scholarly journals Insights into the Abnormalities of Chronic Renal Disease Attributed to Malnutrition

2002 ◽  
Vol 13 (suppl 1) ◽  
pp. S22-S27
Author(s):  
William E. Mitch
Keyword(s):  
Lean Body Mass ◽  
Body Mass ◽  
Protein Turnover ◽  
Serum Proteins ◽  
Chronic Renal Disease ◽  
Protein Levels ◽  
Proteolytic Pathway ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Biochemical Mechanisms

ABSTRACT. Low values of serum proteins and loss of lean body mass are commonly found in patients with chronic renal insufficiency (CRI) and especially in dialysis patients. These abnormalities have been attributed to malnutrition (i.e., an inadequate diet), but available evidence indicates that this is not the principal cause. In contrast, there is persuasive evidence that secondary factors associated with the CRI condition cause abnormalities in protein turnover and ultimately result in low serum protein levels and loss of lean body mass. Recent reports have identified some factors that could interfere with the control of protein turnover in CRI patients, including acidosis, inflammation, and/or resistance to anabolic hormones. Each of these stimulates protein breakdown in muscle and activates a common proteolytic pathway, the ubiquitin-proteasome pathway. Moreover, acidosis or inflammation suppress hepatic albumin synthesis. Understanding the biochemical mechanisms that regulate the ubiquitin-proteasome and other catabolic pathways are required to identify new strategies for preventing protein deficits that are associated with CRI.

scholarly journals Derailing the UPS of Protein Turnover in Cancer and other Human Diseases

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Jit Kong Cheong ◽  
Stephen I-Hong Hsu
Keyword(s):  
Protein Turnover ◽  
Cellular Differentiation ◽  
Cell Cycle Control ◽  
Therapeutic Strategies ◽  
Organelle Biogenesis ◽  
Covalent Linkage ◽  
Ubiquitin Proteasome Pathway ◽  
Cellular Processes ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

Protein modifications by the covalent linkage of ubiquitin have significant involvement in many cellular processes, including stress response, oncogenesis, viral infection, transcription, protein turnover, organelle biogenesis, DNA repair, cellular differentiation, and cell cycle control. We provide a brief overview of the fundamentals of the regulation of protein turnover by the ubiquitin-proteasome pathway and discuss new therapeutic strategies that aim to mitigate the deleterious effects of its dysregulation in cancer and other human disease pathophysiology.

scholarly journals Kaempferol Modulates DNA Methylation and Downregulates DNMT3B in Bladder Cancer

2017 ◽  
Vol 41 (4) ◽  
pp. 1325-1335 ◽  
Author(s):  
Wei Qiu ◽  
Jun Lin ◽  
Yichen Zhu ◽  
Jian Zhang ◽  
Liping Zeng ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Bladder Cancer ◽  
Genomic Dna ◽  
Fruits And Vegetables ◽  
Dna Methyltransferases ◽  
Protein Levels ◽  
Anti Cancer ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Illumina Infinium Humanmethylation

Background: Genomic DNA methylation plays an important role in both the occurrence and development of bladder cancer. Kaempferol (Kae), a natural flavonoid that is present in many fruits and vegetables, exhibits potent anti-cancer effects in bladder cancer. Similar to other flavonoids, Kae possesses a flavan nucleus in its structure. This structure was reported to inhibit DNA methylation by suppressing DNA methyltransferases (DNMTs). However, whether Kae can inhibit DNA methylation remains unclear. Methods: Nude mice bearing bladder cancer were treated with Kae for 31 days. The genomic DNA was extracted from xenografts and the methylation changes was determined using an Illumina Infinium HumanMethylation 450 BeadChip Array. The ubiquitination was detected using immuno-precipitation assay. Results: Our data indicated that Kae modulated DNA methylation in bladder cancer, inducing 103 differential DNA methylation positions (dDMPs) associated with genes (50 hyper-methylated and 53 hypo-methylated). DNA methylation is mostly relied on the levels of DNMTs. We observed that Kae specifically inhibited the protein levels of DNMT3B without altering the expression of DNMT1 or DNMT3A. However, Kae did not downregulate the transcription of DNMT3B. Interestingly, we observed that Kae induced a premature degradation of DNMT3B by inhibiting protein synthesis with cycloheximide (CHX). By blocking proteasome with MG132, we observed that Kae induced an increased ubiquitination of DNMT3B. These results suggested that Kae could induce the degradation of DNMT3B through ubiquitin-proteasome pathway. Conclusion: Our data indicated that Kae is a novel DNMT3B inhibitor, which may promote the degradation of DNMT3B in bladder cancer.

scholarly journals Oestrogen causes ATBF1 protein degradation through the oestrogen-responsive E3 ubiquitin ligase EFP

2012 ◽  
Vol 444 (3) ◽  
pp. 581-590 ◽  
Author(s):  
Xue-Yuan Dong ◽  
Xiaoying Fu ◽  
Songqing Fan ◽  
Peng Guo ◽  
Dan Su ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Protein Degradation ◽  
Ubiquitin Ligase ◽  
Feedback Loop ◽  
E3 Ubiquitin Ligase ◽  
Breast Development ◽  
Protein Levels ◽  
Ubiquitin Proteasome ◽  
Dependent Cell ◽  
Proteasome Pathway

We reported previously that the tumour suppressor ATBF1 (AT motif-binding factor 1) formed an autoregulatory feedback loop with oestrogen–ERα (oestrogen receptor α) signalling to regulate oestrogen-dependent cell proliferation in breast cancer cells. In this loop ATBF1 inhibits the function of oestrogen–ERα signalling, whereas ATBF1 protein levels are fine-tuned by oestrogen-induced transcriptional up-regulation as well as UPP (ubiquitin–proteasome pathway)-mediated protein degradation. In the present study we show that EFP (oestrogen-responsive finger protein) is an E3 ubiquitin ligase mediating oestrogen-induced ATBF1 protein degradation. Knockdown of EFP increases ATBF1 protein levels, whereas overexpression of EFP decreases ATBF1 protein levels. EFP interacts with and ubiquitinates ATBF1 protein. Furthermore, we show that EFP is an important factor in oestrogen-induced ATBF1 protein degradation in which some other factors are also involved. In human primary breast tumours the levels of ATBF1 protein are positively correlated with the levels of EFP protein, as both are directly up-regulated ERα target gene products. However, the ratio of ATBF1 protein to EFP protein is negatively correlated with EFP protein levels. Functionally, ATBF1 antagonizes EFP-mediated cell proliferation. These findings not only establish EFP as the E3 ubiquitin ligase for oestrogen-induced ATBF1 protein degradation, but further support the autoregulatory feedback loop between ATBF1 and oestrogen–ERα signalling and thus implicate ATBF1 in oestrogen-dependent breast development and carcinogenesis.

scholarly journals SOCS-1 Localizes to the Microtubule Organizing Complex-Associated 20S Proteasome

2004 ◽  
Vol 24 (20) ◽  
pp. 9092-9101 ◽  
Author(s):  
Bao Q. Vuong ◽  
Teresita L. Arenzana ◽  
Brian M. Showalter ◽  
Julie Losman ◽  
X. Peter Chen ◽  
...  
Keyword(s):  
Cellular Proliferation ◽  
Sh2 Domain ◽  
Cytokine Signaling ◽  
20S Proteasome ◽  
Signaling Proteins ◽  
Dependent Manner ◽  
Data Link ◽  
Protein Levels ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

ABSTRACT The regulation of cytokine signaling is critical for controlling cellular proliferation and activation during an immune response. SOCS-1 is a potent inhibitor of Jak kinase activity and of signaling initiated by several cytokines. SOCS-1 protein levels are tightly regulated, and recent data suggest that SOCS-1 may regulate the protein levels of some signaling proteins by the ubiquitin proteasome pathway; however, the cellular mechanism by which SOCS-1 directs proteins for degradation is unknown. In this report, SOCS-1 is found to colocalize and biochemically copurify with the microtubule organizing complex (MTOC) and its associated 20S proteasome. The SOCS-1 SH2 domain is required for the localization of SOCS-1 to the MTOC. Overexpression of SOCS-1 targets Jak1 in an SH2-dependent manner to a perinuclear distribution resembling the MTOC-associated 20S proteasome. Analysis of MTOCs fractionated from SOCS-1-deficient cells demonstrates that SOCS-1 may function redundantly to regulate the localization of Jak1 to the MTOC. Nocodazole inhibits the protein turnover of SOCS-1, demonstrating that the minus-end transport of SOCS-1 to the MTOC-associated 20S proteasome is required to regulate SOCS-1 protein levels. These data link SOCS-1 directly with the proteasome pathway and suggest another function for the SH2 domain of SOCS-1 in the regulation of Jak/STAT signaling.

scholarly journals Serogroup-Related Escape of Yersinia enterocolitica YopE from Degradation by the Ubiquitin-Proteasome Pathway

2007 ◽  
Vol 75 (9) ◽  
pp. 4423-4431 ◽  
Author(s):  
Moritz Hentschke ◽  
Konrad Trülzsch ◽  
Jürgen Heesemann ◽  
Martin Aepfelbacher ◽  
Klaus Ruckdeschel
Keyword(s):  
Host Cell ◽  
Yersinia Enterocolitica ◽  
Virulence Proteins ◽  
Ubiquitin Proteasome Pathway ◽  
Protein Levels ◽  
Ubiquitin Proteasome ◽  
Protein Secretion System ◽  
Proteasome Pathway ◽  
Type Iii Protein Secretion ◽  
The Stability

ABSTRACT Pathogenic Yersinia spp. employ a type III protein secretion system that translocates several Yersinia outer proteins (Yops) into the host cell to modify the host immune response. One strategy of the infected host cell to resist the bacterial attack is degradation and inactivation of injected bacterial virulence proteins through the ubiquitin-proteasome pathway. The cytotoxin YopE is a known target protein of this major proteolytic system in eukaryotic cells. Here, we investigated the sensitivity of YopE belonging to different enteropathogenic Yersinia enterocolitica serogroups to ubiquitination and proteasomal degradation. Analysis of the YopE protein levels in proteasome inhibitor-treated versus untreated cells revealed that YopE from the highly pathogenic Y. enterocolitica serotype O8 was subjected to proteasomal destabilization, whereas the YopE isotypes from serogroups O3 and O9 evaded degradation. Accumulation of YopE from serotypes O3 and O9 was accompanied by an enhanced cytotoxic effect. Using Yersinia strains that specifically produced YopE from either Y. enterocolitica O8 or O9, we found that only the YopE protein from serogroup O8 was modified by polyubiquitination, although both YopE isotypes were highly homologous. We determined two unique N-terminal lysines (K62 and K75) in serogroup O8 YopE, not present in serogroup O9 YopE, that served as polyubiquitin acceptor sites. Insertion of either lysine in serotype O9 YopE enabled its ubiquitination and destabilization. These results define a serotype-dependent difference in the stability and activity of the Yersinia effector protein YopE that could influence Y. enterocolitica pathogenesis.

scholarly journals E6AP Ubiquitin Ligase Mediates Ubiquitylation and Degradation of Hepatitis C Virus Core Protein

2006 ◽  
Vol 81 (3) ◽  
pp. 1174-1185 ◽  
Author(s):  
Masayuki Shirakura ◽  
Kyoko Murakami ◽  
Tohru Ichimura ◽  
Ryosuke Suzuki ◽  
Tetsu Shimoji ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Core Protein ◽  
Protein Levels ◽  
The Core ◽  
Hcv Core Protein ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Viral Nucleocapsid

ABSTRACT Hepatitis C virus (HCV) core protein is a major component of viral nucleocapsid and a multifunctional protein involved in viral pathogenesis and hepatocarcinogenesis. We previously showed that the HCV core protein is degraded through the ubiquitin-proteasome pathway. However, the molecular machinery for core ubiquitylation is unknown. Using tandem affinity purification, we identified the ubiquitin ligase E6AP as an HCV core-binding protein. E6AP was found to bind to the core protein in vitro and in vivo and promote its degradation in hepatic and nonhepatic cells. Knockdown of endogenous E6AP by RNA interference increased the HCV core protein level. In vitro and in vivo ubiquitylation assays showed that E6AP promotes ubiquitylation of the core protein. Exogenous expression of E6AP decreased intracellular core protein levels and supernatant HCV infectivity titers in the HCV JFH1-infected Huh-7 cells. Furthermore, knockdown of endogenous E6AP by RNA interference increased intracellular core protein levels and supernatant HCV infectivity titers in the HCV JFH1-infected cells. Taken together, our results provide evidence that E6AP mediates ubiquitylation and degradation of HCV core protein. We propose that the E6AP-mediated ubiquitin-proteasome pathway may affect the production of HCV particles through controlling the amounts of viral nucleocapsid protein.

scholarly journals Strategies for Post-Translational Control of Protein Expression and Their Applications

2021 ◽  
Vol 11 (18) ◽  
pp. 8300
Author(s):  
Yuki Utsugi ◽  
Yusaku Miyamae
Keyword(s):  
Protein Expression ◽  
Translational Control ◽  
Protein Function ◽  
Genetic Manipulation ◽  
Mrna Level ◽  
Expression Levels ◽  
Protein Levels ◽  
Biological Studies ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

Proteins are fundamental biomolecules of living cells, and their expression levels depend on the balance between the synthesis and degradation. Researchers often aim to control protein expression levels for the investigation of protein function and its relationship with physiological phenomena. The genetic manipulation of the target protein using CRISPR/Cas9, Cre/loxP, tetracyclin system, and RNA interference, are widely used for the regulation of proteins at the DNA, transcriptional, or mRNA level. However, the significant time delay in controlling protein levels is a limitation of these techniques; the knockout or knockdown effects cannot be observed until the previously transcribed and synthesized protein is degraded. Recently, researchers have developed various types of molecular tools for the regulation of protein expression at the post-translational level, which rely on harnessing cellular proteolytic machinery including ubiquitin–proteasome pathway, autophagy-lysosome pathway, and endocytosis. The post-translational control of protein expression using small molecules, antibodies, and light can offer significant advantages regarding speed, tunability, and reversibility. These technologies are expected to be applied to pharmacotherapy and cell therapy, as well as research tools for fundamental biological studies. Here, we review the established and recently developed technologies, provide an update on their applications, and anticipate potential future directions.

scholarly journals Combination of Artesunate and WNT974 Induces KRAS Protein Degradation by Upregulating E3 Ligase ANACP2 and β-TrCP in the Ubiquitin–Proteasome Pathway

2021 ◽  
Author(s):  
RUIHONG GONG ◽  
Minting Chen ◽  
Chunhua Huang Huang ◽  
Hoi Leong Xavier Wong ◽  
Hiu Yee Kwan ◽  
...  
Keyword(s):  
Mouse Model ◽  
Synergistic Effect ◽  
Protein Degradation ◽  
Combination Treatment ◽  
Ubiquitin Proteasome Pathway ◽  
Protein Levels ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Kras Protein ◽  
Gsk 3Β

Abstract BackgroundKRAS mutation is one of the dominant gene mutations in colorectal cancer (CRC). Up to present, targeting KRAS for CRC treatment remains a clinical challenge. WNT974 (LGK974) is a porcupine inhibitor that interferes Wnt signaling pathway. Artesunate (ART) is a water-soluble semi-synthetic derivative of artemisinin.MethodsThe synergistic effect of ART and WNT974 combination in reducing CRC cell viability was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. RT-PCR was utilized for the mRNA levels of KRAS, CUL7, ANAPC2, UBE2M, RNF123, SYVN1, or β-TrCP. Western blot assay was utilized for the protein levels of KRAS, ANAPC2, β-TrCP, or GSK-3β. Xenograft mouse model assay was performed for the anti-CRC effect of combination of ART and WNT974 in vivo. IHC assay was utilized for the levels of KRAS, β-TrCP, or GSK-3β in tumor tissues. Results Our study shows that the combination of WNT974 and ART exhibits synergistic effect in reducing CRC growth. The combination treatment significantly reduces KRAS protein level and activity in CRC cells. Interestingly, the combination treatment increases E3 ligases ANAPC2 expression. Our data show that overexpression of ANAPC2 significantly reduces KRAS protein levels, which is reversed by MG132. Knockdown of ANAPC2 in CRC abolishes the combination treatment-reduce KRAS expression. Besides, the treatment also increases the expressions of GSK-3β and E3 ligase β-TrCP that is known to degrade GSK-3β-phosphorylated KRAS protein. Knockdown of β-TrCP- and inhibition of GSK-3β abolish the combination treatment-induce KRAS ubiquitination and reduction in expression.ConclusionsOur data clearly show that the combination treatment significantly enhances KRAS protein degradation via the ubiquitination ubiquitin–proteasome pathway, which is also demonstrated in xenograft mouse model. The study provides strong scientific evidence for the development of the combination of WNT974 and ART as KRAS-targeting therapeutics for CRC treatment.

scholarly journals Proteasomes and Proteasomal Gene Polymorphism in Association with Inflammation and Various Diseases

Medicina ◽  
2013 ◽  
Vol 49 (5) ◽  
pp. 33 ◽  
Author(s):  
Živilė Žemeckienė ◽  
Astra Vitkauskienė ◽  
Tatjana Sjakste ◽  
Brigita Šitkauskienė ◽  
Raimundas Sakalauskas
Keyword(s):  
Protein Quality ◽  
Control Cell ◽  
Proteolytic Pathway ◽  
Genes Encoding ◽  
Proteasomal Genes ◽  
Ubiquitin Proteasome ◽  
Cell Processes ◽  
Central Particle ◽  
Proteasome Pathway

A proteasome, a multicatalytic protein complex, is a central particle of the ubiquitinproteasome proteolytic pathway in all eukaryotic cells. Through the degradation of most intracellular proteins, proteasomes play a significant role in cell processes, such as cell cycle and division, posttranslational protein quality control, cell signaling, and apoptosis. Therefore, the ubiquitinproteasome system is necessary to ensure the normal functioning of cells and an organism. The associations between alterations in the ubiquitin-proteasome pathway and the development of various autoimmune, neurodegenerative, inflammatory and other diseases in humans have been established. Moreover, the findings of some studies suggest that proteasomes may participate in the pathogenesis of asthma through the regulation of the nuclear factor kappa B signaling pathway. Recently, much attention has been given to the associations between genes encoding the proteasome and their polymorphism, and various diseases. Associations between some proteasomal genes and myocardial infarction, type 2 diabetes mellitus, and other diseases have already been established. However, the results are inconclusive or conflicting and need further clarification.

Role of Nedd4-2 and polyubiquitination in epithelial sodium channel degradation in untransfected renal A6 cells expressing endogenous ENaC subunits

2005 ◽  
Vol 289 (1) ◽  
pp. F107-F116 ◽  
Author(s):  
B. Malik ◽  
Q. Yue ◽  
G. Yue ◽  
X. J. Chen ◽  
S. R. Price ◽  
...  
Keyword(s):  
Apical Membrane ◽  
Mdck Cells ◽  
Cell Types ◽  
Xenopus Laevis Oocytes ◽  
A6 Cells ◽  
Native Proteins ◽  
Proteolytic Pathway ◽  
Ubiquitin Proteasome ◽  
Ubiquitin Conjugation ◽  
Proteasome Pathway

Amiloride-sensitive epithelial sodium channels (ENaC) are responsible for transepithelial Na+ transport in the kidney, lung, and colon. The channel consists of three subunits (α, β, and γ). In Madin-Darby canine kidney (MDCK) cells and Xenopus laevis oocytes transfected with all three ENaC subunits, neural precursor cell-expressed developmentally downregulated protein (Nedd4-2) promotes ubiquitin conjugation of ENaC. For native proteins in some cells, ubiquitin conjugation is a signal for their degradation by the ubiquitin-proteasome pathway, whereas in other cell types ubiquitin conjugation is a signal for endocytosis and lysosomal protein degradation. When ENaC are transfected into MDCK cells, ubiquitin conjugation leads to lysosomal degradation. In this paper, we characterize the involvement of the ubiquitin-proteasome proteolytic pathway in the regulation of functional ENaC in untransfected renal A6 cells expressing native ENaC subunits. In contrast to transfected cells, we show that total cellular α-, β-, and γ-ENaC subunits are polyubiquitinated and that ubiquitin conjugation of subunits increases when the cells are treated with a proteasome inhibitor. We show that Nedd4-2 is associated with α- and β-subunits and is associated with the apical membrane. We also show the Nedd4-2 can regulate the number of functional ENaC subunits in the apical membrane. The results reported here suggest that the ubiquitin-proteasome proteolytic pathway is an important determinant of ENaC function in untransfected renal cells expressing endogenous ENaC.

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