scholarly journals The Proteasome Inhibitor, MG132, Attenuates Diabetic Nephropathy by Inhibiting SnoN DegradationIn VivoandIn Vitro

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Wei Huang ◽  
Chen Yang ◽  
Qinling Nan ◽  
Chenlin Gao ◽  
Hong Feng ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
High Glucose ◽  
Proteasome Inhibitor ◽  
Kidney Damage ◽  
Control Group ◽  
Glomerular Mesangial Cells ◽  
Proteasome Inhibitor Mg132 ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

Transforming growth factor-β(TGF-β) has been shown to be involved in diabetic nephropathy (DN). The SnoN protein can regulate TGF-βsignaling through interaction with Smad proteins. Recent studies have shown that SnoN is mainly degraded by the ubiquitin-proteasome pathway. However, the role of SnoN in the regulation of TGF-β/Smad signaling in DN is still unclear. In this study, diabetic rats were randomly divided into a diabetic control group (DC group) and a proteasome inhibitor (MG132) diabetes therapy group (DT group). Kidney damage parameters and the expression of SnoN, Smurf2, and TGF-βwere observed. Simultaneously, we cultured rat glomerular mesangial cells (GMCs) stimulated with high glucose, and SnoN and Arkadia expression were measured. Results demonstrated that 24-hour urine protein, ACR, BUN, and the expression of Smurf2 and TGF-βwere significantly increased (P<0.05), whereas SnoN was significantly decreased in the DC group (P<0.05). However, these changes diminished after treatment with MG132. SnoN expression in GMCs decreased significantly (P<0.05), but Arkadia expression gradually increased due to high glucose stimulation (P<0.05), which could be almost completely reversed by MG132 (P<0.05). The present results support the hypothesis that MG132 may alleviate kidney damage by inhibiting SnoN degradation and TGF-βactivation, suggesting that the ubiquitin-proteasome pathway may become a new therapeutic target for DN.

scholarly journals Correction: Calcium sensing receptor protects high glucose-induced energy metabolism disorder via blocking gp78-ubiquitin proteasome pathway

2020 ◽  
Vol 11 (9) ◽  
Author(s):  
Yuehong Wang ◽  
Ping Gao ◽  
Can Wei ◽  
Hongzhu Li ◽  
Li Zhang ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
High Glucose ◽  
Calcium Sensing Receptor ◽  
Ubiquitin Proteasome Pathway ◽  
Metabolism Disorder ◽  
Calcium Sensing ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Reported Data ◽  
Energy Metabolism Disorder

Since online publication of this article, the authors noticed that there was an error in Figs. 2 and 4. In Fig. 2c the samples were mislabelled, the correct labelling order is ‘Control, HG, HG + NPS R568, HG + Calhex231’. In Fig. 4c, an incorrect image was used to compile the HG + NPS R568 group, meaning the control was accidentally duplicated. The corrected images are provided below. The authors confirm that these errors did not influence the reported data, discussion, or conclusion. The authors apologise for any inconvenience to readers arising from this error.

scholarly journals MG132 Ameliorates Kidney Lesions by Inhibiting the Degradation of Smad7 in Streptozotocin-Induced Diabetic Nephropathy

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Chenlin Gao ◽  
Keri Aqie ◽  
Jianhua Zhu ◽  
Guo Chen ◽  
Ling Xu ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Protein Expression ◽  
Transforming Growth Factor ◽  
Regulatory Protein ◽  
Kidney Damage ◽  
The Body ◽  
Control Group ◽  
Kidney Weight ◽  
Diabetes Group ◽  
Ubiquitin Proteasome

Background. Smad7 is the main negative regulatory protein in the transforming growth factor-β(TGF-β) downstream signaling pathway, which plays an important role in diabetic nephropathy (DN) and may be related to the ubiquitin proteasome pathway (UPP).Aim. We investigated the role of UPP in regulating TGF-β/SMAD signaling and explored the therapeutic effect of the ubiquitin proteasome inhibitor MG132 on DN.Methods. Wistar rats were randomly divided into a diabetes group and a normal control group. Rats in the diabetes group were injected intraperitoneally with streptozotocin. Diabetic rats were then randomly divided into a diabetic nephropathy group (DN group), an MG132 high concentration (MH) group, and an MG132 low concentration (ML) group. After 8 weeks of treatment, 24-hour urinary microalbumin (UAlb), urinary protein/urinary creatinine (Up/Ucr) values, ALT, AST, Bcr, kidney damage, TGF-β, Smad7, fibronectin (FN), and Smurf2 were detected.Results. The body mass and Smad7 protein expression decreased in DN group, but kidney weight, kidney weight index, UAlb, Up/Ucr, FN and Smurf2 mRNA expression, and TGF-βprotein expression increased. However, these changes diminished following treatment with MG132, and a more pronounced effect was evident in MH group compared to ML group.Conclusion. MG132 alleviates kidney damage by inhibiting Smad7 ubiquitin degradation and TGF-βactivation in DN.

The ubiquitin-proteasome pathway regulates lysosomal degradation of the growth hormone receptor and its ligand

2001 ◽  
Vol 29 (4) ◽  
pp. 488-493 ◽  
Author(s):  
P. van Kerkhof ◽  
G. J. Strous
Keyword(s):  
Growth Hormone ◽  
Proteasome Inhibitor ◽  
Growth Hormone Receptor ◽  
Proteasome Inhibitors ◽  
Plasma Membrane Protein ◽  
Lysosomal Degradation ◽  
Ubiquitin Proteasome Pathway ◽  
Gh Receptor ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

The growth hormone (GH) receptor (GHR) is a mammalian plasma membrane protein whose internalization is mediated by the ubiquitin-proteasome pathway. GH internalization and degradation are inhibited when cells are treated with proteasome inhibitors. Here we show that a GHR truncated at residue 369 can enter the cells in the presence of a proteasome inhibitor, but that the subsequent lysosomal degradation of GH is blocked. Lysosomal inhibitors prolong the half-life of both receptor and ligand. Experiments with antibodies against different receptor tail sections show that degradation of the GHR cytosolic domain precedes degradation of the extracellular GH-binding domain. A possible role for the ubiquitin-proteasome pathway in the degradation of the receptor and ligand is discussed.

Mechanical ventilation induces alterations of the ubiquitin-proteasome pathway in the diaphragm

2005 ◽  
Vol 98 (4) ◽  
pp. 1314-1321 ◽  
Author(s):  
Keith C. DeRuisseau ◽  
Andreas N. Kavazis ◽  
Melissa A. Deering ◽  
Darin J. Falk ◽  
Darin Van Gammeren ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Control Group ◽  
20S Proteasome ◽  
Mrna Levels ◽  
Α Subunit ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Conjugating Enzyme ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Conjugating Enzyme

Prolonged mechanical ventilation (MV) results in diaphragmatic atrophy due, in part, to an increase in proteolysis. These experiments tested the hypothesis that MV-induced diaphragmatic proteolysis is accompanied by increased expression of key components of the ubiquitin-proteasome pathway (UPP). To test this postulate, we investigated the effect of prolonged MV on UPP components and determined the trypsin-like and peptidylglutamyl peptide hydrolyzing activities of the 20S proteasome. Adult Sprague-Dawley rats were assigned to either control or 12-h MV groups ( n = 7/group). MV animals were anesthetized, tracheostomized, and ventilated with room air for 12 h. Animals in the control group were acutely anesthetized but not exposed to MV. Compared with controls, MV animals demonstrated increased diaphragmatic mRNA levels of two ubiquitin ligases, muscle atrophy F-box (+8.3-fold) and muscle ring finger 1 (+19.0-fold). However, MV did not alter mRNA levels of 14-kDa ubiquitin-conjugating enzyme, polyubiquitin, proteasome-activating complex PA28, or 20S α-subunit 7. Protein levels of 14-kDa ubiquitin-conjugating enzyme and proteasome-activating complex PA28 were not altered following MV, but 20S α-subunit 7 levels declined (−17.7%). MV increased diaphragmatic trypsin-like activity (+31%) but did not alter peptidylglutamyl peptide hydrolyzing activity. Finally, compared with controls, MV increased ubiquitin-protein conjugates in both the myofibrillar (+24.9%) and cytosolic (+54.7%) fractions of the diaphragm. These results are consistent with the hypothesis that prolonged MV increases diaphragmatic levels of key components within the UPP and that increases in 20S proteasome activity contribute to MV-induced diaphragmatic proteolysis and atrophy.

The Ubiquitin-Proteasome Pathway and Resistance Mechanisms Developed Against the Proteasomal Inhibitors in Cancer Cells

2020 ◽  
Vol 21 (13) ◽  
pp. 1313-1325
Author(s):  
Azmi Yerlikaya ◽  
Ertan Kanbur
Keyword(s):  
Cancer Cells ◽  
Proteasome Inhibitor ◽  
Molecular Mechanisms ◽  
Proteasome Inhibitors ◽  
Resistance Mechanisms ◽  
New Drugs ◽  
Drug Pressure ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

Background: The ubiquitin-proteasome pathway is crucial for all cellular processes and is, therefore, a critical target for the investigation and development of novel strategies for cancer treatment. In addition, approximately 30% of newly synthesized proteins never attain their final conformations due to translational errors or defects in post-translational modifications; therefore, they are also rapidly eliminated by the ubiquitin-proteasome pathway. Objective: Here, an effort was made to outline the recent findings deciphering the new molecular mechanisms involved in the regulation of ubiquitin-proteasome pathway as well as the resistance mechanisms developed against proteasome inhibitors in cell culture experiments and in the clinical trials. Results: Since cancer cells have higher proliferation rates and are more prone to translational errors, they require the ubiquitin-proteasome pathway for selective advantage and sustained proliferation. Therefore, drugs targeting the ubiquitin-proteasome pathway are promising agents for the treatment of both hematological and solid cancers. Conclusions: A number of proteasome inhibitors are approved and used for the treatment of advanced and relapsed multiple myeloma. Unfortunately, drug resistance mechanisms may develop very fast within days of the start of the proteasome inhibitor-treatment either due to the inherent or acquired resistance mechanisms under selective drug pressure. However, a comprehensive understanding of the mechanisms leading to the proteasome inhibitor-resistance will eventually help the design and development of novel strategies involving new drugs and/or drug combinations for the treatment of a number of cancers.

scholarly journals Inhibition of ubiquitin-proteasome pathway activates a caspase-3-like protease and induces Bcl-2 cleavage in human M-07e leukaemic cells

1999 ◽  
Vol 340 (1) ◽  
pp. 127-133 ◽  
Author(s):  
Xue-min ZHANG ◽  
Hong LIN ◽  
Catheryne CHEN ◽  
Ben D.-M. CHEN
Keyword(s):  
Cell Death ◽  
Proteasome Inhibitor ◽  
Caspase 3 ◽  
Specific Inhibitor ◽  
Apoptotic Pathway ◽  
Principal Mechanism ◽  
Ubiquitin Proteasome Pathway ◽  
Gm Csf ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

The ubiquitin-proteasome pathway is the principal mechanism for the degradation of short-lived proteins in eukaryotic cells. Here we examine the possibility that ubiquitin-proteasome is involved in regulating the levels of Bcl-2, which is abundantly expressed in M-07e cells, a granulocyte/macrophage colony-stimulating factor (GM-CSF)-dependent human leukaemic cell line. Apoptosis in M-07e cells, induced by GM-CSF withdrawal, was associated with a gradual cleavage of Bcl-2 into a 22 kDa fragment. Treatment of M-07e cells with benzyloxycarbonyl-Leu-Leu-L-leucinal (Z-LLL-CHO; MG-132), a reversible ubiquitin-proteasome inhibitor, markedly accelerated the cleavage of Bcl-2 and promoted cell death through the apoptotic pathway. The cleavage of Bcl-2 was inhibited by a caspase-3 (CPP32)-specific inhibitor [acetyl-Asp-Glu-Val-Asp-CHO (DEVD-CHO)] but not caspase 1 inhibitor (acetyl-Tyr-Val-Ala-Asp-CHO), suggesting that Bcl-2 is a proteolytic substrate of a caspase-3-like protease activated during apoptosis. The simultaneous addition of recombinant human GM-CSF (rhGM-CSF) to M-07e cultures delayed the activation of caspase 3 and Bcl-2 cleavage triggered by Z-LLL-CHO, suggesting that the activation of the GM-CSF signalling pathway can partly overcome the apoptotic effect induced by Z-LLL-CHO. Apoptosis induced by inhibition of the proteasome pathway was verified in studies with lactacystin, a highly specific and irreversible proteasome inhibitor. Lactacystin-induced apoptosis in M-07e cells was remarkably similar to that induced by Z-LLL-CHO, which included caspase 3 activation, cleavage of Bcl-2 into a 22 kDa fragment and, ultimately, cell death. These results showed that inhibition of the ubiquitin-proteasome pathways can lead to the activation of a DEVD-CHO-sensitive caspase and induces Bcl-2 cleavage, which might have a role in mediating apoptosis in M-07e cells.

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