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Nemo kinase

Xiaoguang Li, Na Liu, Yizhu Wang, Jinglong Liu, Haigang Shi, Zhenzhen Qu, Tingting Du, Bin Guo, Bin Gu
Type 2 diabetes mellitus (T2DM) is associated with inhibited osteogenesis of bone marrow mesenchymal stem cells (BMSCs). Brain and muscle ARNT-like protein 1 (BMAL1) has been linked to the T2DM-related bone remodeling, however, the specific mechanism is still unclear. Herein, we aimed to determine the role of BMAL1 in T2DM-induced suppression of BMSCs osteogenesis. Inhibited osteogenesis and BMAL1 expression were showed in diabetic BMSCs. And while β-catenin and T cell factor (TCF) expression were decreased, the glycogen synthase kinase-3β (GSK-3β) and nemo-like kinase (NLK) expression were increased in diabetic BMSCs...
October 4, 2016: Molecular and Cellular Endocrinology
Linlin Guo, Hannah Heejung Lee, María de Las Mercedes Noriega, Hans-Joachim Paust, Gunther Zahner, Friedrich Thaiss
Acute kidney injury (AKI) is associated with poor patient outcome and a global burden for end-stage renal disease. Ischemia-reperfusion injury (IRI) is one of the major causes of AKI, and experimental work has revealed many details of the inflammatory response in the kidney. Here, we investigated whether deletion of the NF-κB kinases IKK2 or NEMO in lymphocytes or systemic inhibition of IKK2 would cause different kidney inflammatory responses after IRI induction. Serum creatinine, BUN level and renal tubular injury score were significantly increased in CD4creIKK2f/f (CD4xIKK2Δ) and CD4creNEMOf/f (CD4xNEMOΔ) mice compared with CD4cre mice after IRI induction...
August 31, 2016: American Journal of Physiology. Renal Physiology
Xu Yan, Jianxun Liu, Hongjin Wu, Yuna Liu, Sidao Zheng, Chengying Zhang, Cui Yang
BACKGROUND/AIMS: Ginsenoside Rb1 (GS-Rb1) is one of the most important active pharmacological extracts of the Traditional Chinese Medicine ginseng, with extensive evidence of its cardioprotective properties. Mir-208 has been shown to act as a biomarker of acute myocardial infarction in vivo studies including man. However the impact of miR-208 on the protective effect of GS-Rb1 in hypoxia/ischemia injured cardiomyocytes remains unclear. The current study aims to investigate the target gene of miR-208 and the impact on the protective effect of GS-Rb1 in hypoxia/ischemia (H/I) injuried cardiomyocytes...
2016: Cellular Physiology and Biochemistry
Alessandra Pescatore, Elio Esposito, Peter Draber, Henning Walczak, Matilde Valeria Ursini
Incontinentia Pigmenti (IP) is a rare X-linked disease characterized by early male lethality and multiple abnormalities in heterozygous females. IP is caused by NF-κB essential modulator (NEMO) mutations. The current mechanistic model suggests that NEMO functions as a crucial component mediating the recruitment of the IκB-kinase (IKK) complex to tumor necrosis factor receptor 1 (TNF-R1), thus allowing activation of the pro-survival NF-κB response. However, recent studies have suggested that gene activation and cell death inhibition are two independent activities of NEMO...
2016: Cell Death & Disease
Lap Kwan Chan, Melanie Gerstenlauer, Björn Konukiewitz, Katja Steiger, Wilko Weichert, Thomas Wirth, Harald Jakob Maier
OBJECTIVE: Inhibitory κB kinase (IKK)/nuclear factor κB (NF-κB) signalling has been implicated in the pathogenesis of pancreatitis, but its precise function has remained controversial. Here, we analyse the contribution of IKK/NF-κB signalling in epithelial cells to the pathogenesis of pancreatitis by targeting the IKK subunit NF-κB essential modulator (NEMO) (IKKγ), which is essential for canonical NF-κB activation. DESIGN: Mice with a targeted deletion of NEMO in the pancreas were subjected to caerulein pancreatitis...
July 27, 2016: Gut
Christiane Koppe, Patricia Verheugd, Jérémie Gautheron, Florian Reisinger, Karina Kreggenwinkel, Christoph Roderburg, Luca Quagliata, Luigi Terracciano, Nikolaus Gassler, René H Tolba, Yannick Boege, Achim Weber, Michael Karin, Mark Luedde, Ulf P Neumann, Ralf Weiskirchen, Frank Tacke, Mihael Vucur, Christian Trautwein, Bernhard Lüscher, Christian Preisinger, Mathias Heikenwalder, Tom Luedde
UNLABELLED: The IκB-Kinase (IKK) complex-consisting of the catalytic subunits, IKKα and IKKβ, as well as the regulatory subunit, NEMO-mediates activation of the nuclear factor κB (NF-κB) pathway, but previous studies suggested the existence of NF-κB-independent functions of IKK subunits with potential impact on liver physiology and disease. Programmed cell death is a crucial factor in the progression of liver diseases, and receptor-interacting kinases (RIPKs) exerts strategic control over multiple pathways involved in regulating novel programmed cell-death pathways and inflammation...
October 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Sharmistha Dam, Michael Kracht, Stephan Pleschka, M Lienhard Schmitz
UNLABELLED: The role of NF-κB in influenza A virus (IAV) infection does not reveal a coherent picture, as pro- and also antiviral functions of this transcription factor have been described. To address this issue, we used clustered regularly interspaced short palindromic repeat with Cas9 (CRISPR-Cas9)-mediated genome engineering to generate murine MLE-15 cells lacking two essential components of the NF-κB pathway. Cells devoid of either the central NF-κB essential modulator (NEMO) scaffold protein and thus defective in IκB kinase (IKK) activation or cells not expressing the NF-κB DNA-binding and transactivation subunit p65 were tested for propagation of the SC35 virus, which has an avian host range, and its mouse-adapted variant, SC35M...
September 1, 2016: Journal of Virology
Emmanuel Derudder, Sebastian Herzog, Verena Labi, Tomoharu Yasuda, Karl Köchert, Martin Janz, Andreas Villunger, Marc Schmidt-Supprian, Klaus Rajewsky
Although canonical NF-κB signaling is crucial to generate a normal mature B-cell compartment, its role in the persistence of resting mature B cells is controversial. To resolve this conflict, we ablated NF-κB essential modulator (NEMO) and IκB kinase 2 (IKK2), two essential mediators of the canonical pathway, either early on in B-cell development or specifically in mature B cells. Early ablation severely inhibited the generation of all mature B-cell subsets, but follicular B-cell numbers could be largely rescued by ectopic expression of B-cell lymphoma 2 (Bcl2), despite a persisting block at the transitional stage...
May 3, 2016: Proceedings of the National Academy of Sciences of the United States of America
Pantaporn Supakankul, Supamit Mekchay
Nemo-like protein kinase (NLK) is a key enzyme in the noncanonical Wnt signaling pathway and it is involved in adipogenesis. In this study, the associations of the polymorphisms of the NLK gene with intramuscular fat (IMF) content and fatty acid (FA) composition traits were analyzed in crossbred commercial pigs. Three single nucleotide polymorphisms (SNPs) of the porcine NLK gene were identified in 5'-flanking region and introns, consisting of g.403739_403764insdel, g.574462T>C and g.630426A>G. The NLK g...
August 2016: Meat Science
Jian Wang, Zhi-Hong Yang, Hua Chen, Hua-Hui Li, Li-Yong Chen, Zhu Zhu, Ying Zou, Cong-Cong Ding, Jing Yang, Zhi-Wei He
BACKGROUND: Nurr1, a member of the orphan receptor family, plays an important role in several types of cancer. Our previous work demonstrated that increased expression of Nurr1 plays a significant role in the initiation and progression of prostate cancer (PCa), though the mechanisms for regulation of Nurr1 expression remain unknown. In this study, we investigated the hypothesis that Nemo-like kinase (NLK) is a key regulator of Nurr1 expression in PCa. METHODS: Immunohistochemistry and Western blot analysis were used to evaluate levels of NLK and Nurr1 in prostatic tissues and cell lines...
2016: BMC Cancer
Hengning Ke, Katarzyna Chmielarska Masoumi, Kristofer Ahlqvist, Michael J Seckl, Kristina Rydell-Törmänen, Ramin Massoumi
The canonical Wnt signaling can be silenced either through β-catenin-mediated ubiquitination and degradation or through phosphorylation of Tcf and Lef by nemo-like kinase (NLK). In the present study, we generated NLK deficient animals and found that these mice become cyanotic shortly before death because of lung maturation defects. NLK-/- lungs exhibited smaller and compressed alveoli and the mesenchyme remained thick and hyperplastic. This phenotype was caused by epithelial activation of vascular endothelial growth factor (VEGF) via recruitment of Lef1 to the promoter of VEGF...
2016: Scientific Reports
Katerina Vlantis, Andy Wullaert, Apostolos Polykratis, Vangelis Kondylis, Marius Dannappel, Robin Schwarzer, Patrick Welz, Teresa Corona, Henning Walczak, Falk Weih, Ulf Klein, Michelle Kelliher, Manolis Pasparakis
Intestinal epithelial cells (IECs) regulate gut immune homeostasis, and impaired epithelial responses are implicated in the pathogenesis of inflammatory bowel diseases (IBD). IEC-specific ablation of nuclear factor κB (NF-κB) essential modulator (NEMO) caused Paneth cell apoptosis and impaired antimicrobial factor expression in the ileum, as well as colonocyte apoptosis and microbiota-driven chronic inflammation in the colon. Combined RelA, c-Rel, and RelB deficiency in IECs caused Paneth cell apoptosis but not colitis, suggesting that NEMO prevents colon inflammation by NF-κB-independent functions...
March 15, 2016: Immunity
Mehdi Baratchian, Christopher A Davis, Akira Shimizu, David Escors, Claire Bagnéris, Tracey Barrett, Mary K Collins
The viral FLICE-like inhibitory protein (FLIP) protein from Kaposi sarcoma-associated herpesvirus activates the NF-κB pathway by forming a stable complex with a central region (amino acids 150-272) of the inhibitor of NF-κB kinase (IKK) γ subunits, thereby activating IKK. Cellular FLIP (cFLIP) forms are also known to activate the NF-κB pathway via IKK activation. Here we demonstrate that cFLIPL, cFLIPS, and their proteolytic product p22-FLIP all require the C-terminal region of NEMO/IKKγ (amino acids 272-419) and its ubiquitin binding function for activation of the IKK kinase (or kinase complex), but none form a stable complex with IKKγ...
April 1, 2016: Journal of Biological Chemistry
Ying Huang, Yang Yang, Yong He, Cheng Huang, Xiaoming Meng, Jun Li
INTRODUCTION: MicroRNA-208a (miR-208a) exacerbated cardiomyocyte apoptosis via inhibiting nemo-like kinase (NLK). miR-208a is a crucial molecule in the regulation of heart diseases, however, the biological function and underlying mechanism of miR-208a in the progression of cardiomyocyte apoptosis is not clearly elucidated. We hypothesized that miR-208a might potentiate cardiomyocyte apoptosis through inhibiting NLK. METHODS: Male Sprague-Dawley rats were underwent permanent coronary artery ligation to establish myocardial infarction (MI) model...
February 10, 2016: Current Pharmaceutical Design
Dinorah Friedmann-Morvinski, Rajesh Narasimamurthy, Yifeng Xia, Chad Myskiw, Yasushi Soda, Inder M Verma
Glioblastoma multiforme (GBM) is the most common and lethal form of intracranial tumor. We have established a lentivirus-induced mouse model of malignant gliomas, which faithfully captures the pathophysiology and molecular signature of mesenchymal human GBM. RNA-Seq analysis of these tumors revealed high nuclear factor κB (NF-κB) activation showing enrichment of known NF-κB target genes. Inhibition of NF-κB by either depletion of IκB kinase 2 (IKK2), expression of a IκBαM super repressor, or using a NEMO (NF-κB essential modifier)-binding domain (NBD) peptide in tumor-derived cell lines attenuated tumor proliferation and prolonged mouse survival...
January 2016: Science Advances
Xiu-Wei Zhang, Song-Yan Chen, Dong-Wei Xue, Hui-Hui Xu, Lian-He Yang, Hong-Tao Xu, En-Hua Wang
Nemo-like kinase (NLK), as a mitogen activated protein kinase (MAPK)-like kinase, is involved in the development of several human cancers. In this study, we explored the expression of NLK in lung squamous cell carcinoma (SCC) and adenocarcinoma tissues, and investigated the associations among NLK, β-catenin, T-cell factor 4 (TCF4), and the clinicopathological factors of lung cancers. The expressions of NLK, β-catenin, TCF4 were examined in 109 cases of lung cancers using immunohistochemistry method. The expression of NLK was observed in the nuclei of lung cancer tissues, and was significantly higher in lung cancer tissues than that in corresponding normal lung tissues (t = 21...
2015: International Journal of Clinical and Experimental Pathology
Jevgenia Zilberman-Rudenko, Linda Monaco Shawver, Alex W Wessel, Yongquan Luo, Martin Pelletier, Wanxia Li Tsai, Younglang Lee, Spiridon Vonortas, Laurence Cheng, Jonathan D Ashwell, Jordan S Orange, Richard M Siegel, Eric P Hanson
Receptor-induced NF-κB activation is controlled by NEMO, the NF-κB essential modulator. Hypomorphic NEMO mutations result in X-linked ectodermal dysplasia with anhidrosis and immunodeficiency, also referred to as NEMO syndrome. Here we describe a distinct group of patients with NEMO C-terminal deletion (ΔCT-NEMO) mutations. Individuals harboring these mutations develop inflammatory skin and intestinal disease in addition to ectodermal dysplasia with anhidrosis and immunodeficiency. Both primary cells from these patients, as well as reconstituted cell lines with this deletion, exhibited increased IκB kinase (IKK) activity and production of proinflammatory cytokines...
February 9, 2016: Proceedings of the National Academy of Sciences of the United States of America
Carla Reale, Anna Iervolino, Ivan Scudiero, Angela Ferravante, Luca Egildo D'Andrea, Pellegrino Mazzone, Tiziana Zotti, Antonio Leonardi, Luca Roberto, Mariastella Zannini, Tiziana de Cristofaro, Muralitharan Shanmugakonar, Giovambattista Capasso, Manolis Pasparakis, Pasquale Vito, Romania Stilo
The I-κB kinase (IKK) subunit NEMO/IKKγ (NEMO) is an adapter molecule that is critical for canonical activation of NF-κB, a pleiotropic transcription factor controlling immunity, differentiation, cell growth, tumorigenesis, and apoptosis. To explore the functional role of canonical NF-κB signaling in thyroid gland differentiation and function, we have generated a murine strain bearing a genetic deletion of the NEMO locus in thyroid. Here we show that thyrocyte-specific NEMO knock-out mice gradually develop hypothyroidism after birth, which leads to reduced body weight and shortened life span...
March 11, 2016: Journal of Biological Chemistry
Francesca De Falco, Carmen Di Giovanni, Carmen Cerchia, Daniela De Stefano, Antonella Capuozzo, Carlo Irace, Teresa Iuvone, Rita Santamaria, Rosa Carnuccio, Antonio Lavecchia
Nuclear Factor-κB (NF-κB) is a transcription factor regulating several genes involved in important physiological and pathological processes. NF-κB has been found constitutively activated in many inflammatory/immune diseases. In addition, a positive correlation between persistent activation of NF-κB and tumor promotion has been demonstrated. Since the IKK (IκB kinase) activation is an indispensable component of all pro-inflammatory signaling pathways leading to NF-κB activation, considerable efforts have been done in order to develop novel anti-inflammatory therapeutics targeting IKK...
March 15, 2016: Biochemical Pharmacology
Michelle Vincendeau, Kamyar Hadian, Ana C Messias, Jara K Brenke, Jenny Halander, Richard Griesbach, Ute Greczmiel, Arianna Bertossi, Ralf Stehle, Daniel Nagel, Katrin Demski, Hana Velvarska, Dierk Niessing, Arie Geerlof, Michael Sattler, Daniel Krappmann
The IκB kinase (IKK) complex acts as the gatekeeper of canonical NF-κB signaling, thereby regulating immunity, inflammation and cancer. It consists of the catalytic subunits IKKα and IKKβ and the regulatory subunit NEMO/IKKγ. Here, we show that the ubiquitin binding domain (UBAN) in NEMO is essential for IKK/NF-κB activation in response to TNFα, but not IL-1β stimulation. By screening a natural compound library we identified an anthraquinone derivative that acts as an inhibitor of NEMO-ubiquitin binding (iNUB)...
2016: Scientific Reports
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