Proteasome inhibition induces cytokeratin accumulation in vivo

Bardag‐Gorce, Fawzia; Vu, Jennifer; Li, Nan; Riley, Nora E.; Li, Jun; French, Samuel W.

doi:10.1016/j.yexmp.2003.11.004

Cited by 31 publications

(12 citation statements)

References 22 publications

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“…In a separate experiment, rats were injected intraperitoneally at the time of casting with Velcade (0.5 mg/kg body wt; Millenium Pharmaceuticals, Cambridge, MA) or an equivalent volume (0.5 ml) of vehicle (saline). This dose has been used previously to study proteasome function in in vivo cancer and alcoholic hepatitis models (3,7,30). After 3 days of immobilization, muscles were processed as above.…”

Section: Methodsmentioning

confidence: 99%

Hindlimb casting decreases muscle mass in part by proteasome-dependent proteolysis but independent of protein synthesis

Krawiec¹,

Frost²,

Vary³

et al. 2005

American Journal of Physiology-Endocrinology and Metabolism

172

166

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The hypothesis of the present study was that rats subjected to shortterm unilateral hindlimb immobilization would incur skeletal muscle wasting and concomitant alterations in protein synthesis, controllers of translation, and indexes of protein degradation. Rats were unilaterally casted for 1, 3, or 5 days to avoid complications associated with other disuse models. In the casted limb, gastrocnemius wet weight decreased 12% after 3 days and thereafter remained constant. In contrast, the contralateral control leg displayed a steady growth rate over time. The rate of protein synthesis and translational efficiency were unchanged in the immobilized muscle at day 5. The total amount and phosphorylation state of regulators of translational initiation and elongation were unaltered. The mRNA contents of polyubiquitin and the ubiquitin ligases muscle atrophy F-box (MAFbx)/Atrogin-1 and muscle RING finger 1 (MuRF1) were elevated in immobilized muscle at all time points, with peak expression occurring at day 3. Daily injection of the type II glucocorticoid receptor antagonist RU-486 did not prevent decreases in gastrocnemius wet weight nor increases in mRNA for MAFbx/Atrogin-1 and MuRF1. However, in vivo administration of the proteasome inhibitor Velcade prevented 53% of wet weight loss associated with 3 days of immobilization. These data suggest that the loss of skeletal muscle mass in this model of disuse appears to be glucocorticoid independent, can be partially rescued with a potent proteasome inhibitor, and is associated with enhanced mRNA expression of multiple factors that contribute to ubiquitinproteasome-dependent degradation and are likely to control the remodeling of immobilized skeletal muscle during atrophy.Atrogin-1; muscle RING finger 1; disuse; eukaryotic initiation factor; translation SKELETAL MUSCLE DEMONSTRATES a remarkable degree of plasticity in response to alterations in mechanical loading. Removal of normal weight-bearing stress results in quantitative and qualitative adaptations in protein content that are phenotypically epitomized by decreased muscle wet weight, fiber diameter, force output, fatigue resistance, and a slow-to-fast

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Section: Methodsmentioning

confidence: 99%

Hindlimb casting decreases muscle mass in part by proteasome-dependent proteolysis but independent of protein synthesis

Krawiec¹,

Frost²,

Vary³

et al. 2005

American Journal of Physiology-Endocrinology and Metabolism

172

166

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“…A malfunction in the ubiquitin-proteasome degradation pathway is hypothesized to be one cause of Mallory body formation in the hepatocytes of patients with chronic liver disorders (Bardag-Gorce et al, 2003;Bardag-Gorce et al, 2004;Denk et al, 2000). Mallory bodies are inclusions composed of the keratin intermediate filaments keratin 8 (K8; also known as Krt8) and keratin 18 (K18; also known as Krt18), as well as ubiquitin, the proteasome complex and molecular chaperones, including heat shock protein 70 (HSP70; HSPA1B) and heat shock protein 90 (HSP90) (Coulombe and Omary, 2002).…”

Section: Introductionmentioning

confidence: 99%

“…Mallory bodies are inclusions composed of the keratin intermediate filaments keratin 8 (K8; also known as Krt8) and keratin 18 (K18; also known as Krt18), as well as ubiquitin, the proteasome complex and molecular chaperones, including heat shock protein 70 (HSP70; HSPA1B) and heat shock protein 90 (HSP90) (Coulombe and Omary, 2002). Cells that have been treated with a chemical inhibitor of proteasome function (Bardag-Gorce et al, 2004) or that contain the UBB +1 ubiquitin mutation (Bardag-Gorce et al, 2003) form Mallory bodies due to an accumulation of non-degraded keratin.Misfolded proteins also tend to aggregate. Proper protein folding within a cell often does not occur spontaneously and, thus, molecular chaperones are required for some proteins to reach its native state efficiently (Hartl and Hayer-Hartl, 2002).…”

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confidence: 99%

The Mrj co-chaperone mediates keratin turnover and prevents the formation of toxic inclusion bodies in trophoblast cells of the placenta

et al. 2007

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DEVELOPMENT 1809 DEVELOPMENT AND DISEASE RESEARCH ARTICLE INTRODUCTIONProtein aggregation and the formation of intracellular protein inclusion bodies are associated with many degenerative disorders, including Parkinson's and Huntington's diseases, and with cirrhosis of the liver (Carrell, 2005). In many cases, the role of protein aggregates in disease pathogenesis is unclear. Efforts to understand aggregation disorders have focused mainly on mutations within the disease-associated protein. However, mounting evidence suggests that a major cause of protein inclusion body formation is failure of the protein quality-control system (McClellan et al., 2005). This surveillance mechanism recruits both molecular chaperones and proteases to safeguard against protein aggregation by maintaining the equilibrium between protein folding and degradation (Hohfeld et al., 2001). A malfunction in the ubiquitin-proteasome degradation pathway is hypothesized to be one cause of Mallory body formation in the hepatocytes of patients with chronic liver disorders (Bardag-Gorce et al., 2003;Bardag-Gorce et al., 2004;Denk et al., 2000). Mallory bodies are inclusions composed of the keratin intermediate filaments keratin 8 (K8; also known as Krt8) and keratin 18 (K18; also known as Krt18), as well as ubiquitin, the proteasome complex and molecular chaperones, including heat shock protein 70 (HSP70; HSPA1B) and heat shock protein 90 (HSP90) (Coulombe and Omary, 2002). Cells that have been treated with a chemical inhibitor of proteasome function (Bardag-Gorce et al., 2004) or that contain the UBB +1 ubiquitin mutation (Bardag-Gorce et al., 2003) form Mallory bodies due to an accumulation of non-degraded keratin.Misfolded proteins also tend to aggregate. Proper protein folding within a cell often does not occur spontaneously and, thus, molecular chaperones are required for some proteins to reach its native state efficiently (Hartl and Hayer-Hartl, 2002). Hsp70 is a ubiquitous chaperone that, together with diverse co-chaperone binding partners, facilitates protein folding and the presentation of proteins to the proteasome for degradation (Esser et al., 2004). Co-chaperones of the DnaJ (Hsp40) protein family are characterized by a conserved Jdomain that regulates substrate binding and release by activating the ATPase activity of Hsp70 (Fan et al., 2003). These co-chaperones differ in their tissue and subcellular patterns of expression, and convey substrate specificity to Hsp70 (Fan et al., 2003). However, little is known about the precise substrates that are regulated in this manner.The Mrj (Mammalian relative of DnaJ; also known as Dnajb6 -Mouse Genome Informatics) gene encodes a co-chaperone that is widely expressed throughout the adult mouse and during development of the embryo and placenta (Chuang et al., 2002;Dai et al., 2005;Hunter et al., 1999;Izawa et al., 2000;Seki et al., 1999). Mrj -/-embryos die at mid-gestation due to a failure of chorioallantoic attachment during placental development (Hunter et al., 1999). Recently, a few diverse ...

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“…CYP2E1 turnover is mediated by the proteasome, because several lowmolecular weight inducers of CYP2E1 such as ethanol, dimethyl sulfoxide, and pyrazole elevate CYP2E1 by stabilizing the enzyme against proteasome-catalyzed degradation (Roberts, 1997;Yang and Cederbaum, 1997;Huan et al, 2004). Moreover, the compromised proteasome function is believed to be involved in the formation of Mallory bodies, a hallmark of alcohol-induced liver disease (Bardag-Gorce et al, 2004). In view of the importance of the proteasome in removing oxidized/damaged proteins and in regulating CYP2E1 levels and the possibility that the decrease in proteasome activity may play a role in the development of alcoholic liver injury, the current study was carried out to assess proteasome peptidase activities in HepG2 cells overexpressing CYP2E1 (E47 cells) as compared with control cells transfected with the empty pCI vector (C34 cells).…”

mentioning

confidence: 99%

The Effect of CYP2E1-Dependent Oxidant Stress on Activity of Proteasomes in HepG2 Cells

Kessova

Cederbaum²

2005

J Pharmacol Exp Ther

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A reduction in proteasome activity and accumulation of oxidized proteins may play a role in alcoholic liver disease. The current study assessed proteasome peptidase activities and oxidative modifications of proteasomes during oxidative stress generated by CYP2E1. The model of toxicity by arachidonic acid (AA) and iron [ferric-nitrilotriacetate (Fe-NTA)] in HepG2 cells overexpressing CYP2E1 (E47 cells) and control C34 cells was used. AA/Fe-NTA treatment decreased trypsin-like (T-L) activity of the proteasome in E47 cells but not in C34 cells. This inhibition was abolished by antioxidants. Chymotrypsin-like activity of the proteasome was increased in E47 cells, and activity was not altered by AA/Fe-NTA treatment. There were no changes in content of subunits of 20S proteasomes or 19S regulator ATPase subunits S4 and p42 by AA/Fe-NTA treatment. An increased content of the PA28␣ subunit of the 11S regulator of proteasomes was detected in E47 cells. In proteasome pellets, the decline of T-L activity was accompanied by increased content of carbonyl adducts, suggesting oxidative modification of proteasomes. Higher levels of ubiquitinated, 3-nitrotyrosine-and 4-hydroxynonenal-modified proteins and lower levels of free ubiquitin were detected in untreated E47 cells in comparison with C34 cells. Accumulation of protein cross-linked, detergent-insoluble aggregates was increased with AA/Fe-NTA treatment in E47 cells. Thus, reactive oxygen species generated upon CYP2E1-dependent oxidative stress mediated a decline in T-L proteasome function, increased carbonyl adducts in proteasomes, and promoted protein aggregate formation; this may alter the balance among protein oxidation, ubiquitination, and degradation.

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Proteasome inhibition induces cytokeratin accumulation in vivo

Cited by 31 publications

References 22 publications

Hindlimb casting decreases muscle mass in part by proteasome-dependent proteolysis but independent of protein synthesis

Hindlimb casting decreases muscle mass in part by proteasome-dependent proteolysis but independent of protein synthesis

The Mrj co-chaperone mediates keratin turnover and prevents the formation of toxic inclusion bodies in trophoblast cells of the placenta

The Effect of CYP2E1-Dependent Oxidant Stress on Activity of Proteasomes in HepG2 Cells

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