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ubiquitin ligase

Callie A S Corsa, Gemma L Pearson, Aaron Renberg, Matthew M Askar, Tracy Vozheiko, Ormond A MacDougald, Scott A Soleimanpour
The E3 ubiquitin ligase parkin is a critical regulator of mitophagy and has been identified as a susceptibility gene for type 2 diabetes (T2D). However, its role in metabolically active tissues that precipitate T2D development is unknown. Specifically, pancreatic β cells and adipocytes both rely heavily on mitochondrial function in the regulation of optimal glycemic control to prevent T2D, but parkin's role in preserving quality control of β-cell or adipocyte mitochondria is unclear. Although parkin has been previously reported to control mitophagy, here we show that parkin surprisingly is dispensable for glucose homeostasis in both β cells and adipocytes during diet-induced insulin resistance in mice...
March 15, 2019: Journal of Biological Chemistry
Yoshiharu Muto, Toshiro Moroishi, Kazuya Ichihara, Masaaki Nishiyama, Hideyuki Shimizu, Hidetoshi Eguchi, Kyoji Moriya, Kazuhiko Koike, Koshi Mimori, Masaki Mori, Yuta Katayama, Keiichi I Nakayama
Hepatic iron overload is a risk factor for progression of hepatocellular carcinoma (HCC), although the molecular mechanisms underlying this association have remained unclear. We now show that the iron-sensing ubiquitin ligase FBXL5 is a previously unrecognized oncosuppressor in liver carcinogenesis in mice. Hepatocellular iron overload elicited by FBXL5 ablation gave rise to oxidative stress, tissue damage, inflammation, and compensatory proliferation of hepatocytes and to consequent promotion of liver carcinogenesis induced by exposure to a chemical carcinogen...
March 15, 2019: Journal of Experimental Medicine
Shih-Han Kao, Wei-Chung Cheng, Yi-Ting Wang, Han-Tsang Wu, Han-Yu Yeh, Yu-Ju Chen, Ming-Hsui Tsai, Kou-Juey Wu
Markers of cancer stemness predispose patients to tumor aggressiveness, drug and immunotherapy resistance, relapse, and metastasis. DDX17 is a co-factor of the Drosha-DGCR8 complex in miRNA biogenesis and transcriptional coactivator and has been associated with cancer stem-like properties. However, the precise mechanism by which DDX17 controls cancer stem-like features remains elusive. Here we show that the E3 ligase HectH9 mediated K63-polyubiquitination of DDX17 under hypoxia to control stem-like properties and tumor-initiating capabilities...
March 15, 2019: Cancer Research
Joel Ricci-López, Abraham Vidal-Limon, Matías Zunñiga, Verónica A Jimènez, Joel B Alderete, Carlos A Brizuela, Sergio Aguila
High-risk strains of human papillomavirus (HPV) have been identified as the etiologic agent of some anogenital tract, head, and neck cancers. Although prophylactic HPV vaccines have been approved; it is still necessary a drug-based treatment against the infection and its oncogenic effects. The E6 oncoprotein is one of the most studied therapeutic targets of HPV, it has been identified as a key factor in cell immortalization and tumor progression in HPV-positive cells. E6 can promote the degradation of p53, a tumor suppressor protein, through the interaction with the cellular ubiquitin ligase E6AP...
2019: PloS One
Thomas Bonacci, Michael J Emanuele
The Anaphase-Promoting Complex/Cyclosome (APC/C) is an E3 ubiquitin ligase and key regulator of cell cycle progression. By triggering the degradation of mitotic cyclins, APC/C controls cell cycle-dependent oscillations in Cyclin Dependent Kinase (CDK) activity. Thus, the dynamic activities of both APC/C and CDK sit at the core of the cell cycle oscillator. The APC/C controls a large number of substrates and is regulated through multiple mechanisms, including cofactor-dependent activation. These cofactors, Cdc20 and Cdh1, recognize substrates, while the specific E2 enzymes UBE2C/UbcH10 and UBE2S cooperate with APC/C to build K11-linked ubiquitin chains on substrates to target them for proteasomal degradation...
March 15, 2019: Cell Cycle
Andrew Sandstrom, Patrick S Mitchell, Lisa Goers, Edward W Mu, Cammie F Lesser, Russell E Vance
Inflammasomes are multi-protein platforms that initiate innate immunity by recruitment and activation of Caspase-1. The NLRP1B inflammasome is activated upon direct cleavage by the anthrax lethal toxin protease. However, the mechanism by which cleavage results in NLRP1B activation is unknown. Here we find that cleavage results in proteasome-mediated degradation of the N-terminal domains of NLRP1B, liberating a C-terminal fragment that is a potent Caspase-1 activator. Proteasome-mediated degradation of NLRP1B is both necessary and sufficient for NLRP1B activation...
March 14, 2019: Science
Arti B Dumbrepatil, Soumi Ghosh, Kelcie A Zegalia, Paige A Malec, J Damon Hoff, Robert T Kennedy, E Neil G Marsh
Virus-inhibitory protein, endoplasmic reticulum-associated, interferon-inducible (viperin) is a radical SAM enzyme that plays a multifaceted role in the cellular antiviral response. Viperin has recently been shown to catalyze the SAM-dependent formation of 3'-deoxy-3',4'-didehydro-CTP (ddhCTP), which inhibits some viral RNA polymerases. Viperin is also implicated in regulating Lys-63-linked polyubiquitination of interleukin-1 receptor-associated kinase-1 (IRAK1) by the E3 ubiquitin ligase TNF receptor-associated factor 6 (TRAF6) as part of the Toll-like receptor-7 and 9 (TLR7/9) innate immune signaling pathways...
March 14, 2019: Journal of Biological Chemistry
Andrea Braganza, Kelly Quesnelle, Janelle Bickta, Christopher Reyes, Yinna Wang, Morgan Jessup, Claudette St Croix, Julie Scott, Shivendra V Singh, Sruti Shiva
Myoglobin is a monomeric heme protein expressed ubiquitously in skeletal and cardiac muscle and is traditionally considered to function as an oxygen reservoir for mitochondria during hypoxia. It is now well established that low concentrations of myoglobin are aberrantly expressed in a significant proportion of breast cancer tumors. Despite being expressed only at low levels in these tumors, myoglobin is associated with attenuated tumor growth and a better prognosis in breast cancer patients, but the mechanism of this myoglobin-mediated protection against further cancer growth remains unclear...
March 14, 2019: Journal of Biological Chemistry
Kelly M DeMars, Changjun Yang, Eduardo Candelario-Jalil
Neuroinflammation after stroke significantly contributes to neuronal cell death. Bromodomain and Extra Terminal Domain (BET) proteins are essential to inflammatory gene transcription. BET proteins (BRD2, BRD3, BRD4, and BRDT) have varied effects including chromatin remodeling, histone acetyltransferase activity, and as scaffolds to recruit transcription factors; they couple chromatin remodeling with transcription. BRD2/4 are of particularly interest to stroke-induced neuroinflammation that contributes to delayed cell death as they are required for NF-κB-dependent gene transcription...
March 11, 2019: Neurochemistry International
Monte S Willis, Traci L Parry, David I Brown, Roberto I Mota, Wei Huang, Ju Youn Beak, Michael Sola, Cynthia Zhou, Sean T Hicks, Melissa C Caughey, Ralph B D'Agostino, Jennifer Jordan, W Gregory Hundley, Brian C Jensen
Background Anthracycline chemotherapeutics, such as doxorubicin, are used widely in the treatment of numerous malignancies. The primary dose-limiting adverse effect of anthracyclines is cardiotoxicity that often presents as heart failure due to dilated cardiomyopathy years after anthracycline exposure. Recent data from animal studies indicate that anthracyclines cause cardiac atrophy. The timing of onset and underlying mechanisms are not well defined, and the relevance of these findings to human disease is unclear...
March 2019: Circulation. Heart Failure
Montserrat Cairó, Laura Campderrós, Aleix Gavaldà-Navarro, Rubén Cereijo, Alejandro Delgado-Anglés, Tania Quesada-López, Marta Giralt, Joan Villarroya, Francesc Villarroya
Parkin is an ubiquitin-E3 ligase that acts as a key component of the cellular machinery for mitophagy. We show here that Parkin expression is reciprocally regulated in brown adipose tissue in relation to thermogenic activity. Thermogenic stimuli repress Parkin gene expression via transcriptional mechanisms that are elicited by noradrenergic and PPARα-mediated pathways that involve intracellular lipolysis in brown adipocytes. Parkin-KO mice show over-activated brown adipose tissue thermogenic activity and exhibit improved metabolic parameters, especially when fed a high-fat diet...
March 13, 2019: EMBO Reports
Fee Klupp, Christina Giese, Niels Halama, Clemens Franz, Felix Lasitschka, Arne Warth, Thomas Schmidt, Matthias Kloor, Alexis Ulrich, Martin Schneider
Purpose: Smurf2 is a member of the homologous to E6-AP carboxyl terminus family of E3 ubiquitin ligases. Changes in their expression pattern are known to contribute to tumorigenesis. Smurf2 plays a decisive role in cell differentiation, proliferation, and migration and exhibits a dual role in cancer - functioning as both oncogene and tumor suppressor. Dysregulation of Smurf2 in different cancer types has been described, besides colorectal cancer (CRC). We therefore examined the expression and oncogenic potential of Smurf2 in human CRC patients...
2019: Cancer Management and Research
Gregory Blass, Christine A Klemens, Michael W Brands, Oleg Palygin, Alexander Staruschenko
Recent studies have suggested that postprandial increases in insulin directly contribute to reduced urinary sodium excretion. An abundance of research supports the ability of insulin to augment epithelial sodium channel (ENaC) transport. This study hypothesized that ENaC contributes to the increase in renal sodium reabsorption following a meal. To test this, we used fasted or 4 hour postprandial Sprague Dawley rats to analyze ENaC expression and activity. We also assessed total expression of additional sodium transporters (Na+ -Cl- cotransporter (NCC), Na+ -K+ -2Cl- cotransporter (NKCC2), and Na+ -K+ -ATPase (NKA)) and circulating hormones involved in the renin-angiotensin-aldosterone system (RAAS)...
March 12, 2019: Scientific Reports
Françoise Vuillier, Zhi Li, Pierre-Henri Commere, Lasse Toftdal Dynesen, Sandra Pellegrini
USP18 is an isopeptidase that cleaves the ubiquitin-like ISG15 from conjugates and is also an essential negative feedback regulator of type I interferon signaling. We and others reported that USP18 protein is stabilized by ISG15 and targeted for degradation by SKP2 (S-phase kinase associated protein 2), the substrate-recognition subunit of the SCFSKP2 ubiquitin E3 ligase complex, which operates in cell cycle progression. Here, we have analyzed how, under non stimulated conditions, USP18, ISG15 and SKP2 communicate with each other, by enforcing or silencing their expression...
March 11, 2019: Scientific Reports
Andrew C Giles, Muriel Desbois, Karla J Opperman, Rubens Tavora, Marissa J Maroni, Brock Grill
Inhibitory GABAergic transmission is required for proper circuit function in the nervous system. However, our understanding of molecular mechanisms that preferentially influence GABAergic transmission, particularly presynaptic mechanisms, remains limited. We previously reported that the ubiquitin ligase  EEL-1 preferentially regulates GABAergic presynaptic transmission. To further explore how EEL-1 functions, here we performed affinity purification proteomics using C. elegans, and identified the O-GlcNAc transferase OGT-1 as an EEL-1 binding protein...
March 11, 2019: Journal of Biological Chemistry
Imane Bjij, Shama Khan, Pritika Ramharak, Driss Cherqaoui, Mahmoud E S Soliman
The development of covalent drugs, specifically in cancer therapeutics, has recently sparked interest among the pharmaceutical research community. While representing a significant fraction of the drugs in the market, very few have been deliberately designed to interact covalently with their biological target. One of the enzymes that have been both covalently and noncovalently targeted is the Neural Precursor Cell Expressed Developmentally Downregulated gene 4-1 (Nedd4-1). This enzyme has been found to have multiple physiological implications, including its involvement in cancer invasion...
March 10, 2019: Journal of Cellular Biochemistry
Alexander J Garvin, Ahmed H A Khalaf, Alessandro Rettino, Jerome Xicluna, Laura Butler, Joanna R Morris, David M Heery, Nicole M Clarke
IRF1 (Interferon Regulatory Factor-1) is the prototype of the IRF family of DNA binding transcription factors. IRF1 protein expression is regulated by transient up-regulation in response to external stimuli followed by rapid degradation via the ubiquitin-proteasome system. Here we report that DNA bound IRF1 turnover is promoted by GSK3β (Glycogen Synthase Kinase 3β) via phosphorylation of the T181 residue which generates a phosphodegron for the SCF (Skp-Cul-Fbox) ubiquitin E3-ligase receptor protein Fbxw7α (F-box/WD40 7)...
March 11, 2019: Nucleic Acids Research
Sara Schesser Bartra, Cherish Lorica, Lianfen Qian, Xin Gong, Wael Bahnan, Henry Barreras, Rosmely Hernandez, Zhongwei Li, Gregory V Plano, Kurt Schesser
Yersinia pestis , the causative agent of plague, possesses a number of virulence mechanisms that allows it to survive and proliferate during its interaction with the host. To discover additional infection-specific Y. pestis factors, a transposon site hybridization (TraSH)-based genome-wide screen was employed to identify genomic regions required for its survival during cellular infection. In addition to several well-characterized infection-specific genes, this screen identified three chromosomal genes ( y3397, y3399 , and y3400 ), located in an apparent operon, that promoted successful infection...
2019: Frontiers in Cellular and Infection Microbiology
Jennifer D Robison, Yuji Yamasaki, Stephen K Randall
During cold stress, soybean CBF/DREB1 transcript levels increase rapidly; however, expected downstream targets appear unresponsive. Here, we asked whether the ethylene signaling pathway, which is enhanced in the cold can negatively regulate the soybean CBF/DREB1 cold responsive pathway; thus contributing to the relatively poor cold tolerance of soybean. Inhibition of the ethylene signaling pathway resulted in a significant increase in GmDREB1A;1 and GmDREB1A;2 transcripts, while stimulation led to decreased GmDREB1A;1 and GmDREB1B;1 transcripts...
2019: Frontiers in Plant Science
M J Fernández-Aceñero, M Cruz, J Sastre-Varela, J I Casal, M A Cerón Nieto, L Del Puerto-Nevado, J García-Foncillas, A Cebrián
Large bowel adenocarcinoma is one of the most frequent human neoplasms and despite recent insights into the pathophysiology and molecular basis of this disease, mortality remains high in advanced and metastatic cases. Most guidelines recommend adjuvant chemotherapy for tumours involving lymph nodes, but not for patients with localized stage I or II disease. However, it is well known that approximately 20% of stage II colorectal carcinoma patients eventually recur, mainly with distant or peritoneal involvement and show bad prognosis...
March 9, 2019: Pathology Oncology Research: POR
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