Browsing by Subject "NF-KAPPA-B"

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  • Näkki, Annu; Kouhia, Sanna T.; Saarela, Janna; Harilainen, Arsi; Tallroth, Kaj; Videman, Tapio; Battie, Michele C.; Kaprio, Jaakko; Peltonen, Leena; Kujala, Urho M. (2010)
    BACKGROUND: In search for genes predisposing to osteoarthritis (OA), several genome wide scans have provided evidence for linkage on 2q. In this study we targeted a 470 kb region on 2q11.2 presenting the locus with most evidence for linkage to severe OA of distal interphalangeal joints (DIP) in our genome wide scan families. METHODS: We genotyped 32 single nucleotide polymorphisms (SNPs) in this 470 kb region comprising six genes belonging to the interleukin 1 superfamily and monitored for association with individual SNPs and SNP haplotypes among severe familial hand OA cases (material extended from our previous linkage study; n = 134), unrelated end-stage bilateral primary knee OA cases (n = 113), and population based controls (n = 436). RESULTS: Four SNPs in the IL1R1 gene, mapping to a 125 kb LD block, provided evidence for association with hand OA in family-based and case-control analysis, the strongest association being with SNP rs2287047 (p-value = 0.0009). CONCLUSIONS: This study demonstrates an association between severe hand OA and IL1R1 gene. This gene represents a highly relevant biological candidate since it encodes protein that is a known modulator of inflammatory processes associated with joint destruction and resides within a locus providing consistent evidence for linkage to hand OA. As the observed association did not fully explain the linkage obtained in the previous study, it is plausible that also other variants in this genome region predispose to hand OA.
  • Pawlowski, Rafal; Rajakylä, Eeva; Vartiainen, Maria K.; Treisman, Richard (2010)
  • Imle, Andrea; Abraham, Libin; Tsopoulidis, Nikolaos; Hoflack, Bernard; Saksela, Kalle; Fackler, Oliver T. (2015)
    Human immunodeficiency virus type 1 (HIV-1) Nef enhances virus replication and contributes to immune evasion in vivo, but the underlying molecular mechanisms remain incompletely defined. Nef interferes with host cell actin dynamics to restrict T lymphocyte responses to chemokine stimulation and T cell receptor engagement. This relies on the assembly of a labile multiprotein complex including the host kinase PAK2 that Net usurps to phosphorylate and inactivate the actin-severing factor cofilin. Components of the exocyst complex (EXOC), an octameric protein complex involved in vesicular transport and actin remodeling, were recently reported to interact with Nef via the same molecular surface that mediates PAK2 association. Exploring the functional relevance of EXOC in Nef-PAK2 complex assembly/function, we found Nef-EXOC interactions to be specifically mediated by the PAK2 interface of Net to occur in infected human T lymphocytes, and to be conserved among lentiviral Net proteins. In turn, EXOC was dispensable for direct downstream effector functions of Nef-associated PAK2. Surprisingly, PAK2 was essential for Nef-EXOC association, which required a functional Rac1/Cdc42 binding site but not the catalytic activity of PAK2. EXOC was dispensable for Nef functions in vesicular transport but critical for inhibition of actin remodeling and proximal signaling upon T cell receptor engagement. Thus, Nef exploits PAK2 in a stepwise mechanism in which its kinase activity cooperates with an adaptor function for EXOC to inhibit host cell actin dynamics. IMPORTANCE Human immunodeficiency virus type 1 (HIV-1) Nef contributes to AIDS pathogenesis, but the underlying molecular mechanisms remain incompletely understood. An important aspect of Nef function is to facilitate virus replication by disrupting T lymphocyte actin dynamics in response to stimulation via its association with the host cell kinase PAK2. We report here that the molecular surface of Nef for PAK2 association also mediates interaction of Nef with EXOC and establish that PAK2 provides an essential adaptor function for the subsequent formation of Nef-EXOC complexes. PAK2 and EXOC specifically cooperate in the inhibition of actin dynamics and proximal signaling induced by T cell receptor engagement by Nef. These results establish EXOC as a functionally relevant Nef interaction partner, emphasize the suitability of the PAK2 interaction surface for future therapeutic interference with Nef function, and show that such strategies need to target activity-independent PAK2 functions.
  • Li, Xiaolei; Wu, Zhiqiang; An, Xiaojing; Mei, Qian; Bai, Miaomiao; Hanski, Leena; Li, Xiang; Ahola, Tero; Han, Weidong (2017)
    Acquired therapeutic resistance by tumors is a substantial impediment to reducing the morbidity and mortality that are attributable to human malignancies. The mechanisms responsible for the dramatic shift between chemosensitivity and chemoresistance in colorectal carcinoma have not been defined. Here, we report that LRP16 selectively interacts and activates double-stranded RNA-dependent kinase (PKR), and also acts as scaffolds to assist the formation of a ternary complex of PKR and IKK beta, prolonging the polymers of ADP-ribose (PAR)-dependent nuclear factor kappa B (NF-kappa B) transactivation caused by DNA-damaging agents and confers acquired chemoresistance. We also identified a small molecule, MRS2578, which strikingly abrogated the binding of LRP16 to PKR and IKK beta, converting LRP16 into a death molecule and forestalling colon tumorigenesis. Inclusion of MRS2578 with etoposide, versus each drug alone, exhibited synergistic antitumor cytotoxicity in xenografts. Our combinatorial approach introduces a strategy to enhance the efficacy of genotoxicity therapies for the treatment of tumors.
  • Turunen, Antti; Kuuliala, Antti; Mustonen, Harri; Puolakkainen, Pauli; Kylänpää, Leena; Kuuliala, Krista (2021)
    Objectives Clinical practice lacks biomarkers to predict the severity of acute pancreatitis (AP). We studied if intracellular signaling of circulating leukocytes could predict persistent organ dysfunction (OD) and secondary infections in AP. Methods A venous blood sample was taken from 174 patients with AP 72 hours or less from onset of symptoms and 31 healthy controls. Phosphorylation levels (p) of appropriately stimulated signal transducer and activator of transcription 1 (STAT1), STAT6, nuclear factor-kappa B (NF-kappa B), Akt, and nonstimulated STAT3 in monocytes, neutrophils, and lymphocytes was measured using phosphospecific flow cytometry. Results The patients showed higher pSTAT3 and lower pSTAT1, pSTAT6, pNF-kappa B, and pAkt than healthy controls. pSTAT3 in all leukocyte subtypes studied increased, and pSTAT1 in monocytes and T cells decreased in an AP severity-wise manner. In patients without OD at sampling, high pSTAT3 in monocytes and T lymphocytes were associated with development of persistent OD. In patients with OD, low interleukin-4-stimulated pSTAT6 in monocytes and neutrophils and Escherichia coli-stimulated pNF-kappa B in neutrophils predicted OD persistence. High pSTAT3 in monocytes, CD8(+) T cells, and neutrophils; low pSTAT1 in monocytes and T cells; and low pNF-kappa B in lymphocytes predicted secondary infections. Conclusions Leukocyte STAT3, STAT1, STAT6, and NF-kappa Beta phosphorylations are potential predictors of AP severity.
  • Strippoli, Raffaele; Loureiro, Jesus; Moreno, Vanessa; Benedicto, Ignacio; Perez Lozano, Maria Luisa; Barreiro, Olga; Pellinen, Teijo; Minguet, Susana; Foronda, Miguel; Teresa Osteso, Maria; Calvo, Enrique; Vazquez, Jesus; Lopez Cabrera, Manuel; Angel del Pozo, Miguel (2015)
  • Lorenzini, Tiziana; Fliegauf, Manfred; Klammer, Nils; Frede, Natalie; Proietti, Michele; Bulashevska, Alla; Camacho-Ordonez, Nadezhda; Varjosalo, Markku; Kinnunen, Matias; de Vries, Esther; van der Meer, Jos W.M.; Ameratunga, Rohan; Roifman, Chaim M.; Schejter, Yael D.; Kobbe, Robin; Hautala, Timo; Atschekzei, Faranaz; Schmidt, Reinhold E.; Schröder, Claudia; Stepensky, Polina; Shadur, Bella; Pedroza, Luis A.; van der Flier, Michiel; Martínez-Gallo, Mónica; Gonzalez-Granado, Luis Ignacio; Allende, Luis M.; Shcherbina, Anna; Kuzmenko, Natalia; Zakharova, Victoria; Neves, João Farela; Svec, Peter; Fischer, Ute; Ip, Winnie; Bartsch, Oliver; Barış, Safa; Klein, Christoph; Geha, Raif; Chou, Janet; Alosaimi, Mohammed; Weintraub, Lauren; Boztug, Kaan; Hirschmugl, Tatjana; Dos Santos Vilela, Maria Marluce; Holzinger, Dirk; Seidl, Maximilian; Lougaris, Vassilios; Plebani, Alessandro; Alsina, Laia; Piquer-Gibert, Monica; Deyà-Martínez, Angela; Slade, Charlotte A.; Aghamohammadi, Asghar; Abolhassani, Hassan; Hammarström, Lennart; Kuismin, Outi; Helminen, Merja; Allen, Hana Lango; Thaventhiran, James E.; Freeman, Alexandra F.; Cook, Matthew; Bakhtiar, Shahrzad; Christiansen, Mette; Cunningham-Rundles, Charlotte; Patel, Niraj C.; Rae, William; Niehues, Tim; Brauer, Nina; Syrjänen, Jaana; Seppänen, Mikko R.J.; Burns, Siobhan O.; Tuijnenburg, Paul; Kuijpers, Taco W.; Warnatz, Klaus; Grimbacher, Bodo (2020)
    Background: An increasing number of NFKB1 variants are being identified in patients with heterogeneous immunologic phenotypes. Objective: To characterize the clinical and cellular phenotype as well as the management of patients with heterozygous NFKB1 mutations. Methods: In a worldwide collaborative effort, we evaluated 231 individuals harboring 105 distinct heterozygous NFKB1 variants. To provide evidence for pathogenicity, each variant was assessed in silico; in addition, 32 variants were assessed by functional in vitro testing of nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-kappa B) signaling. Results: We classified 56 of the 105 distinct NFKB1 variants in 157 individuals from 68 unrelated families as pathogenic. Incomplete clinical penetrance (70%) and age-dependent severity of NFKB1-related phenotypes were observed. The phenotype included hypogammaglobulinemia (88.9%), reduced switched memory B cells (60.3%), and respiratory (83%) and gastrointestinal (28.6%) infections, thus characterizing the disorder as primary immunodeficiency. However, the high frequency of autoimmunity (57.4%), lymphoproliferation (52.4%), noninfectious enteropathy (23.1%), opportunistic infections (15.7%), autoinflammation (29.6%), and malignancy (16.8%) identified NF-kappa B1-related disease as an inborn error of immunity with immune dysregulation, rather than a mere primary immunodeficiency. Current treatment includes immunoglobulin replacement and immunosuppressive agents. Conclusions: We present a comprehensive clinical overview of the NF-kappa B1-related phenotype, which includes immunodeficiency, autoimmunity, autoinflammation, and cancer. Because of its multisystem involvement, clinicians from each and every medical discipline need to be made aware of this autosomal-dominant disease. Hematopoietic stem cell transplantation and NF-kappa B1 pathway-targeted therapeutic strategies should be considered in the future.
  • Galluzzi, Lorenzo; Vitale, Ilio; Warren, Sarah; Adjemian, Sandy; Agostinis, Patrizia; Martinez, Aitziber Buqué; Chan, Timothy A; Coukos, George; Demaria, Sandra; Deutsch, Eric; Draganov, Dobrin; Edelson, Richard L; Formenti, Silvia C; Fucikova, Jitka; Gabriele, Lucia; Gaipl, Udo S; Gameiro, Sofia R; Garg, Abhishek D; Golden, Encouse; Han, Jian; Harrington, Kevin J; Hemminki, Akseli; Hodge, James W; Hossain, Dewan Md Sakib; Illidge, Tim; Karin, Michael; Kaufman, Howard L; Kepp, Oliver; Kroemer, Guido; Lasarte, Juan Jose; Loi, Sherene; Lotze, Michael T; Manic, Gwenola; Merghoub, Taha; Melcher, Alan A; Mossman, Karen L; Prosper, Felipe; Rekdal, Øystein; Rescigno, Maria; Riganti, Chiara; Sistigu, Antonella; Smyth, Mark J; Spisek, Radek; Stagg, John; Strauss, Bryan E; Tang, Daolin; Tatsuno, Kazuki; van Gool, Stefaan W; Vandenabeele, Peter; Yamazaki, Takahiro; Zamarin, Dmitriy; Zitvogel, Laurence; Cesano, Alessandra; Marincola, Francesco M (2020)
    Cells succumbing to stress via regulated cell death (RCD) can initiate an adaptive immune response associated with immunological memory, provided they display sufficient antigenicity and adjuvanticity. Moreover, multiple intracellular and microenvironmental features determine the propensity of RCD to drive adaptive immunity. Here, we provide an updated operational definition of immunogenic cell death (ICD), discuss the key factors that dictate the ability of dying cells to drive an adaptive immune response, summarize experimental assays that are currently available for the assessment of ICD in vitro and in vivo, and formulate guidelines for their interpretation.
  • Boije af Gennäs, Gustav; Talman, Virpi; Yli-Kauhaluoma, Jari; Tuominen, Raimo K.; Ekokoski, Elina (2011)
    The second messenger diacylglycerol (DAG) plays a central role in the signal transduction of G-protein coupled receptors and receptor tyrosine kinases by binding to C1 domain of effector proteins. C1 domain was first identified in protein kinase C (PKC) which comprises a family of ten isoforms that play roles in diverse cellular processes such as proliferation, apoptosis and differentiation. Aberrant signaling through PKC isoforms and other C1 domain-containing proteins has been implicated in several pathological disorders. Drug discovery concerning C1 domains has exploited both natural products and rationally designed compounds. Currently, molecules from several classes of C1 domain-binding compounds are in clinical trials; however, still more have the potential to enter the drug development pipeline. This review gives a summary of the recent developments in C1 domain-binding compounds.
  • Kaustio, Meri; Haapaniemi, Emma; Göös, Helka; Hautala, Timo; Park, Giljun; Syrjänen, Jaana; Einarsdottir, Elisabet; Sahu, Biswajyoti; Kilpinen, Sanna; Rounioja, Samuli; Fogarty, Christopher L.; Glumoff, Virpi; Kulmala, Petri; Katayama, Shintaro; Tamene, Fitsum; Trotta, Luca; Morgunova, Ekaterina; Krjutskov, Kaarel; Nurmi, Katariina; Eklund, Kari; Lagerstedt, Anssi; Helminen, Merja; Martelius, Timi; Mustjoki, Satu; Taipale, Jussi; Saarela, Janna; Kere, Juha; Varjosalo, Markku; Seppanen, Mikko (2017)
    Background: The nuclear factor kappa light-chain enhancer of activated B cells (NF-kappa B) signaling pathway is a key regulator of immune responses. Accordingly, mutations in several NF-kappa B pathway genes cause immunodeficiency. Objective: We sought to identify the cause of disease in 3 unrelated Finnish kindreds with variable symptoms of immunodeficiency and autoinflammation. Methods: We applied genetic linkage analysis and next-generation sequencing and functional analyses of NFKB1 and its mutated alleles. Results: In all affected subjects we detected novel heterozygous variants in NFKB1, encoding for p50/p105. Symptoms in variant carriers differed depending on the mutation. Patients harboring a p.I553M variant presented with antibody deficiency, infection susceptibility, and multiorgan autoimmunity. Patients with a p.H67R substitution had antibody deficiency and experienced autoinflammatory episodes, including aphthae, gastrointestinal disease, febrile attacks, and small-vessel vasculitis characteristic of Behc, et disease. Patients with a p.R157X stop-gain experienced hyperinflammatory responses to surgery and showed enhanced inflammasome activation. In functional analyses the p.R157X variant caused proteasome-dependent degradation of both the truncated and wild-type proteins, leading to a dramatic loss of p50/p105. The p.H67R variant reduced nuclear entry of p50 and showed decreased transcriptional activity in luciferase reporter assays. The p.I553M mutation in turn showed no change in p50 function but exhibited reduced p105 phosphorylation and stability. Affinity purification mass spectrometry also demonstrated that both missense variants led to altered protein-protein interactions. Conclusion: Our findings broaden the scope of phenotypes caused by mutations in NFKB1 and suggest that a subset of autoinflammatory diseases, such as Behcet disease, can be caused by rare monogenic variants in genes of the NF-kappa B pathway.
  • Qin, Nanbing; Bayat, Ali-Reza; Trevisi, Erminio; Minuti, Andrea; Kairenius, Piia; Viitala, Sirja; Mutikainen, Mervi; Leskinen, Heidi; Elo, Kari Tapani; Kokkonen, Tuomo Juhani; Vilkki, Johanna (2018)
    To investigate the metabolic (.11, !I:2.es in the adipose tissue (AT) of dairy cows under milk fat depression (MFD), 30 cows were randomly allocated to a control diet, a conjugated linoleic acid (CLA)-supplemented diet, or a high-starch diet supplemented with a mixture of sunflower and fish oil (2:1; as HSO diet) from 1 to 112 d in milk. Performance of animals, milk yield, milk composition, energy balance, and blood metabolites were measured during lactation. Quantitative PCR analyses were conducted on the AT samples collected at wk 3 and 15 of lactation. The CLA and HSO diets considerably depressed milk fat yield and milk fat content at both wk 3 and 15 in the absence of significant changes in milk protein and lactose contents. In addition, the HSO diet lowered milk yield at wk 15 and decreased dry matter intake of cows from wk 3 to 15. Compared with the control, both CLA and HSO groups showed reduced body weight loss, improved energy balance, and decreased plasma concentrations of nonesterified fatty acids and beta-hydroxybutyrate at early lactation. The gene expression analyses reflected suppressed lipolysis in AT of the CLA and HSO groups compared with the control at wk 3, as suggested by the downregulation of hormone-sensitive lipase and fatty acid binding protein 4 and the upregulation of perilipin 2. In addition, the HSO diet promoted lipogenesis in AT at wk 15 through the upregulation of 1-acylglycerol-3-phosphate O-acyltransferase 2, mitochondria' glycerol-3-phosphate acyltransferase, perilipin 2, and peroxisome proliferator-activated receptor gamma. The CLA diet likely regulated insulin sensitivity in AT as it upregulated the transcription of various genes involved in insulin signaling, inflammatory responses, and ceramide metabolism, including protein kinase B2, nuclear factor kappa B1, toll-like receptor 4, caveolin 1, serine palmitoyltransferase long chain base subunit 1, and N-acylsphingosine amidohydrolase 1. In contrast, the HSO diet resulted in little or no change in the pathways relevant to insulin sensitivity. In conclusion, the CLA and HSO diets induced a shift in energy partitioning toward AT instead of mammary gland during lactation through the regulation of different pathways.
  • Ahtiainen, Laura; Uski, Isa; Thesleff, Irma; Mikkola, Marja L. (2016)
    During organogenesis, cell fate specification and patterning are regulated by signaling centers, specialized clusters of morphogen-expressing cells. In many organs, initiation of development is marked by bud formation, but the cellular mechanisms involved are ill defined. Here, we use the mouse incisor tooth as a model to study budding morphogenesis. We show that a group of nonproliferative epithelial cells emerges in the early tooth primordium and identify these cells as a signaling center. Confocal live imaging of tissue explants revealed that although these cells reorganize dynamically, they do not reenter the cell cycle or contribute to the growing tooth bud. Instead, budding is driven by proliferation of the neighboring cells. We demonstrate that the activity of the ectodysplasin/Edar/nuclear factor kappa B pathway is restricted to the signaling center, and its inactivation leads to fewer quiescent cells and a smaller bud. These data functionally link the signaling center size to organ size and imply that the early signaling center is a prerequisite for budding morphogenesis.
  • Danilova, Tatiana; Lindahl, Maria (2018)
    Mesencephalic astrocyte-derived neurotrophic factor (MANF) was originally identified as a secreted trophic factor for dopamine neurons in vitro. It protects and restores damaged cells in rodent models of Parkinson's disease, brain and heart ischemia, spinocerebellar ataxia and retina in vivo. However, its exact mechanism of action is not known. MANF is widely expressed in most human and mouse organs with high levels in secretory tissues. Intracellularly, MANF localizes to the endoplasmic reticulum (ER) and ER stress increases it's expression in cells and tissues. Furthermore, increased MANF levels has been detected in the sera of young children with newly diagnosed Type 1 (T1D) diabetes and Type 2 (T2D) diabetic patients. ER stress is caused by the accumulation of misfolded and aggregated proteins in the ER. It activates a cellular defense mechanism, the unfolded protein response (UPR), a signaling cascade trying to restore ER homeostasis. However, if prolonged, unresolved ER stress leads to apoptosis. Unresolved ER stress contributes to the progressive death of pancreatic insulin-producing beta cells in both T1D and T2D. Diabetes mellitus is characterized by hyperglycemia, caused by the inability of the beta cells to maintain sufficient levels of circulating insulin. The current medications, insulin and antidiabetic drugs, alleviate diabetic symptoms but cannot reconstitute physiological insulin secretion which increases the risk of devastating vascular complications of the disease. Thus, one of the main strategies in improving current diabetes therapy is to define and validate novel approaches to protect beta cells from stress as well as activate their regeneration. Embryonic deletion of the Manf gene in mice led to gradual postnatal development of insulin-deficient diabetes caused by reduced beta cell proliferation and increased beta cell death due to increased and sustained ER stress. In vitro, recombinant MANF partly protected mouse and human beta cells from ER stress-induced beta cell death and potentiated mouse and human beta cell proliferation. Importantly, in vivo overexpression of MANF in the pancreas of T1D mice led to increased beta cell proliferation and decreased beta cell death, suggesting that MANF could be a new therapeutic candidate for beta cell protection and regeneration in diabetes.
  • Nurmi, Katariina; Virkanen, Juhani; Rajamaki, Kristiina; Niemi, Katri; Kovanen, Petri T.; Eklund, Kari K. (2013)
  • Niemela, Tytti Maaria; Tulamo, Riitta-Mari; Uriel Carmona, Jorge; Lopez, Catalina (2019)
    Background: Inflammatory and degenerative activity inside the joint can be studied in vivo by analysis of synovial fluid biomarkers. In addition to pro-inflammatory mediators, several anabolic and anti-inflammatory substances are produced during the disease process. They counteract the catabolic effects of the pro-inflammatory cytokines and thus diminish the cartilage damage. The response of synovial fluid biomarkers after intra-articular hyaluronan injection, alone or in combination with other substances, has been examined only in a few equine studies. The effects of hyaluronan on some pro-inflammatory mediators, such as prostaglandin E-2, have been documented but especially the effects on synovial fluid anti-inflammatory mediators are less studied. In animal models hyaluronan has been demonstrated to reduce pain via protecting nociceptive nerve endings and by blocking pain receptor channels. However, the results obtained for pain-relief of human osteoarthritis are contradictory. The aim of the study was to measure the synovial fluid IL-1ra, PDGF-BB, TGF-beta(1) and TNF-alpha concentrations before and after surgically induced cartilage defect, and following intra-articular hyaluronan injection in horses. Eight Standardbred horses underwent bilateral arthroscopic surgeries of their intercarpal joints under general anaesthesia, and cartilage defect was created on the dorsal edge of the third carpal bone of one randomly selected intercarpal joint of each horse. Five days post-surgery, one randomly selected intercarpal joint was injected intra-articular with 3 mL HA (20 mg/mL). Results: Operation type had no significant effect on the synovial fluid IL-1ra, PDGF-BB, TGF-beta(1) and TNF-alpha concentrations but compared with baseline, synovial fluid IL-1ra and TNF-alpha concentrations increased. Intra-articular hyaluronan had no significant effect on the biomarker concentrations but a trend of mild improvement in the clinical signs of intra-articular inflammation was seen. Conclusions: Creation of the cartilage defect and sham-operation lead to an increase of synovial fluid IL-1ra and TNF-alpha concentrations but changes in concentrations of anabolic growth factors TGF-beta(1) and PDGF-BB could not be documented 5 days after the arthroscopy. Intra-articular hyaluronan was well tolerated. Further research is needed to document possible treatment effects of intra-articular hyaluronan on the synovial fluid biomarkers of inflammation and cartilage metabolism.
  • Parmar, Amarjit; Greco, Dario; Venalainen, Jarkko; Gentile, Massimiliano; Dukes, Emma; Saavalainen, Päivi (2013)
  • Hällfors, Jenni; Palviainen, Teemu; Surakka, Ida; Gupta, Richa; Buchwald, Jadwiga; Raevuori, Anu; Ripatti, Samuli; Korhonen, Tellervo; Jousilahti, Pekka; Madden, Pamela A. F.; Kaprio, Jaakko; Loukola, Anu (2019)
    The heritability of nicotine dependence based on family studies is substantial. Nevertheless, knowledge of the underlying genetic architecture remains meager. Our aim was to identify novel genetic variants responsible for interindividual differences in smoking behavior. We performed a genome-wide association study on 1715 ever smokers ascertained from the population-based Finnish Twin Cohort enriched for heavy smoking. Data imputation used the 1000 Genomes Phase I reference panel together with a whole genome sequence-based Finnish reference panel. We analyzed three measures of nicotine addiction-smoking quantity, nicotine dependence and nicotine withdrawal. We annotated all genome-wide significant SNPs for their functional potential. First, we detected genome-wide significant association on 16p12 with smoking quantity (P = 8.5 x 10(-9)), near CLEC19A. The lead-SNP stands 22 kb from a binding site for NF-kappa B transcription factors, which play a role in the neurotrophin signaling pathway. However, the signal was not replicated in an independent Finnish population-based sample, FINRISK (n = 6763). Second, nicotine withdrawal showed association on 2q21 in an intron of TMEM163 (P = 2.1 x 10(-9)), and on 11p15 (P = 6.6 x 10(-8)) in an intron of AP2A2, and P = 4.2 x 10(-7) for a missense variant in MUC6, both involved in the neurotrophin signaling pathway). Third, association was detected on 3p22.3 for maximum number of cigarettes smoked per day (P = 3.1 x 10(-8)) near STAC. Associating CLEC19A and TMEM163 SNPs were annotated to influence gene expression or methylation. The neurotrophin signaling pathway has previously been associated with smoking behavior. Our findings further support the role in nicotine addiction.
  • Peltonen, Karita; Colis, Laureen; Liu, Hester; Jaamaa, Sari; Moore, Henna M.; Enback, Juulia; Laakkonen, Pirjo; Vaahtokari, Anne; Jones, Richard J.; af Hallstrom, Taija M.; Laiho, Marikki (2010)
  • Peuhu, Emilia; Salomaa, Siiri I.; De Franceschi, Nicola; Potter, Christopher S.; Sundberg, John P.; Pouwels, Jeroen (2017)
    SHARPIN (Shank-Associated RH Domain-Interacting Protein) is a component of the linear ubiquitin chain assembly complex (LUBAC), which enhances TNF-induced NF-kappa B activity. SHARPIN-deficient (Sharpin(cpdm/cpdm)) mice display multi-organ inflammation and chronic proliferative dermatitis (cpdm) due to TNF-induced keratinocyte apoptosis. In cells, SHARPIN also inhibits integrins independently of LUBAC, but it has remained enigmatic whether elevated integrin activity levels in the dermis of Sharpin(cpdm/cpdm) mice is due to increased integrin activity or is secondary to inflammation. In addition, the functional contribution of increased integrin activation to the Sharpin(cpdm/cpdm) phenotype has not been investigated. Here, we find increased integrin activity in keratinocytes from Tnfr1(-/-) Sharpin(cpdm/cpdm) double knockout mice, which do not display chronic inflammation or proliferative dermatitis, thus suggesting that SHARPIN indeed acts as an integrin inhibitor in vivo. In addition, we present evidence for a functional contribution of integrin activity to the Sharpin(cpdm/cpdm) skin phenotype. Treatment with an integrin beta 1 function blocking antibody reduced epidermal hyperproliferation and epidermal thickness in Sharpin(cpdm/cpdm) mice. Our data indicate that, while TNF-induced cell death triggers the chronic inflammation and proliferative dermatitis, absence of SHARPIN-dependent integrin inhibition exacerbates the epidermal hyperproliferation in Sharpin(cpdm/cpdm) mice.
  • Danilova, Tatiana; Belevich, Ilya; Li, Huini; Palm, Erik; Jokitalo, Eija; Otonkoski, Timo; Lindahl, Maria (2019)
    Global lack of mesencephalic astrocyte-derived neurotropic factor (MANF) leads to progressive postnatal loss of β-cells mass and insulin-dependent diabetes in mice. Similarly to Manf -/- mice, embryonic ablation of MANF specifically from the pancreas results in diabetes. In this study, we assessed the importance of MANF for the postnatal expansion of the pancreatic β-cell mass and for adult β-cell maintenance in mice. Detailed analysis of Pdx-1Cre +/- ::Manf fl/fl mice revealed mosaic MANF expression in postnatal pancreases and significant correlation between the number of MANF-positive β-cells and β-cell mass in individual mice. In vitro, recombinant MANF induced β-cell proliferation in islets from aged mice and protected from hyperglycemia-induced endoplasmic reticulum (ER) stress. Consequently, excision of MANF from β-cells of adult MIP-1Cre ERT ::Manf fl/fl mice resulted in reduced β-cell mass and diabetes caused largely by β-cell ER stress and apoptosis, possibly accompanied by β-cell de-differentiation and reduced rates of β-cell proliferation. Thus, MANF expression in adult mouse β-cells is needed for their maintenance in vivo. We also revealed a mechanistic link between ER stress, and inflammatory signaling pathways leading to β-cell death in the absence of MANF. Hence, MANF might be a potential target for regenerative therapy in diabetes.