 22

The heart is constantly under stress and cardiomyocytes face enormous challenges to correctly fold nascent polypeptides and keep mature proteins from denaturing. To meet the challenge, cardiomyocytes have developed multi-layered protein quality control (PQC) mechanisms which are carried out primarily by chaperones and ubiquitin-proteasome system mediated proteolysis. Autophagy may also participate in PQC in cardiomyocytes, especially under pathological conditions. Cardiac PQC often becomes inadequate in heart disease, which may play an important role in the development of congestive heart failure.
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PMID:Protein quality control and degradation in cardiomyocytes. 1849 53

We present here a case of severe congestive cardiac failure, in a 47-year-old patient with myeloma who had no prior cardiac history, after receiving bortezomib. Bortezomib is a boron-containing molecule, which reversibly inhibits the proteasome, an intracellular organelle, which is central to the breakdown of ubiquitinated proteins and consequently crucial for normal cellular homeostasis. Phase II clinical trials demonstrate that it is effective for the treatment of relapsed refractory myeloma. Acute development of congestive cardiac failure associated with bortezomib therapy occurs very rarely or may be underestimated. Inhibition of proteasome activity may impair cardiac function due to accumulation of unfolded, damaged and undegraded proteins in myocytes. Patients with or without cardiac disease or previously received anthracycline-containing regimes should be closely monitored when being subjected to treatment with bortezomib.
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PMID:Acute severe cardiac failure in a myeloma patient due to proteasome inhibitor bortezomib. 1863 93

Congestive heart failure (CHF) causes arrhythmogenic, structural and contractile remodeling, with important atrial-ventricular differences: atria show faster and greater inflammation, cell-death and fibrosis. The present study assessed time-dependent left atrial (LA) and ventricular (LV) gene-expression changes in CHF. Groups of dogs were submitted to ventricular tachypacing (VTP, 240 bpm) for 24 h or 2 weeks, and compared to sham-instrumented animals. RNA from isolated LA and LV cardiomyocytes of each dog was analyzed by canine-specific microarrays (>21,700 probe-sets). LA showed dramatic gene-expression changes, with 4785 transcripts significantly-altered (Q<5) at 24-hour and 6284 at 2-week VTP. LV gene-changes were more limited, with 52 significantly-altered at 24-hour and 130 at 2-week VTP. Particularly marked differences were seen in ECM genes, with 153 changed in LA (e.g. approximately 65-fold increase in collagen-1) at 2-week VTP versus 2 in LV; DNA/RNA genes (LA=358, LV=7); protein biosynthesis (LA=327, LV=14); membrane transport (LA=230, LV=8); cell structure and mobility (LA=159, LV=6) and coagulation/inflammation (LA=147, LV=1). Noteworthy changes in LV were genes involved in metabolism (35 genes; creatine-kinase B increased 8-fold at 2-week VTP) and Ca(2+)-signalling. LA versus LV differential gene-expression decreased over time: 1567 genes were differentially expressed (Q<1) at baseline, 1499 at 24-hour and 897 at 2-week VTP. Pathway analysis revealed particularly-important changes in LA for mitogen-activated protein-kinase, apoptotic, and ubiquitin/proteasome systems, and LV for Krebs cycle and electron-transfer complex I/II genes. VTP-induced CHF causes dramatically more gene-expression changes in LA than LV, dynamically altering the LA-LV differential gene-expression pattern. These results are relevant to understanding chamber-specific remodeling in CHF.
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PMID:Marked differences between atrial and ventricular gene-expression remodeling in dogs with experimental heart failure. 1880 23


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