New targeted approaches against the ubiquitin–proteasome system in gastrointestinal malignancies

Grande, Enrique; Earl, Julie; Fuentes, R.; Carrato, Alfredo

doi:10.1586/era.12.26

Cited by 7 publications

(5 citation statements)

References 111 publications

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“…Recently, the rapid down-regulation of the UPP proteins was observed following CHIKV infection in a hepatic cell line; however, none of the same proteins were detected relative to this study [22]. Notably, several molecules targeting E3-ligases, DUBs or the proteasome are candidates for cancer treatment [85], which highlights novel potential therapeutic strategies targeting the UPP in CHIKV infection.…”

Section: Discussioncontrasting

confidence: 53%

Kinetic Analysis of Mouse Brain Proteome Alterations Following Chikungunya Virus Infection before and after Appearance of Clinical Symptoms

et al. 2014

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Recent outbreaks of Chikungunya virus (CHIKV) infection have been characterized by an increasing number of severe cases with atypical manifestations including neurological complications. In parallel, the risk map of CHIKV outbreaks has expanded because of improved vector competence. These features make CHIKV infection a major public health concern that requires a better understanding of the underlying physiopathological processes for the development of antiviral strategies to protect individuals from severe disease. To decipher the mechanisms of CHIKV infection in the nervous system, a kinetic analysis on the host proteome modifications in the brain of CHIKV-infected mice sampled before and after the onset of clinical symptoms was performed. The combination of 2D-DIGE and iTRAQ proteomic approaches, followed by mass spectrometry protein identification revealed 177 significantly differentially expressed proteins. This kinetic analysis revealed a dramatic down-regulation of proteins before the appearance of the clinical symptoms followed by the increased expression of most of these proteins in the acute symptomatic phase. Bioinformatic analyses of the protein datasets enabled the identification of the major biological processes that were altered during the time course of CHIKV infection, such as integrin signaling and cytoskeleton dynamics, endosome machinery and receptor recycling related to virus transport and synapse function, regulation of gene expression, and the ubiquitin-proteasome pathway. These results reveal the putative mechanisms associated with severe CHIKV infection-mediated neurological disease and highlight the potential markers or targets that can be used to develop diagnostic and/or antiviral tools.

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Section: Discussioncontrasting

confidence: 53%

Kinetic Analysis of Mouse Brain Proteome Alterations Following Chikungunya Virus Infection before and after Appearance of Clinical Symptoms

et al. 2014

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“…Same results were obtained with specific inhibitors . While another strategy would be to target E3 ligases, recent studies highlight the existence of more than thousand different E3 isoforms and only few of them have been described in intestinal tissues . We thus decided to identify polyubiquitinated proteins during intestinal inflammatory response, which can lead further to E3 enzyme identifications.…”

Section: Introductionmentioning

confidence: 85%

Evaluation of ubiquitinated proteins by proteomics reveals the role of the ubiquitin proteasome system in the regulation of Grp75 and Grp78 chaperone proteins during intestinal inflammation

et al. 2013

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The ubiquitin proteasome system (UPS) is the major pathway of intracellular protein degradation and may be involved in the pathophysiology of inflammatory bowel diseases or irritable bowel syndrome. UPS specifically degrades proteins tagged with an ubiquitin chain. We aimed to identify polyubiquitinated proteins during inflammatory response in intestinal epithelial HCT-8 cells by a proteomic approach. HCT-8 cells were incubated with interleukin 1β, tumor necrosis factor-α, and interferon-γ for 2 h. Total cellular protein extracts were separated by 2D gel electrophoresis and analyzed by an immunodetection using antiubiquitin antibody. Differential ubiquitinated proteins were then identified by LC-ESI MS/MS. Seven proteins were differentially ubiquitinated between control and inflammatory conditions. Three of them were chaperones: Grp75 and Hsc70 were more ubiquitinated (p < 0.05) and Grp78 was less ubiquitinated (p < 0.05) under inflammatory conditions. The results for Grp75 and Grp78 were then confirmed in HCT-8 cells and in 2-4-6-trinitrobenzen sulfonic acid induced colitis in rats mimicking inflammatory bowel disease by immunoprecipitation. No difference was observed in irritable bowel syndrome like model. In conclusion, we showed that a proteomic approach is suitable to identify ubiquitinated proteins and that UPS-regulated expression of Grp75 and Grp78 may be involved in inflammatory response. Further studies should lead to the identification of ubiquitin ligases responsible for Grp75 and Grp78 ubiquitination.

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“…In summary, the four proteins screened in the present study have both direct and indirect relationships with the ubiquitin-proteasome pathway. The dysregulation of the ubiquitin-proteasome pathway is closely associated with the development of a variety of diseases, including diseases of the cardiovascular system (19)(20)(21), lymphoma (22), kidney disease (23,24), nervous system disorders (25,26), gastrointestinal malignancies (27)(28)(29) and has an especially strong association with the development of many cancers. HSPC238 has a RING-finger domain and E3 enzyme activity.…”

Section: Discussionmentioning

confidence: 99%

Screening and verification of proteins that interact with HSPC238

et al. 2015

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HSPC238 is a recently identified tumor suppressor and demonstrates ubiquitin ligase E3 enzyme activity. HSPC238 was found to be significantly downregulated in human hepatocellular carcinoma (HCC) in vivo and to inhibit the proliferation and invasion of hepatoma cells in vitro; however, the underlying molecular mechanism is largely unknown. In the present study, we screened for and identified proteins that physically interact with HSPC238. A bait vector for yeast two-hybrid was constructed with human HSPC238 gene cDNA. Yeast two-hybrid screening was performed using a human fetal liver cDNA library. Multiple reporter gene assays, DNA sequencing and BLAST comparison analysis were performed on positive clones. Protein interaction of screened candidates with HSPC238 was further validated by confocal microscopy, co-immunoprecipitation and pull-down assays. Yeast two-hybrid screening demonstrated 124 positive clones. Multiple reporter gene assays with LacZ, HIS and ADE2 selective media identified 12 genes. Further co-localization, co-immunoprecipitation and pull-down assays demonstrated that HMOX1, RPS27A, ubiquitinB and MT2A interacted with HSPC238. These four proteins are involved in tumor development and progression, and are associated with the ubiquitin-proteasome pathway. Our results suggest that HSPC238 may play a tumor suppressor role and interact with these proteins via the ubiquitin-proteasome pathway. The identification and validation of proteins interacting with HSP238 may lead to the discovery of novel mechanisms through which HSPC238 suppresses tumorigenesis in human hepatocellular carcinoma.

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New targeted approaches against the ubiquitin–proteasome system in gastrointestinal malignancies

Cited by 7 publications

References 111 publications

Kinetic Analysis of Mouse Brain Proteome Alterations Following Chikungunya Virus Infection before and after Appearance of Clinical Symptoms

Kinetic Analysis of Mouse Brain Proteome Alterations Following Chikungunya Virus Infection before and after Appearance of Clinical Symptoms

Evaluation of ubiquitinated proteins by proteomics reveals the role of the ubiquitin proteasome system in the regulation of Grp75 and Grp78 chaperone proteins during intestinal inflammation

Screening and verification of proteins that interact with HSPC238

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