Identification of a Novel Anti-apoptotic E3 Ubiquitin Ligase That Ubiquitinates Antagonists of Inhibitor of Apoptosis Proteins SMAC, HtrA2, and ARTS

Kim, Jung-bin; Kim, Sang Hyun; Kim, Byeong Mo; Lee, Hunjin; Kim, Insook; Yun, Jeanho; Jo, Yejin; Oh, Taeheun; Jo, Yongsam; Chae, Hee-Don; Shin, Deug Y.

doi:10.1074/jbc.m112.436113

Cited by 43 publications

(53 citation statements)

References 30 publications

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“…Although the panel was expressed less frequently in ADC than the other 2 tumor types, the combined sensitivity of the panel and conventional cytology was significantly better than cytology alone ( P< .00001) in detecting ADCs in bronchial brushings. To our knowledge, KIAA1522 and KIAA0317 are uncharacterized proteins that were screened from many high‐throughput methods, and only a few functional studies were reported . In our current study, the expression status of the proteins and their correlation with clinicopathologic features were evaluated in bronchial brushings.…”

Section: Discussionmentioning

confidence: 99%

A panel of protein markers for the early detection of lung cancer with bronchial brushing specimens

Liu

Jiang

Wang

et al. 2014

Cancer Cytopathology

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BACKGROUND To date, no robust biomarkers have been available in clinical practice that can provide an early diagnostic evaluation of lung cancer. The objective of this study was to identify potential biomarkers for the early detection of lung cancer using bronchial brushing specimens. METHODS Immunocytochemistry was used to investigate the expression of 35 proteins in 880 bronchial brushing specimens from both outpatients and inpatients who had either lung cancer or benign lung lesions. An optimal panel was identified that had high sensitivity and considerable specificity for detecting lung cancer. Associations between protein expression and clinicopathologic parameters were assessed. RESULTS Tumor protein 53 (TP53), TP63, Ki67, epidermal growth factor receptor (EGFR), minichromosome maintenance complex component 6 (MCM6), MCM7, uncharacterized proteins KIAA1522 and KIAA0317, and ubiquitin‐protein ligase UHR1 (ICBP90) frequently presented high expression in bronchial brushing specimens from patients who had lung cancer compared with patients who had benign lung lesions. A 6‐protein panel consisting of TP53, Ki67, MCM6, MCM7, KIAA1522, and KIAA0317 was identified as the best combination, with sensitivity of 81.1% (309 of 381 specimens) for detecting nonsmall cell lung cancer (NSCLC) and 86.8% (145 of 167 specimens) for detecting small cell lung cancer (SCLC) (specificity, 83.3%; 65 of 78 specimens). The combination of cytology and the protein panel significantly improved the sensitivity of bronchial brushing examination for detecting lung cancer (P<.00001), which increased from 49.1% to 81% in early stage NSCLC (stage I and II). In combined analyses, the protein panel was positively associated with patient sex (P=.00033), tumor type (P<.00001), tumor location (P<.00001), and lymph node metastasis (P=.028). CONCLUSIONS The 6‐protein panel is a potential biomarker for the early detection of lung cancer in bronchial brushings. Cancer (Cancer Cytopathol) 2014;122:833–841. © 2014 American Cancer Society.

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Section: Discussionmentioning

confidence: 99%

A panel of protein markers for the early detection of lung cancer with bronchial brushing specimens

Liu

Jiang

Wang

et al. 2014

Cancer Cytopathology

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“…Most importantly, we identified a shift from cytosine methylation towards hydroxymethylation, a modification commonly associated with increased gene expression activity, at the cg08753407 probe mapping to the AREL1 gene in MSA patients. The AREL1 gene codes for an E3 ubiquitin ligase involved in protein ubiquitination and degradation [53]. Further, E3 ubiquitin ligases mark proteins for degradation in the proteasome which is necessary for antigen presentation through MHC Class I complexes (reviewed by Loureiro & Ploegh [54]).…”

Section: Discussionmentioning

confidence: 99%

“…2a, b), two probes showed a mean difference > 5% with one probe mapping to AREL1 (cg08753407, change (Δ) in methylation (β) = − 9.1%, P = 1.47E-07; Fig. 2b) belonging to the E3 ubiquitin ligase family [53] necessary for antigen presentation [54]. Hence, this change in methylation indicates an immune activation in MSA patients.…”

Section: Arel1 Presents a Shift From Cytosine Methylation To Cytosinementioning

confidence: 95%

Epigenetic modulation of AREL1 and increased HLA expression in brains of multiple system atrophy patients

Rydbirk

Folke

Busato

et al. 2020

acta neuropathol commun

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Multiple system atrophy (MSA) is a rare disease with a fatal outcome. To date, little is known about the molecular processes underlying disease development. Its clinical overlap with related neurodegenerative movement disorders underlines the importance for expanding the knowledge of pathological brain processes in MSA patients to improve distinction from similar diseases. In the current study, we investigated DNA methylation changes in brain samples from 41 MSA patients and 37 healthy controls. We focused on the prefrontal cortex, a moderately affected area in MSA. Using Illumina MethylationEPIC arrays, we investigated 5-methylcytosine (5mC) as well as 5-hydroxymethylcytosine (5hmC) changes throughout the genome. We identified five significantly different 5mC probes (adj. P < 0.05), of which one probe mapping to the AREL1 gene involved in antigen presentation was decreased in MSA patients. This decrease correlated with increased 5hmC levels. Further, we identified functional DNA methylation modules involved in inflammatory processes. As expected, the decreased 5mC levels on AREL1 was concordant with increased gene expression levels of both AREL1 as well as MHC Class I HLA genes in MSA brains. We also investigated whether these changes in antigen-related processes in the brain associated with changes in peripheral mononuclear cells. Using flow cytometry on an independent cohort of MSA patients, we identified a decrease in circulating non-classical CD14 + CD16 ++ blood monocytes, whereas T and NK cell populations were unchanged. Taken together, our results support the view of an active neuroimmune response in brains of MSA patients.

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“…cIAP1 was also reported to inhibit apoptosis by targeting the downstream of cytochrome c , via the interaction with activated caspase-9 and thus disrupting caspase-9 and the downstream activation of procaspase-3 (Burke, Smith, & Smith, 2010). These mitochondrial IAP antagonists are in turn ubiquitinated in the cytosol of apoptosis-stimulated cells by AREL1 E3 ligase to inhibit apoptosis (Kim et al, 2013). …”

Section: Dubs In Regulation Of Apoptosis Pathways In Cancersmentioning

confidence: 99%

Emerging role of DUBs in tumor metastasis and apoptosis: Therapeutic implication

Zhou

et al. 2017

Pharmacology & Therapeutics

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Malfunction of ubiquitin-proteasome system is tightly linked to tumor formation and tumor metastasis. Targeting the ubiquitin-pathway provides a new strategy for anti-cancer therapy. Despite the parts played by ubiquitin modifiers, removal of ubiquitin from the functional proteins by the deubiquitinating enzymes (DUBs) plays an important role in governing the multiple steps of the metastatic cascade, including local invasion, dissemination, and eventual colonization of the tumor to distant organs. Both deregulated ubiquitination and deubiquitination could lead to dysregulation of various critical events and pathways such as apoptosis and epithelial-mesenchymal transition (EMT). Recent TCGA study has further revealed the connection between mutations of DUBs and various types of tumors. In addition, emerging drug design targeting DUBs provides a new strategy for anti-cancer therapy. In this review, we will summarize the role of deubiquitination and highlight the recent discoveries of DUBs with regards to multiple metastatic events including anti-apoptosis pathway and EMT. We will further discuss the regulation of deubiquitination as a novel strategy for anti-cancer therapy.

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Identification of a Novel Anti-apoptotic E3 Ubiquitin Ligase That Ubiquitinates Antagonists of Inhibitor of Apoptosis Proteins SMAC, HtrA2, and ARTS

Cited by 43 publications

References 30 publications

A panel of protein markers for the early detection of lung cancer with bronchial brushing specimens

A panel of protein markers for the early detection of lung cancer with bronchial brushing specimens

Epigenetic modulation of AREL1 and increased HLA expression in brains of multiple system atrophy patients

Emerging role of DUBs in tumor metastasis and apoptosis: Therapeutic implication

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