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Ji-Ung Jung, Sowndharya Ravi, Dong W Lee, Kassandra McFadden, Michael L Kamradt, L Gerard Toussaint, Raquel Sitcheran
Although the role of NF-κB-inducing kinase (NIK) in immunity is well established, its relevance in cancer is just emerging. Here we describe novel functions for NIK in regulating mitochondrial dynamics and motility to promote cell invasion. We show that NIK is localized to mitochondria in cancer cell lines, ex vivo tumor tissue, and mouse embryonic fibroblasts (MEFs). NIK promotes mitochondrial fission, velocity, and directional migration, resulting in subcellular distribution of mitochondria to the periphery of migrating cells...
December 19, 2016: Current Biology: CB
Alberto Ortiz, Holger Husi, Laura Gonzalez-Lafuente, Lara Valiño-Rivas, Manuel Fresno, Ana Belen Sanz, William Mullen, Amaya Albalat, Sergio Mezzano, Tonia Vlahou, Harald Mischak, Maria Dolores Sanchez-Niño
An improved understanding of pathogenic pathways in AKI may identify novel therapeutic approaches. Previously, we conducted unbiased liquid chromatography-tandem mass spectrometry-based protein expression profiling of the renal proteome in mice with acute folate nephropathy. Here, analysis of the dataset identified enrichment of pathways involving NFκB in the kidney cortex, and a targeted data mining approach identified components of the noncanonical NFκB pathway, including the upstream kinase mitogen-activated protein kinase kinase kinase 14 (MAP3K14), the NFκB DNA binding heterodimer RelB/NFκB2, and proteins involved in NFκB2 p100 ubiquitination and proteasomal processing to p52, as upregulated...
September 12, 2016: Journal of the American Society of Nephrology: JASN
Wei Shi, Zhihua Ye, Li Zhuang, Yingchang Li, Wendi Shuai, Zhixiang Zuo, Xueli Mao, Ranyi Liu, Jiangxue Wu, Shuai Chen, Wenlin Huang
Uncontrolled growth and distant metastasis are hallmarks of colorectal cancer (CRC), but the mechanisms are poorly understood. Olfactomedin 1 (OLFM1), a member of the olfactomedin domain-containing protein family, plays an important role in the development of neurogenic tissues. Recently, OLFM1 deregulation was frequently observed in several cancers, and it was induced in colon cell lines after treatment with the demethylating agent 5-aza-2'-deoxycytidine. However, the function of OLFM1 in CRC remains unknown...
August 24, 2016: Journal of Pathology
Katharina L Willmann, Roberto Sacco, Rui Martins, Wojciech Garncarz, Ana Krolo, Sylvia Knapp, Keiryn L Bennett, Kaan Boztug
NF-κB signaling is a central pathway of immunity and integrates signal transduction upon a wide array of inflammatory stimuli. Noncanonical NF-κB signaling is activated by a small subset of TNF family receptors and characterized by NF-κB2/p52 transcriptional activity. The medical relevance of this pathway has recently re-emerged from the discovery of primary immunodeficiency patients that have loss-of-function mutations in the MAP3K14 gene encoding NIK. Nevertheless, knowledge of protein interactions that regulate noncanonical NF-κB signaling is sparse...
September 2, 2016: Journal of Proteome Research
Megan B Wood, Daniel Rios, Ifor R Williams
Microfold (M) cells are phagocytic intestinal epithelial cells in the follicle-associated epithelium of Peyer's patches that transport particulate antigens from the gut lumen into the subepithelial dome. Differentiation of M cells from epithelial stem cells in intestinal crypts requires the cytokine receptor activator of NF-κB ligand (RANKL) and the transcription factor Spi-B. We used three-dimensional enteroid cultures established with small intestinal crypts from mice as a model system to investigate signaling pathways involved in M cell differentiation and the influence of other cytokines on RANKL-induced M cell differentiation...
September 1, 2016: American Journal of Physiology. Cell Physiology
C L Duran, D W Lee, J-U Jung, S Ravi, C B Pogue, L G Toussaint, K J Bayless, R Sitcheran
A growing body of evidence implicates the noncanonical NF-κB pathway as a key driver of glioma invasiveness and a major factor underlying poor patient prognoses. Here, we show that NF-κB-inducing kinase (NIK/MAP3K14), a critical upstream regulator of the noncanonical NF-κB pathway, is both necessary and sufficient for cell-intrinsic invasion, as well as invasion induced by the cytokine TWEAK, which is strongly associated with tumor pathogenicity. NIK promotes dramatic alterations in glioma cell morphology that are characterized by extensive membrane branching and elongated pseudopodial protrusions...
June 6, 2016: Oncogenesis
Marc A Weniger, Ralf Küppers
Hodgkin and Reed/Sternberg (HRS) cells in classical Hodgkin lymphoma (HL) show constitutive activity of both the canonical and non-canonical NF-κB signaling pathways. The central pathogenetic role of this activity is indicated from studies with HL cell lines, which undergo apoptosis upon NF-κB inhibition. Multiple factors contribute to the strong NF-κB activity of HRS cells. This includes interaction with other cells in the lymphoma microenvironment through CD30, CD40, BCMA and other receptors, but also recurrent somatic genetic lesions in various factors of the NF-κB pathway, including destructive mutations in negative regulators of NF-κB signaling (e...
August 2016: Seminars in Cancer Biology
Michael Rudnicki, Paul Perco, Barbara D Haene, Johannes Leierer, Andreas Heinzel, Irmgard Mühlberger, Ninella Schweibert, Judith Sunzenauer, Heinz Regele, Andreas Kronbichler, Pieter Mestdagh, Jo Vandesompele, Bernd Mayer, Gert Mayer
BACKGROUND: MicroRNAs (miRNAs) contribute to chronic kidney disease (CKD) progression via regulating mRNAs involved in renal homeostasis. However, their association with clinical outcome remains poorly understood. MATERIALS AND METHODS: We performed miRNA and mRNA expression profiling on renal biopsy sections by qPCR (miRNA) and microarrays (mRNA) in a discovery (n = 43) and in a validation (n = 29) cohort. miRNAs differentiating stable and progressive cases were inversely correlated with putative target mRNAs, which were further characterized by pathway analysis using KEGG pathways...
March 2016: European Journal of Clinical Investigation
Ingegerd Elvers, Jason Turner-Maier, Ross Swofford, Michele Koltookian, Jeremy Johnson, Chip Stewart, Cheng-Zhong Zhang, Steven E Schumacher, Rameen Beroukhim, Mara Rosenberg, Rachael Thomas, Evan Mauceli, Gad Getz, Federica Di Palma, Jaime F Modiano, Matthew Breen, Kerstin Lindblad-Toh, Jessica Alföldi
Lymphoma is the most common hematological malignancy in developed countries. Outcome is strongly determined by molecular subtype, reflecting a need for new and improved treatment options. Dogs spontaneously develop lymphoma, and the predisposition of certain breeds indicates genetic risk factors. Using the dog breed structure, we selected three lymphoma predisposed breeds developing primarily T-cell (boxer), primarily B-cell (cocker spaniel), and with equal distribution of B- and T-cell lymphoma (golden retriever), respectively...
November 2015: Genome Research
Olivia M de Goede, Hamid R Razzaghian, E Magda Price, Meaghan J Jones, Michael S Kobor, Wendy P Robinson, Pascal M Lavoie
BACKGROUND: Genome-wide DNA methylation (DNAm) studies have proven extremely useful to understand human hematopoiesis. Due to their active DNA content, nucleated red blood cells (nRBCs) contribute to epigenetic and transcriptomic studies derived from whole cord blood. Genomic studies of cord blood hematopoietic cells isolated by fluorescence-activated cell sorting (FACS) may be significantly altered by heterotopic interactions with nRBCs during conventional cell sorting. RESULTS: We report that cord blood T cells, and to a lesser extent monocytes and B cells, physically engage with nRBCs during FACS...
2015: Clinical Epigenetics
Ming-ming Wang, Mei-xia Fang, Li-guo Chen, Hua-qiang Wang, Hong-jie Liu, Hai-lan Tang
OBJECTIVE: To screen out blood-stasis syndrome (BSS)-associated microRNA and therefore determine the possible target for treating hypertension. METHODS: A high-energy sequencing method and digital gene expression sequencing theory were adopted to sequence microRNA (miRNA) and messenger RNA (mRNA), and to determine differential expression in human umbilical vein endothelial cells incubated with serum samples from hypertension patients with or without BSS, and healthy controls...
November 2015: Chinese Journal of Integrative Medicine
Chunlong Zhang, Hongyan Zhao, Jie Li, Hongbo Liu, Fang Wang, Yanjun Wei, Jianzhong Su, Dongwei Zhang, Tiefu Liu, Yan Zhang
Abnormal DNA methylation is known as playing an important role in the tumorgenesis. It is helpful for distinguishing the specificity of diagnosis and therapeutic targets for cancers based on characteristics of DNA methylation patterns across cancers. High throughput DNA methylation analysis provides the possibility to comprehensively filter the epigenetics diversity across various cancers. We integrated whole-genome methylation data detected in 798 samples from seven cancers. The hierarchical clustering revealed the existence of cancer-specific methylation pattern...
2015: PloS One
Marina Evangelou, Deborah J Smyth, Mary D Fortune, Oliver S Burren, Neil M Walker, Hui Guo, Suna Onengut-Gumuscu, Wei-Min Chen, Patrick Concannon, Stephen S Rich, John A Todd, Chris Wallace
Pathway analysis can complement point-wise single nucleotide polymorphism (SNP) analysis in exploring genomewide association study (GWAS) data to identify specific disease-associated genes that can be candidate causal genes. We propose a straightforward methodology that can be used for conducting a gene-based pathway analysis using summary GWAS statistics in combination with widely available reference genotype data. We used this method to perform a gene-based pathway analysis of a type 1 diabetes (T1D) meta-analysis GWAS (of 7,514 cases and 9,045 controls)...
December 2014: Genetic Epidemiology
Po Y Mak, Duncan H Mak, Vivian Ruvolo, Rodrigo Jacamo, Steven M Kornblau, Hagop Kantarjian, Michael Andreeff, Bing Z Carter
Overexpression of the apoptosis repressor with caspase recruitment domain (ARC, also termed NOL3) protein predicts adverse outcome in patients with acute myeloid leukaemia (AML) and confers drug resistance to AML cells. The second mitochondrial-derived activator of caspases (SMAC, also termed DIABLO) mimetic, birinapant, promotes extrinsic apoptosis in AML cells. SMAC mimetics induce cleavage of cellular inhibitor of apoptosis (cIAP) proteins, leading to stabilization of the nuclear factor-κB (NF-κB)-inducing kinase (MAP3K14, also termed NIK) and activation of non-canonical NF-κB signalling...
November 2014: British Journal of Haematology
S Bank, P S Andersen, J Burisch, N Pedersen, S Roug, J Galsgaard, S Y Turino, J B Brodersen, S Rashid, B K Rasmussen, S Avlund, T B Olesen, H J Hoffmann, M K Thomsen, V Ø Thomsen, M Frydenberg, B A Nexø, J Sode, U Vogel, V Andersen
Antitumor necrosis factor-α (TNF-α) is used for treatment of severe cases of inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC). However, one-third of the patients do not respond to the treatment. Genetic markers may predict individual response to anti-TNF therapy. Using a candidate gene approach, 39 mainly functional single nucleotide polymorphisms (SNPs) in 26 genes regulating inflammation were assessed in 738 prior anti-TNF-naive Danish patients with IBD. The results were analyzed using logistic regression (crude and adjusted for age, gender and smoking status)...
December 2014: Pharmacogenomics Journal
Rami Rahal, Mareike Frick, Rodrigo Romero, Joshua M Korn, Robert Kridel, Fong Chun Chan, Barbara Meissner, Hyo-eun Bhang, Dave Ruddy, Audrey Kauffmann, Ali Farsidjani, Adnan Derti, Daniel Rakiec, Tara Naylor, Estelle Pfister, Steve Kovats, Sunkyu Kim, Kerstin Dietze, Bernd Dörken, Christian Steidl, Alexandar Tzankov, Michael Hummel, John Monahan, Michael P Morrissey, Christine Fritsch, William R Sellers, Vesselina G Cooke, Randy D Gascoyne, Georg Lenz, Frank Stegmeier
Mantle cell lymphoma (MCL) is an aggressive malignancy that is characterized by poor prognosis. Large-scale pharmacological profiling across more than 100 hematological cell line models identified a subset of MCL cell lines that are highly sensitive to the B cell receptor (BCR) signaling inhibitors ibrutinib and sotrastaurin. Sensitive MCL models exhibited chronic activation of the BCR-driven classical nuclear factor-κB (NF-κB) pathway, whereas insensitive cell lines displayed activation of the alternative NF-κB pathway...
January 2014: Nature Medicine
Marina Parry, Matthew J J Rose-Zerilli, Jane Gibson, Sarah Ennis, Renata Walewska, Jade Forster, Helen Parker, Zadie Davis, Anne Gardiner, Andrew Collins, David G Oscier, Jonathan C Strefford
The pathogenesis of splenic marginal zone lymphoma (SMZL) remains largely unknown. Recent high-throughput sequencing studies have identified recurrent mutations in key pathways, most notably NOTCH2 mutations in >25% of patients. These studies are based on small, heterogeneous discovery cohorts, and therefore only captured a fraction of the lesions present in the SMZL genome. To identify further novel pathogenic mutations within related biochemical pathways, we applied whole exome sequencing (WES) and copy number (CN) analysis to a biologically and clinically homogeneous cohort of seven SMZL patients with 7q abnormalities and IGHV1-2*04 gene usage...
2013: PloS One
Susan E Murray
NF-κB inducing kinase (NIK, MAP3K14) is a key signaling molecule in non-canonical NF-κB activation, and NIK deficient mice have been instrumental in deciphering the immunologic role of this pathway. Global ablation of NIK prevents lymph node development, impairs thymic stromal development, and drastically reduces B cells. Despite altered thymic selection, T cell numbers are near normal in NIK deficient mice. The exception is CD4(+) regulatory T cells (Tregs), which are reduced in the thymus and periphery...
2013: PloS One
Alexander M Rowe, Susan E Murray, Hans-Peter Raué, Yoshinobu Koguchi, Mark K Slifka, David C Parker
NF-κB-inducing kinase [(NIK), MAP3K14] is an essential kinase linking a subset of TNFR family members to the noncanonical NF-κB pathway. To assess the cell-intrinsic role of NIK in murine T cell function, we generated mixed bone marrow chimeras using bone marrow from NIK knockout (KO) and wild-type (WT) donor mice and infected the chimeras with lymphocytic choriomeningitis virus (LCMV). The chimeras possess an apparently normal immune system, including a mixture of NIK KO and WT T cells, and the virus was cleared normally...
October 1, 2013: Journal of Immunology: Official Journal of the American Association of Immunologists
Nicola Zanesi, Veronica Balatti, Jesse Riordan, Aaron Burch, Lara Rizzotto, Alexey Palamarchuk, Luciano Cascione, Alessandro Lagana, Adam J Dupuy, Carlo M Croce, Yuri Pekarsky
TCL1 oncogene is overexpressed in aggressive form of human chronic lymphocytic leukemia (CLL) and its dysregulation in mouse B cells causes a CD5-positive leukemia similar to the aggressive form of human CLLs. To identify oncogenes that cooperate with Tcl1, we performed genetic screen in Eμ-TCL1 mice using Sleeping Beauty transposon-mediated mutagenesis. Analysis of transposon common insertion sites identified 7 genes activated by transposon insertions. Overexpression of these genes in mouse CLL was confirmed by real time reverse transcription-polymerase chain reaction...
May 23, 2013: Blood
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