The ubiquitin–proteasome system: Focus on the heart

Zolk, Oliver; Schenke, Carolus; Sarikas, Antonio

doi:10.1016/j.cardiores.2005.12.021

Cited by 102 publications

(71 citation statements)

References 76 publications

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“…These tumor derived and locally produced cytokines interact with their cognate receptors on skeletal muscle to activate the NF-κB transcription factor, which induces atrophy by activating the ubiquitin proteasome system to degrade the sarcomere [1,[3][4][5]13,16,[24][25][26][27]29,38,49,56,66,74,80]. The significance of the convergence of these signaling pathways on NF-κB in cancerrelated muscle atrophy has been shown experimentally in a number of different ways.…”

Section: Introductionmentioning

confidence: 99%

Selective Inhibition of NF-kappa-B with NBD Peptide Reduces Tumor- Induced Wasting in a Murine Model of Cancer Cachexia In vivo

Wysong¹,

Asher

Yin

et al. 2011

JCST

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Cancer cachexia is a severe wasting syndrome characterized by the progressive loss of lean body mass and systemic inflammation, which is seen in as many as 80% of patients with advanced malignancy. It accounts for an estimated 20-30% of all cancer-related deaths. The mechanism by which cancer induces skeletal muscle atrophy in cachexia involves tumor-derived cytokines, including TNFα, IL-1, and IL-6. Upon interaction with their unique receptors on skeletal muscle, these cytokines activate NF-kappaB, a transcription factor crucial for atrophy related sarcomere proteolysis to occur. The significance of NF-κB is highlighted in studies demonstrating that genetic inhibition of NF-κB ameliorates cancer-induced muscle loss in vivo. In the present study, we evaluate a selective NF-kappaB inhibitor (NBD peptide) which targets the IkappaB complex to prevent cancer-induced skeletal muscle atrophy in an established mouse model (C26 adenocarcinoma). We identified for the first time that NBD peptide can directly inhibit tumor-induced NFkappaB activation in skeletal muscle, resulting in a decrease loss of lean muscle. We also identified that NBD peptide reduces the expression of the tumor induced ubiquitin ligases MuRF-1 and MAFbx/Atrogin-1 necessary for atrophy. These findings highlight that NBD peptide may be a potential selective therapeutic agent for the treatment of cancer cachexia.

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Section: Introductionmentioning

confidence: 99%

Selective Inhibition of NF-kappa-B with NBD Peptide Reduces Tumor- Induced Wasting in a Murine Model of Cancer Cachexia In vivo

Wysong¹,

Asher

Yin

et al. 2011

JCST

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“…In UPS, proteins are first covalently modified by ubiquitin, and then degraded by the 26S proteasome. (reviewed in [48,49]) Majority of mam-malian intracellular proteins are degraded via the UPS, and UPS is believed to play a role in the replacement of myofilament proteins subjected to wear and tear [49]. Interestingly, UPS activity increased in an animal model of dilated cardiomyopathy (DCM), and protein ubiquitination was markedly increased [50].…”

Section: Degradationmentioning

confidence: 99%

Myofilament proteins: From cardiac disorders to proteomic changes

Yuan

Solaro

2008

Proteomics Clinical Apps

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Myofilament proteins of the cardiac sarcomere house the molecular machinery responsible for generating tension and pressure. Release of intracellular Ca 21 triggers myofilament tension generation and shortening, but the response to Ca 21 is modulated by changes in key regulatory proteins. We review how these proteomic changes are essential to adaptive physiological regulation of cardiac output and become maladaptive in cardiac disorders. We also review the essentials of proteomic techniques used to study myofilament protein changes, including degradation, isoform expression, phosphorylation and oxidation. Selected proteomic studies illustrate the applications of these approaches.

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“…This inhibition is often unsuccessful in decreasing cell size, probably because of the overwhelming redundancy of prohypertrophic signaling pathways [4] . Additional mechanisms must be involved to account for the incomplete inhibition of cardiac hypertrophy, and may include a decrease in protein degradation [5] . In contrast, activation of atrophy signaling pathways may reverse hypertrophy by increasing proteolysis even in the presence of prohypertrophic signaling in the heart [4] .…”

Section: Introductionmentioning

confidence: 99%

“…The ubiquitin-proteasome system (UPS) is the most important mechanism of proteolysis in cardiac myocytes [5,6] , degrading about 80% of the intracellular proteins [7] . The role of the UPS in the heart is primarily linked to cardiac atrophy.…”

Section: Introductionmentioning

confidence: 99%

Activation of AMPK inhibits cardiomyocyte hypertrophy by modulating of the FOXO1/MuRF1 signaling pathway in vitro

Chen

Wang

et al. 2010

Acta Pharmacol Sin

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Aim: To examine the inhibitory effects of adenosine monophosphate-activated protein kinase (AMPK) activation on cardiac hypertrophy in vitro and to investigate the underlying molecular mechanisms. Methods: Cultured neonatal rat cardiomyocytes were treated with the specifi c AMPK activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) and the specifi c AMPK antagonist Compound C, and then stimulated with phenylephrine (PE). The Muscle RING fi nger 1 (MuRF1)-small interfering RNA (siRNA) was transfected into cardiomyocytes using Lipofectamine 2000. The surface area of cultured cardiomyocytes was measured using planimetry. The protein degradation was determined using high performance liquid chromatography (HPLC). The expression of β-myosin heavy chain (β-MHC) and MuRF1, as well as the phosphorylation levels of AMPK and Forkhead box O 1 (FOXO1), were separately measured using Western blot or real-time polymerase chain reaction. Results: Activation of AMPK by AICAR 0.5 mmol/L inhibited PE-induced increase in cardiomyocyte area and β-MHC protein expression and PE-induced decrease in protein degradation. Furthermore, AMPK activation increased the activity of transcription factor FOXO1 and up-regulated downstream atrogene MuRF1 mRNA and protein expression. Treatment of hypertrophied cardiomyocytes with Compound C 1 μmol/L blunted the effects of AMPK on cardiomyocyte hypertrophy and changes to the FOXO1/MuRF1 pathway. The effects of AICAR on cardiomyocyte hypertrophy were also blocked after MuRF1 was silenced by transfection of cardiomyocytes with MuRF1-siRNA. Conclusion: The present study demonstrates that AMPK activation attenuates cardiomyocyte hypertrophy by modulating the atrophyrelated FOXO1/MuRF1 signaling pathway in vitro.

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The ubiquitin–proteasome system: Focus on the heart

Cited by 102 publications

References 76 publications

Selective Inhibition of NF-kappa-B with NBD Peptide Reduces Tumor- Induced Wasting in a Murine Model of Cancer Cachexia In vivo

Selective Inhibition of NF-kappa-B with NBD Peptide Reduces Tumor- Induced Wasting in a Murine Model of Cancer Cachexia In vivo

Myofilament proteins: From cardiac disorders to proteomic changes

Activation of AMPK inhibits cardiomyocyte hypertrophy by modulating of the FOXO1/MuRF1 signaling pathway in vitro

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