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)

Sensing and responding to changes in oxygen partial pressure assures that the cellular oxygen supply is tightly controlled in order to balance the risks of oxidative damage vs. oxygen deficiency. The hypoxia inducible factor (HIF) regulatory system is controlled by prolyl hydroxylases (PHDs), the von Hippel Lindau protein (pVHL), and the 26S proteasome and transduces changes in oxygenation to adequate intracellular adaptive responses. A functional HIF response requires stabilization of the alpha-subunit, e.g. HIF-1alpha, during hypoxia and dimerization with HIF-1beta, to drive target gene activation. Intriguingly, high concentrations of nitric oxide (NO) stabilize HIF-1alpha and thus mimic a hypoxic response under normoxia. Mechanistically, NO blocks PHD activity and attenuates proline hydroxylation of HIF-1alpha. This causes dissociation of pVHL from HIF-1alpha and, consequently, HIF-1alpha accumulates because proteasomal destruction is impaired. However, during hypoxia low concentrations of NO facilitate destruction of HIF-1alpha and thus reverse HIF signaling. Under these conditions, NO impairs respiration and avoids oxygen gradients that limit PHD activity. An additional layer of complexity comprises the interaction of NO with O(2)(-). Signaling qualities attributed to NO are antagonized by compensatory flux rates of O(2)(-) and vice versa to adjust levels of HIF-1alpha under normoxia and hypoxia. The liaison of NO and hypoxia is versatile and ranges from courting to matrimony and divorce.
Cardiovasc Res 2007 Jul 15
PMID:Nitric oxide and superoxide: interference with hypoxic signaling. 1741 15

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.
Cardiovasc Diabetol 2007 Oct 30
PMID:The possible role of the ubiquitin proteasome system in the development of atherosclerosis in diabetes. 1797 Dec 5

The ubiquitin-proteasome system (UPS) displays an important cellular quality control function, by removing abnormal proteins from the cytosol, the nucleus and the endoplasmic reticulum. It controls the intracellular levels of short-lived and regulatory proteins, which are important for a variety of basic cellular processes. The pathway involves an enzymatic cascade through which multiple 76-amino acid ubiquitin monomers are covalently attached via a three-step process to the protein substrate, which is then degraded by the 26S proteasome complex. The proteasome is a cylindrical organelle that recognizes ubiquitinated proteins, degrades a large proportion of intracellular proteins, and recycles ubiquitin. Alterations in the proteasome proteolytic pathway have been thought to contribute to protein alterations associated with aging and, in fact, dysregulation of the UPS has been linked to several disease states including neurodegenerative diseases, malignancies, and inflammatory-related disorders. Strong preclinical data now exist supporting the use of reversible proteasome inhibitors to treat a variety of disease states including cancer, autoimmune and inflammatory diseases, myocardial infarction, and ischemic brain injury. Bortezomib (Velcade) has recently been licensed for the treatment of patients with multiple myeloma and is also undergoing further evaluation for the treatment of chronic lymphocytic leukemia (CLL) and a variety of solid tumors. MLN-519 is a small-molecular-weight lactacystin analogue and is being studied for the potential treatment of inflammatory disease and acute stroke. MLN-519 has demonstrated a neuroprotective effect in rat models of middle cerebral artery occlusion by reducing infarct volume, brain oedema and improving neurological outcome with a therapeutic window of up to 6-hrs. This review article focuses on the recent progress in the use of proteasome inhibitors in nervous system diseases with emphasis on the bench-to-bedside research effort which provided the foundation for clinical development of proteasome inhibitors in the treatment of neurological disorders.
Cardiovasc Hematol Disord Drug Targets 2007 Dec
PMID:The ubiquitin-proteasome system and proteasome inhibitors in central nervous system diseases. 1822 Jul 25

The cardiac proteasome is increasingly recognized as a complex, heterogeneous, and dynamic organelle contributing to the modulation of cardiac function in health and diseases. The emerging picture of the proteasome system reveals a highly regulated and organized molecular machine integrated into multiple biologic processes of the cell. Full appreciation of its cardiovascular relevance requires an understanding of its proteolytic function as well as its underlying regulatory mechanisms, of which assembly, stoichiometry, posttranslational modification, and the role of the associating partners are increasingly poignant.
Trends Cardiovasc Med 2008 Apr
PMID:Understanding proteasome assembly and regulation: importance to cardiovascular medicine. 1843 47

Myopathy has been reported in a small percentage of statin-treated patients for the past 30 years, but the etiologic mechanisms for inducing muscle injury have not yet been fully characterized. Statin-induced myopathy is now understood to be a heterogeneous condition that may be due to: mechanisms of the drug itself; interactions with other drugs; or genetic, metabolic and immunological vulnerabilities in individual patients. In some cases, statins may unmask latent conditions (e.g., asymptomatic baseline myopathy) that predispose patients to muscle toxicity. The definitions, epidemiology, clinical features, risk factors and proposed mechanisms of statin-induced myopathy are reviewed. Muscle metabolism can be adversely impacted by statin therapy, including changes in fatty acid oxidation, possibly reduced coenzyme Q(10) biosynthesis, and increased myocyte protein degradation via the activity of atrogin-1 and the ubiquitin-proteasome pathway. Statin therapy may also activate a variety of autoimmune phenomena that potentiate myocellular injury. Improving our understanding of statin-induced myopathy is a high clinical priority given the large number of patients eligible for statin therapy and the fact that the development of myalgia and myopathy are leading reasons cited by patients for statin discontinuation.
Expert Rev Cardiovasc Ther 2008 Aug
PMID:Clinical characterization and molecular mechanisms of statin myopathy. 1866 46

The assembly and maintenance of the cardiac sarcomere, which contains the basic contractile components of actin and myosin, are essential for cardiac function. While often described as a static structure, the sarcomere is actually dynamic and undergoes constant turnover, allowing it to adapt to physiological changes while still maintaining function. A host of new factors have been identified that play a role in the regulation of protein quality control in the sarcomere, including chaperones that mediate the assembly of sarcomere components and ubiquitin ligases that control their specific degradation. There is clear evidence of sarcomere disorganization in animal models lacking muscle-specific chaperone proteins, illustrating the importance of these molecules in sarcomere structure and function. Although ubiquitin ligases have been found within the sarcomere structure itself, the role of the ubiquitin proteasome system in cardiac sarcomere regulation, and the factors that control its activity, are only just now being elucidated. The number of ubiquitin ligases identified with specificity for sarcomere proteins, each with distinct target substrates, is growing, allowing for tight regulation of this system. In this review, we highlight the dynamic interplay between sarcomere-specific chaperones and ubiquitin-dependent degradation of sarcomere proteins that is necessary in order to maintain structure and function of the cardiac sarcomere.
Cardiovasc Res 2009 Feb 15
PMID:Build it up-Tear it down: protein quality control in the cardiac sarcomere. 1897 44

In response to an increased hemodynamic load, such as pressure or volume overload, cardiac hypertrophy ensues as an adaptive mechanism. Although hypertrophy initially maintains ventricular function, a yet undefined derailment in this process eventually leads to compromised function (decompensation) and eventually culminates in congestive heart failure (CHF). Therefore, determining the molecular signatures induced during compensatory growth is important to delineate specific mechanisms responsible for the transition into CHF. Compensatory growth involves multiple processes. At the cardiomyocyte level, one major event is increased protein turnover where enhanced protein synthesis is accompanied by increased removal of deleterious proteins. Many pathways that mediate protein turnover depend on a key molecule, mammalian target of rapamycin (mTOR). In pressure-overloaded myocardium, adrenergic receptors, growth factor receptors, and integrins are known to activate mTOR in a PI3K-dependent and/or independent manner with the involvement of specific PKC isoforms. mTOR, described as a sensor of a cell's nutrition and energy status, is uniquely positioned to activate pathways that regulate translation, cell size, and the ubiquitin-proteasome system (UPS) through rapamycin-sensitive and -insensitive signaling modules. The rapamycin-sensitive complex, known as mTOR complex 1 (mTORC1), consists of mTOR, rapamycin-sensitive adaptor protein of mTOR (Raptor) and mLST8 and promotes protein translation and cell size via molecules such as S6K1. The rapamycin-insensitive complex (mTORC2) consists of mTOR, mLST8, rapamycin-insensitive companion of mTOR (Rictor), mSin1 and Protor. mTORC2 regulates the actin cytoskeleton in addition to activating Akt (Protein kinase B) for the subsequent removal of proapoptotic factors via the UPS for cell survival. In this review, we discuss pathways and key targets of mTOR complexes that mediate growth and survival of hypertrophying cardiomyocytes and the therapeutic potential of mTOR inhibitor, rapamycin.
Cardiovasc Hematol Agents Med Chem 2009 Jan
PMID:mTOR in growth and protection of hypertrophying myocardium. 1914 44

Thrombotic microangiopathies (TMA) encompass various diseases characterized by a microangiopathic hemolytic anemia, platelet clumping, and organ failure of variable severity. Thrombotic thrombocytopenic purpura (TTP) is a particularly severe form of TMA characterized by systemic organ failure which results from a severe defect in ADAMTS13, a plasma enzyme specifically involved in the cleavage of highly hemostatic unusually large (UL) von Willebrand factor (VWF) multimers into smaller and less adhesive VWF forms. Failure to degrade these UL-VWF multimers leads to excessive platelet aggregates and capillary occlusion. ADAMTS13 deficiency results from bi-allelic mutations in hereditary TTP, whereas in acquired forms it results from autoantibodies that alter the protein function. Patients with acquired idiopathic TTP have a trend to develop autoimmunity, since a clinical context of autoimmunity may be found in 30 p. cent of cases. Moreover, the remarkable efficiency of monoclonal antibodies directed against CD20 antigen of B lymphocytes in refractory or chronic relapsing forms provides an additional indirect argument to consider acquired TTP as an autoimmune disease. Hemolytic uremic syndrome (HUS) is characterized prominently by a renal failure. In most cases, HUS is caused by entero-hemorrhagic Escherichia coli (diarrhea-positive HUS). Diarrhea-negative HUS, termed atypical HUS, was associated with a dysfunction in complement pathway involving mutations in factor H, factor I, CD46/MCP, factor B and C3 components. The major improvement in our understanding of TMA pathophysiology allows now a more accurate molecular classification of TMA syndromes, which opens fascinating perspectives of targeted therapies in the forthcoming years.
Cardiovasc Hematol Disord Drug Targets 2009 Mar
PMID:Thrombotic microangiopathies: towards a pathophysiology-based classification. 1927 76

New chemotherapeutic agents are still required to further optimise treatment of leukemia patients. Proteasome inhibition by bortezomib, PR-171 (carfilzomib) and NPI-0052 (salinosporamide A) has been successfully used for the treatment of multiple myeloma and mantle cell lymphoma and is considered also as novel treatment strategy in leukemia. Combination of proteasome inhibitors bortezomib and NPI-0052 induces synergistic anti-multiple myeloma activity both in vitro using multiple myeloma cells and in vivo in a human plasmacytoma xenograft mouse model. Cell death resulting from proteasome inhibition requires caspase activation and increased levels of reactive oxygen species. While bortezomib induces several caspases, NPI-0052 activates predominantly caspase-8-dependent pathway. We studied the effect of bortezomib (10 nM) on DNA synthesis and apoptosis in human acute myeloid cell lines KASUMI-1, ML-1, ML-2 and CTV-1 cells. Bortezomib was potent inhibitor of DNA synthesis in all four types of leukemia cells and induced apoptosis in KASUMI-1, ML-2 and CTV-1 cells but not in ML-1 cells. Other research groups showed that histone deacetylase inhibitors (valproic acid or benzamide derivative MS-275) in combination with NPI-0052 or PR-171 induced greater levels of acute leukemia cell death than in combination with bortezomib. Proteasome inhibition as monotherapy and its combination with many conventional therapies as novel treatment strategies in leukemia are promising. Malignant cells are more sensitive to this treatment than normal hematopoietic cells.
Cardiovasc Hematol Disord Drug Targets 2009 Mar
PMID:Antiproliferative and proapoptotic effects of proteasome inhibitors and their combination with histone deacetylase inhibitors on leukemia cells. 1927 78

Activation of the ubiquitin-proteasome system has been described in different models of cardiac hypertrophy. Cardiac cell growth in response to pressure or volume overload, as well as physiological adaptive hypertrophy, is accompanied by an increase in protein ubiquitination, proteasome subunit expression, and proteasome activity. Importantly, an inhibition of proteasome activity prevents and reverses cardiac hypertrophy and remodelling in vivo. The focus of this review is to provide an update about the mechanisms by which proteasome inhibitors affect cardiac cell growth in adaptive and maladaptive models of cardiac hypertrophy. In the first part, we summarize how the proteasome affects both proteolysis and protein synthesis in a context of cardiac cell growth. In the second part, we show how proteasome inhibition can prevent and reverse cardiac hypertrophy and remodelling in response to different conditions of overload.
Cardiovasc Res 2010 Jan 15
PMID:Proteasome inhibitors and cardiac cell growth. 1957 73


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