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  • 1.
    Aguilo, Francesca
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences. Umea Univ, WCMM, SE-90185 Umea, Sweden; Icahn Sch Med Mt Sinai, Dept Pharmacol Sci, New York, NY 10029 USA.
    Walsh, Martin J.
    The N-6-Methyladenosine RNA modification in pluripotency and reprogramming2017In: Current Opinion in Genetics and Development, ISSN 0959-437X, E-ISSN 1879-0380, Vol. 46, p. 77-82Article, review/survey (Refereed)
    Abstract [en]

    Chemical modifications of RNA provide a direct and rapid way to manipulate the existing transcriptome, allowing rapid responses to the changing environment further enriching the regulatory capacity of RNA. N-6-Methyladenosine(m(6)A) has been identified as the most abundant internal modification of messenger RNA in eukaryotes, linking external stimuli to an intricate network of transcriptional, post-transcriptional and translational processes. M(6)A modification affects a broad spectrum of cellular functions, including maintenance of the pluripotency of embryonic stem cells (ESCs) and the reprogramming of somatic cells into induced pluripotent stem cells (iPSCs). In this review, we summarize the most recent findings on m(6)A modification with special focus on the different studies describing how m(6)A is implicated in ESC self-renewal, cell fate specification and iPSC generation.

  • 2.
    Al-Furoukh, Natalie
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Ianni, Alessandro
    Nolte, Hendrik
    Hölper, Soraya
    Krüger, Marcus
    Wanrooij, Sjoerd
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Braun, Thomas
    ClpX stimulates the mitochondrial unfolded protein response (UPRmt) in mammalian cells2015In: Biochimica et Biophysica Acta. Molecular Cell Research, ISSN 0167-4889, E-ISSN 1879-2596, Vol. 1853, no 10, p. 2580-2591Article in journal (Refereed)
    Abstract [en]

    Proteostasis is crucial for life and maintained by cellular chaperones and proteases. One major mitochondrial protease is the ClpXP complex, which is comprised of a catalytic ClpX subunit and a proteolytic ClpP subunit. Based on two separate observations, we hypothesized that ClpX may play a leading role in the cellular function of ClpXP. Therefore, we analyzed the effect of ClpX overexpression on a myoblast proteome by quantitative proteomics. ClpX overexpression results in the upregulation of markers of the mitochondria( proteostasis pathway, known as the "mitochondrial unfolded protein response" (UPRmt). Although this pathway is described in detail in Caenorhabditis elegans, it is not clear whether it is conserved in mammals. Therefore, we compared features of the classical nematode UPRmt with our mammalian ClpX-triggered UPRmt dataset. We show that they share the same retrograde mitochondria-to-nucleus signaling pathway that involves the key UPRmt transcription factor CHOP (also known as Ddit3, CEBPZ or GADD153). In conclusion, our data confirm the existence of a mammalian UPRmt that has great similarity to the C elegans pathway. Furthermore, our results illustrate that ClpX overexpression is a good and simple model to study the underlying mechanisms of the UPRmt in mammalian cells.

  • 3.
    Bagge, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    In situ hybridization studies favouring the occurrence of a local production of BDNF in the human Achilles tendon2012In: Histology and Histopathology, ISSN 0213-3911, E-ISSN 1699-5848, Vol. 27, no 9, p. 1239-1246Article in journal (Refereed)
    Abstract [en]

    Brain derived neurotrophic factor (BDNF) is a multipotent neurotrophin known for its growth-influencing and apoptosis-modulating functions, as well as for its function to interact with neurotransmitters/neuromodulators. BDNF is reported to be mainly produced in the brain. BDNF can be absorbed into peripheral tissue from the blood stream. Expression of this neurotrophin at the protein level, as well as of the neurotrophin receptor p75, has been previously shown for the principal cells (tenocytes) of the Achilles tendon. However, there is no proof at the mRNA level that BDNF is produced by the tenocytes. As the Achilles tendon tenocytes show "neuronal-like" characteristics, in the form of expressions favouring synthesis of several neuromodulators/neurotransmitters, and as BDNF especially is produced in neurons, it is of interest to confirm this. In the present study, therefore, in situ hybridization for demonstration of BDNF mRNA was performed on biopsies from Achilles tendons of patients with tendinosis and pain-free non-tendinosis individuals. The results showed that the tenocytes of both groups exhibited BDNF mRNA reactions. These observations indeed favour the idea that BDNF is produced by tenocytes in the human Achilles tendon, why Achilles tendon tissue is a tissue in which BDNF can be locally produced. BDNF can have modulatory functions for the tenocytes, including apoptosis-modifying effects via actions on the p75 receptor and interactive effects with neurotransmitters/neuromodulators produced in these cells. This possibility should be further studied for Achilles tendon tissue.

  • 4. Bagnato, Paola
    et al.
    Castagnino, Alessia
    Cortese, Katia
    Bono, Maria
    Grasso, Silvia
    Bellese, Grazia
    Daniele, Tiziana
    Lundmark, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Defilippi, Paola
    Castagnola, Patrizio
    Tacchetti, Carlo
    Cooperative but distinct early co-signaling events originate from ERBB2 and ERBB1 receptors upon trastuzumab treatment in breast cancer cells2017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 36, p. 60109-60122Article in journal (Refereed)
    Abstract [en]

    ERBB2 receptor belongs to the ERBB tyrosine kinase receptor family. At variance to the other family members, ERBB2 is a constitutively active orphan receptor. Upon ligand binding and activation, ERBB receptors form homo-or hetero-dimers with the other family members, including ERBB2, promoting an intracellular signaling cascade. ERBB2 is the preferred dimerization partner and ERBB2 heterodimers signaling is stronger and longer acting compared to heterodimers between other ERBB members. The specific contribution of ERBB2 in heterodimer signaling is still undefined. Here we report the formation of circular dorsal ruffles (CDRs) upon treatment of the ERBB2-overexpressing breast cancer cell lines SK-BR-3 and ZR751 with Trastuzumab, a therapeutic humanized monoclonal antibody directed against ERBB2. We found that in SK-BR-3 cells Trastuzumab leads to surface redistribution of ERBB2 and ERBB1 in CDRs, and that the ERBB2-dependent ERK1/2 phosphorylation and ERBB1 expression are both required for CDR formation. In particular, in these cells CDR formation requires activation of both the protein regulator of actin polymerization N-WASP, mediated by ERK1/2, and of the actin depolymerizing protein cofilin, mediated by ERBB1. Furthermore, we suggest that this latter event may be inhibited by the negative cell motility regulator p140Cap, as we found that p140Cap overexpression led to cofilin deactivation and inhibition of CDR formation. In conclusion, here we show for the first time an ERBB2-specific signaling contribution to an ERBB2/ERBB1 heterodimer, in the activation of a complex biological process such as the formation of CDRs.

  • 5.
    Baranov, Vladimir
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Nagaeva, Olga
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Hammarström, Sten
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Lipids are a constitutive component of cytolytic granules.2000In: Histochemistry and Cell Biology, ISSN 0948-6143, E-ISSN 1432-119X, Vol. 114, no 2, p. 167-71Article in journal (Refereed)
    Abstract [en]

    Cytolytic granules are specific organelles of activated cytotoxic lymphocytes mediating storage and regulated excretion of lytic molecules for killing of target cells. A variety of the other granule components may also participate in granule-mediated cytotoxicity. In this study, the subcellular localization of lipids in the granules of human decidual CD56+ natural killer-like cells was determined by staining with malachite green aldehyde and imidazole-buffered osmium tetroxide. Lipids were shown, for the first time, to be a constitutive component of cytolytic granules. Lipids formed an additional structural microdomain, located between the granule-limiting membrane and the granule core. Images of the granules on serial sections suggested that intragranular lipids wrap the core. We speculate that granule lipids participate in packing of lytic molecules inside the granules, in autocrine signaling ending granule secretion, and in the killing process.

  • 6.
    Beier, Frank
    et al.
    Institut für Experimentelle Medizin, Universität Erlangen-Nürnberg, Erlangen, Germany; Department of Medical Biochemistry, University of Calgary, Calgary, Canada.
    Vornehm, Silvia
    Institut für Experimentelle Medizin, Universität Erlangen-Nürnberg, Erlangen, Germany.
    Pöschl, Ernst
    Institut für Experimentelle Medizin, Universität Erlangen-Nürnberg, Erlangen, Germany.
    von der Mark, Klaus
    Institut für Experimentelle Medizin, Universität Erlangen-Nürnberg, Erlangen, Germany.
    Lammi, Mikko
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Localization of silencer and enhancer elements in the human type X collagen gene.1997In: Journal of Cellular Biochemistry, ISSN 0730-2312, E-ISSN 1097-4644, Vol. 66, no 2, p. 210-218, article id 9213222Article in journal (Refereed)
    Abstract [en]

    Collagen type X is a short, network-forming collagen expressed temporally and spatially tightly controlled in hypertrophic chondrocytes during endochondral ossification. Studies on chicken chondrocytes indicate that the regulation of type X collagen gene expression is regulated at the transcriptional level. In this study, we have analyzed the regulatory elements of the human type X collagen (Col10a1) by reporter gene constructs and transient transfections in chondrogenic and nonchondrogenic cells. Four different promoter fragments covering up to 2,864 bp of 5'-flanking sequences, either including or lacking the first intron, were linked to luciferase reporter gene and transfected into 3T3 fibroblasts, HT1080 fibrosarcoma cells, prehypertrophic chondrocytes from the resting zone, hypertrophic chondrocytes, and chondrogenic cell lines. The results indicated the presence of three regulatory elements in the human Col10a1 gene besides the proximal promoter. First, a negative regulatory element located between 2.4 and 2.8 kb upstream of the transcription initiation site was active in all nonchondrogenic cells and in prehypertrophic chondrocytes. Second, a positive, but also non-tissue-specific positive regulatory element was present in the first intron. Third, a cell-type-specific enhancer element active only in hypertrophic chondrocytes was located between -2.4 and -0.9 kb confirming a previous report by Thomas et al. [(1995): Gene 160:291-296]. The enhancing effect, however, was observed only when calcium phosphate was either used for transfection or included in the culture medium after lipofection. These findings demonstrate that the rigid control of human Col10a1 gene expression is achieved by both positive and negative regulatory elements in the gene and provide the basis for the identification of factors binding to those elements.

  • 7.
    Benedict, Catherine
    et al.
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Skinner, J. S.
    Meng, R.
    Chang, Y.
    Bhalerao, R.
    Finn, C.
    Chen, T. H. H.
    Umeå University, Faculty of Science and Technology.
    Hurry, Vaughan
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    The Role of the CBF-dependent Signalling Pathway in Woody Perennials2006In: Cold Hardiness in Plants: Molecular Genetics, Cell Biology and Physiology / [ed] T Chen, M Uemura, S Fujikawa, Wallingford: CABI Publishing, 2006, p. 167-180Chapter in book (Other academic)
  • 8. Best, Myron G.
    et al.
    Sol, Nik
    Kooi, Irsan
    Tannous, Jihane
    Westerman, Bart A.
    Rustenburg, Francois
    Schellen, Pepijn
    Verschueren, Heleen
    Post, Edward
    Koster, Jan
    Ylstra, Bauke
    Ameziane, Najim
    Dorsman, Josephine
    Smit, Egbert F.
    Verheul, Henk M.
    Noske, David P.
    Reijneveld, Jaap C.
    Nilsson, R. Jonas A.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Tannous, Bakhos A.
    Wesseling, Pieter
    Wurdinger, Thomas
    RNA-Seq of Tumor-Educated Platelets Enables Blood-Based Pan-Cancer, Multiclass, and Molecular Pathway Cancer Diagnostics2015In: Cancer Cell, ISSN 1535-6108, E-ISSN 1878-3686, Vol. 28, no 5, p. 666-676Article in journal (Refereed)
    Abstract [en]

    Tumor-educated blood platelets (TEPs) are implicated as central players in the systemic and local responses to tumor growth, thereby altering their RNA profile. We determined the diagnostic potential of TEPs by mRNA sequencing of 283 platelet samples. We distinguished 228 patients with localized and metastasized tumors from 55 healthy individuals with 96% accuracy. Across six different tumor types, the location of the primary tumor was correctly identified with 71% accuracy. Also, MET or HER2-positive, and mutant KRAS, EGFR, or PIK3CA tumors were accurately distinguished using surrogate TEP mRNA profiles. Our results indicate that blood platelets provide a valuable platform for pan-cancer, multiclass cancer, and companion diagnostics, possibly enabling clinical advances in blood-based "liquid biopsies".

  • 9. Bhalerao, Rishikesh P
    et al.
    Eklöf, Jan
    Umeå Plant Science Centre, Department of Forest Genetics and Plant Physiology, The Swedish University of Agricultural Sciences, SE-901 83, Umeå, Sweden.
    Ljung, Karin
    Marchant, Alan
    Bennett, Malcolm
    Sandberg, Göran
    Shoot-derived auxin is essential for early lateral root emergence in Arabidopsis seedlings2002In: The Plant Journal, ISSN 0960-7412, E-ISSN 1365-313X, Vol. 29, no 3, p. 325-332Article in journal (Refereed)
    Abstract [en]

    Lateral root formation is profoundly affected by auxins. Here we present data which indicate that light influences the formation of indole-3-acetic acid (IAA) in germinating Arabidopsis seedlings. IAA transported from the developing leaves to the root system is detectable as a short-lived pulse in the roots and is required for the emergence of the lateral root primordia (LRP) during early seedling development. LRP emergence is inhibited by the removal of apical tissues prior to detection of the IAA pulse in the root, but this treatment has minimal effects on LRP initiation. Our results identify the first developing true leaves as the most likely source for the IAA required for the first emergence of the LRP, as removal of cotyledons has only a minor effect on LRP emergence in contrast to removal of the leaves. A basipetal IAA concentration gradient with high levels of IAA in the root tip appears to control LRP initiation, in contrast to their emergence. A significant increase in the ability of the root system to synthesize IAA is observed 10 days after germination, and this in turn is reflected in the reduced dependence of the lateral root emergence on aerial tissue-derived auxin at this stage. We propose a model for lateral root formation during early seedling development that can be divided into two phases: (i) an LRP initiation phase dependent on a root tip-localized IAA source, and (ii) an LRP emergence phase dependent on leaf-derived IAA up to 10 days after germination.

  • 10. Bieling, Peter
    et al.
    Laan, Liedewij
    Schek, Henry
    Munteanu, E Laura
    Sandblad, Linda
    European Mol Biol Lab, Cell Biol & Biophys Unit, D-69117 Heidelberg, Germany .
    Dogterom, Marileen
    Brunner, Damian
    Surrey, Thomas
    Reconstitution of a microtubule plus-end tracking system in vitro2007In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 450, no 7172, p. 1100-1105Article in journal (Refereed)
    Abstract [en]

    The microtubule cytoskeleton is essential to cell morphogenesis. Growing microtubule plus ends have emerged as dynamic regulatory sites in which specialized proteins, called plus-end-binding proteins (+TIPs), bind and regulate the proper functioning of microtubules. However, the molecular mechanism of plus-end association by +TIPs and their ability to track the growing end are not well understood. Here we report the in vitro reconstitution of a minimal plus-end tracking system consisting of the three fission yeast proteins Mal3, Tip1 and the kinesin Tea2. Using time-lapse total internal reflection fluorescence microscopy, we show that the EB1 homologue Mal3 has an enhanced affinity for growing microtubule end structures as opposed to the microtubule lattice. This allows it to track growing microtubule ends autonomously by an end recognition mechanism. In addition, Mal3 acts as a factor that mediates loading of the processive motor Tea2 and its cargo, the Clip170 homologue Tip1, onto the microtubule lattice. The interaction of all three proteins is required for the selective tracking of growing microtubule plus ends by both Tea2 and Tip1. Our results dissect the collective interactions of the constituents of this plus-end tracking system and show how these interactions lead to the emergence of its dynamic behaviour. We expect that such in vitro reconstitutions will also be essential for the mechanistic dissection of other plus-end tracking systems.

  • 11.
    Björnham, Oscar
    et al.
    Umeå University, Faculty of Science and Technology, Department of Applied Physics and Electronics.
    Nilsson, Håkan
    Umeå University, Faculty of Science and Technology, Department of Applied Physics and Electronics.
    Andersson, Magnus
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Schedin, Staffan
    Umeå University, Faculty of Science and Technology, Department of Applied Physics and Electronics.
    Physical properties of the specific PapG–galabiose binding in E. coli P pili-mediated adhesion2009In: European Biophysics Journal, ISSN 0175-7571, E-ISSN 1432-1017, Vol. 38, no 2, p. 245-254Article in journal (Refereed)
    Abstract [en]

    Detailed analyses of the mechanisms thatmediate binding of the uropathogenic Escherichia coli tohost cells are essential, as attachment is a prerequisite forthe subsequent infection process. We explore, by means offorce measuring optical tweezers, the interaction betweenthe galabiose receptor and the adhesin PapG expressed byP pili on single bacterial cells. Two variants of dynamicforce spectroscopy were applied based on constant andnon-linear loading force. The specific PapG–galabiosebinding showed typical slip-bond behaviour in the forceinterval (30–100 pN) set by the pilus intrinsic biomechanicalproperties. Moreover, it was found that the bondhas a thermodynamic off-rate and a bond length of2.6×10-3 s-1 and 5.0 Å , respectively. Consequently, thePapG–galabiose complex is significantly stronger thanthe internal bonds in the P pilus structure that stabilizes thehelical chain-like macromolecule. This finding suggeststhat the specific binding is strong enough to enable the Ppili rod to unfold when subjected to strong shear forces inthe urinary tract. The unfolding process of the P pili rodpromotes the formation of strong multipili interaction,which is important for the bacterium to maintain attachmentto the host cells.

  • 12.
    Boal, Frédéric
    et al.
    INSERM U1048, I2MC and Universite´ Paul Sabatier, 31432 Toulouse, France.
    Puhar, Andrea
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). INSERM U1202, Unite´ de Pathogénie Microbienne Moléculaire, Institut Pasteur, 75724 Paris Cedex 15, France.
    Xuereb, Jean-Marie
    INSERM U1048, I2MC and Universite´ Paul Sabatier, 31432 Toulouse, France.
    Kunduzova, Oksana
    INSERM U1048, I2MC and Universite´ Paul Sabatier, 31432 Toulouse, France.
    Sansonetti, Philippe J.
    INSERM U1202, Unite´ de Pathogénie Microbienne Moléculaire, Institut Pasteur, 75724 Paris Cedex 15, France.
    Payrastre, Bernard
    INSERM U1048, I2MC and Universite´ Paul Sabatier, 31432 Toulouse, France; .
    Tronchére, Héléne
    INSERM U1048, I2MC and Universite´ Paul Sabatier, 31432 Toulouse, France.
    PI5P Triggers ICAM-1 Degradation in Shigella Infected Cells, Thus Dampening Immune Cell Recruitment2016In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 14, no 4, p. 750-759Article in journal (Refereed)
    Abstract [en]

    Shigella flexneri, the pathogen responsible for bacillary dysentery, has evolved multiple strategies to control the inflammatory response. Here, we show that Shigella subverts the subcellular trafficking of the intercellular adhesion molecule-1 (ICAM-1), a key molecule in immune cell recruitment, in a mechanism dependent on the injected bacterial enzyme IpgD and its product, the lipid mediator PI5P. Overexpression of IpgD, but not a phosphatase dead mutant, induced the internalization and the degradation of ICAM-1 in intestinal epithelial cells. Remarkably, addition of permeant PI5P reproduced IpgD effects and led to the inhibition of neutrophil recruitment. Finally, these results were confirmed in an in vivo model of Shigella infection where IpgD-dependent ICAM-1 internalization reduced neutrophil adhesion. In conclusion, we describe here an immune evasion mechanism used by the pathogen Shigella to divert the host cell trafficking machinery in order to reduce immune cell recruitment.

  • 13. Boija, Ann
    et al.
    Mahat, Dig Bijay
    Zare, Aman
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Holmqvist, Per-Henrik
    Philip, Philge
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Meyers, David J
    Cole, Philip A
    Lis, John T
    Stenberg, Per
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Mannervik, Mattias
    CBP Regulates Recruitment and Release of Promoter-Proximal RNA Polymerase II2017In: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 68, no 3, p. 491-503.e5Article in journal (Refereed)
    Abstract [en]

    Transcription activation involves RNA polymerase II (Pol II) recruitment and release from the promoter into productive elongation, but how specific chromatin regulators control these steps is unclear. Here, we identify a novel activity of the histone acetyltransferase p300/CREB-binding protein (CBP) in regulating promoter-proximal paused Pol II. We find that Drosophila CBP inhibition results in "dribbling" of Pol II from the pause site to positions further downstream but impedes transcription through the +1 nucleosome genome-wide. Promoters strongly occupied by CBP and GAGA factor have high levels of paused Pol II, a unique chromatin signature, and are highly expressed regardless of cell type. Interestingly, CBP activity is rate limiting for Pol II recruitment to these highly paused promoters through an interaction with TFIIB but for transit into elongation by histone acetylation at other genes. Thus, CBP directly stimulates both Pol II recruitment and the ability to traverse the first nucleosome, thereby promoting transcription of most genes.

  • 14. Bykova, Natalia V.
    et al.
    Møller, Ian M.
    Gardeström, Per
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    Igamberdiev, Abir U.
    The function of glycine decarboxylase complex is optimized to maintain high photorespiratory flux via buffering of its reaction products2014In: Mitochondrion (Amsterdam. Print), ISSN 1567-7249, E-ISSN 1872-8278, Vol. 19, p. 357-364Article in journal (Refereed)
    Abstract [en]

    Oxidation of glycine in photorespiratory pathway is the major flux through mitochondria of C3 plants in the light. It sustains increased intramitochondrial concentrations of NADH and NADPH, which are required to engage the internal rotenone-insensitive NAD(P)H dehydrogenases and the alternative oxidase. We discuss here possible mechanisms of high photorespiratory flux maintenance in mitochondria and suggest that it is fulfilled under conditions where the concentrations of glycine decarboxylase reaction products NADH and CO2 achieve an equilibrium provided by malate dehydrogenase and carbonic anhydrase, respectively. This results in the removal of these products from the glycine decarboxylase multienzyme active sites and in the maintenance of their concentrations at levels sufficiently low to prevent substrate inhibition of the reaction. 

  • 15. Cha, Shih-Ting
    et al.
    Chen, Pai-Sheng
    Johansson, Gunnar
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Umeå University.
    Chu, Chia-Yu
    Wang, Ming-Yang
    Jeng, Yung-Ming
    Yu, Sung-Liang
    Chen, Jin-Shing
    Chang, King-Jen
    Jee, Shiou-Hwa
    Tan, Ching-Ting
    Lin, Ming-Tsan
    Kuo, Min-Liang
    MicroRNA-519c suppresses hypoxia-inducible factor-1alpha expression and tumor angiogenesis.2010In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 70, no 7, p. 2675-85Article in journal (Refereed)
    Abstract [en]

    Hypoxia-inducible factor-1alpha (HIF-1alpha) is widely considered to be one of the key regulators of tumor angiogenesis. The upstream regulation is complex and involves several growth factors, cytokines, and hypoxia. Herein, we have identified miR-519c as a hypoxia-independent regulator of HIF-1alpha, acting through direct binding to the HIF-1alpha 3' untranslated region and leading to reduced tumor angiogenesis. Overexpression of miR-519c resulted in a significant decrease of HIF-1alpha protein levels and reduced the tube formation of human umbilical vein endothelial cells; similarly, antagomir inhibition of miR-519c increased the level of HIF-1alpha protein and enhanced angiogenic activity, suggesting an important role of miR-519c in HIF-1alpha-mediated angiogenesis. Consistent with the overexpression of miR-519c in cancer patients with better prognosis, mice injected with miR-519c-overexpressing cells exhibited dramatically reduced HIF-1alpha levels, followed by suppressed tumor angiogenesis, growth, and metastasis. In addition, we found that hepatocyte growth factor (HGF), a known HIF-1alpha inducer, reduced the miR-519c levels through an Akt-dependent pathway. This regulation was posttranscriptional and may be mediated by suppression of miR-519c maturation. Taken together, our findings provide the first evidence that miR-519c is a pivotal regulator of tumor angiogenesis and that microenvironmental HGF contributes to regulating miR-519c biogenesis in cancer cells.

  • 16.
    Chang, Yanhai
    et al.
    Department of Orthopaedics, The Third Affiliated Hospital (Shaanxi Provincial People's Hospital), Health Science Center of Xi’an Jiaotong University, Xi’an, PR China.
    Wang, Xiao
    Department of Galactophore, Shaanxi Provincial Cancer Hospital, Xi’an, PR China.
    Sun, Zhengming
    Department of Orthopaedics, The Third Affiliated Hospital (Shaanxi Provincial People's Hospital), Health Science Center of Xi’an Jiaotong University, Xi’an, PR China.
    Jin, Zhankui
    Department of Orthopaedics, The Third Affiliated Hospital (Shaanxi Provincial People's Hospital), Health Science Center of Xi’an Jiaotong University, Xi’an, PR China.
    Chen, Ming
    Department of Orthopaedics, The Third Affiliated Hospital (Shaanxi Provincial People's Hospital), Health Science Center of Xi’an Jiaotong University, Xi’an, PR China.
    Wang, Xiaoqing
    Department of Orthopaedics, The Third Affiliated Hospital (Shaanxi Provincial People's Hospital), Health Science Center of Xi’an Jiaotong University, Xi’an, PR China.
    Lammi, Mikko
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Guo, Xiong
    School of Public Health, Xi’an Jiaotong University Health Science Center, Key Laboratory of Trace Elements and Endemic Diseases, Ministry of Health, Xi’an, China.
    Inflammatory cytokine of IL-1β is involved in T-2 toxin-triggered chondrocyte injury and metabolism imbalance by the activation of Wnt/β-catenin signaling.2017In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 91, p. 195-201, article id 28963928Article in journal (Refereed)
    Abstract [en]

    Mycotoxin T-2 exerts a causative role in Kashin-Beck disease (KBD) suffering chondrocyte apoptosis and cartilage matrix homeostasis disruption. Recent research corroborated the aberrant levels of pro-inflammatory cytokine IL-1ß in KBD patients and mycotoxin environment. In the present study, we investigated the relevance of IL-1ß in T-2 toxin-evoked chondrocyte cytotoxic injury and aberrant catabolism. High levels of IL-1ß were detected in serum and cartilages from KBD patients and in T-2-stimulated chondrocytes. Moreover, knockdown of IL-1ß antagonized the adverse effects of T-2 on cytotoxic injury by enhancing cell viability and inhibiting apoptosis. However, exogenous supplementation of IL-1β further aggravated cell damage in response to T-2. Additionally, cessation of IL-1β rescued T-2-elicited tilt of matrix homeostasis toward catabolism by elevating the transcription of collagen II and aggrecan, promoting release of sulphated glycosaminoglycans (sGAG) and TIMP1, and suppressing matrix metalloproteinases production including MMP-1, MMP-3 and MMP-13. Conversely, IL-1β stimulation deteriorated T-2-induced disruption of matrix metabolism balance toward catabolism. Mechanistic analysis found the high activation of Wnt/β-catenin in KBD patients and chondrocytes upon T-2. Furthermore, this activation was mitigated after IL-1β inhibition, but further enhanced following IL-1β precondition. Importantly, blocking this pathway by transfection with β-catenin alleviated the adverse roles of IL-1β on cytotoxic injury and metabolism disorders under T-2 conditioning. Together, this study elucidates a new insight into how T-2 deteriorates the pathological progression of KBD by regulating inflammation-related pathways, indicating a promising anti-inflammation strategy for KBD therapy.

  • 17. Chen, Chi-Kuan
    et al.
    Yang, Ching-Yao
    Hua, Kuo-Tai
    Hua, Kuo-Ti
    Ho, Ming-Chih
    Johansson, Gunnar
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Umeå University.
    Jeng, Yung-Ming
    Chen, Chiung-Nien
    Chen, Min-Wei
    Lee, Wei-Jiunn
    Su, Jen-Liang
    Lai, Tsung-Ching
    Chou, Chi-Chi
    Ho, Bing-Ching
    Chang, Chuan-Fa
    Lee, Po-Huang
    Chang, King-Jen
    Hsiao, Michael
    Lin, Ming-Tsan
    Kuo, Min-Liang
    Leukocyte cell-derived chemotaxin 2 antagonizes MET receptor activation to suppress hepatocellular carcinoma vascular invasion by protein tyrosine phosphatase 1B recruitment.2014In: Hepatology, ISSN 0270-9139, E-ISSN 1527-3350, Vol. 59, no 3, p. 974-85Article in journal (Refereed)
    Abstract [en]

    UNLABELLED: Leukocyte cell-derived chemotoxin 2 (LECT2) has been shown to act as a tumor suppressor in hepatocellular carcinoma (HCC). However, the underlying mechanism has not yet been completely defined. Here, we employ a LECT2-affinity column plus liquid chromatography coupled with tandem mass spectrometry to identify LECT2-binding proteins and found that MET receptor strongly interacted with LECT2 protein. Despite the presence of hepatocyte growth factor, the LECT2 binding causes an antagonistic effect to MET receptor activation through recruitment of protein tyrosine phosphatase 1B. The antagonistic effect of LECT2 on MET activation also mainly contributes to the blockage of vascular invasion and metastasis of HCC. Furthermore, serial deletions and mutations of LECT2 showed that the HxGxD motif is primarily responsible for MET receptor binding and its antagonistic effects.

    CONCLUSION: These findings reveal a novel, specific inhibitory function of LECT2 in HCC by the direct binding and inactivation of MET, opening a potential avenue for treating MET-related liver cancer.

  • 18. Chen, Min-Wei
    et al.
    Hua, Kuo-Tai
    Kao, Hsin-Jung
    Chi, Chia-Chun
    Wei, Lin-Hung
    Johansson, Gunnar
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Umeå University.
    Shiah, Shine-Gwo
    Chen, Pai-Sheng
    Jeng, Yung-Ming
    Cheng, Tsu-Yao
    Lai, Tsung-Ching
    Chang, Jeng-Shou
    Jan, Yi-Hua
    Chien, Ming-Hsien
    Yang, Chih-Jen
    Huang, Ming-Shyan
    Hsiao, Michael
    Kuo, Min-Liang
    H3K9 histone methyltransferase G9a promotes lung cancer invasion and metastasis by silencing the cell adhesion molecule Ep-CAM.2010In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 70, no 20, p. 7830-40Article in journal (Refereed)
    Abstract [en]

    G9a is a mammalian histone methyltransferase that contributes to the epigenetic silencing of tumor suppressor genes. Emerging evidence suggests that G9a is required to maintain the malignant phenotype, but the role of G9a function in mediating tumor metastasis has not been explored. Here, we show that G9a is expressed in aggressive lung cancer cells, and its elevated expression correlates with poor prognosis. RNAi-mediated knockdown of G9a in highly invasive lung cancer cells inhibited cell migration and invasion in vitro and metastasis in vivo. Conversely, ectopic G9a expression in weakly invasive lung cancer cells increased motility and metastasis. Mechanistic investigations suggested that repression of the cell adhesion molecule Ep-CAM mediated the effects of G9a. First, RNAi-mediated knockdown of Ep-CAM partially relieved metastasis suppression imposed by G9a suppression. Second, an inverse correlation between G9a and Ep-CAM expression existed in primary lung cancer. Third, Ep-CAM repression was associated with promoter methylation and an enrichment for dimethylated histone H3K9. G9a knockdown reduced the levels of H3K9 dimethylation and decreased the recruitment of the transcriptional cofactors HP1, DNMT1, and HDAC1 to the Ep-CAM promoter. Our findings establish a functional contribution of G9a overexpression with concomitant dysregulation of epigenetic pathways in lung cancer progression.

  • 19. Chien, Ming-Hsien
    et al.
    Ku, Chia-Chi
    Johansson, Gunnar
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Umeå University.
    Chen, Min-Wei
    Hsiao, Michael
    Su, Jen-Liang
    Inoue, Hiroyasu
    Hua, Kuo-Tai
    Wei, Lin-Hung
    Kuo, Min-Liang
    Vascular endothelial growth factor-C (VEGF-C) promotes angiogenesis by induction of COX-2 in leukemic cells via the VEGF-R3/JNK/AP-1 pathway.2009In: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 30, no 12, p. 2005-13Article in journal (Refereed)
    Abstract [en]

    Vascular endothelial growth factor (VEGF)-C is recognized as a tumor lymphangiogenic factor based on the effects of activated VEGF-R3 on lymphatic endothelial cells. Many tumor cells express VEGF-R3 but the function of this receptor in tumor cells is largely unknown. It has been reported that the VEGF-C/VEGF-R3 axis is activated in subsets of leukemia patients. Herein, we have shown that VEGF-C induces angiogenic activity in the tube formation assay invitro and Matrigel plug assay in vivo by upregulating an angiogenic factor, cyclooxygenase-2 (COX-2), through VEGF-R3 in the human acute myeloid leukemia (AML) cell line, THP-1. COX-2 induction by VEGF-C was also observed in other VEGF-R3(+) human AML cell lines (U937 and HL60). Moreover, immunohistochemical analysis of bone marrow specimens of 37 patients diagnosed with AML revealed that VEGF-C expression in specimens was associated with the expression of COX-2 (P < 0.001). The manner by which signaling pathways transduced by VEGF-C is responsible for COX-2 upregulation was further investigated. Blocking the p42/44 mitogen-activated protein kinase (MAPK) pathway with the MAPK kinase inhibitor, PD 98059, failed to inhibit VEGF-C-mediated COX-2 expression. However, VEGF-C-induced COX-2 upregulation was effectively abolished by overexpression of dominant-negative c-Jun N-terminal kinase (JNK) or treatment with the JNK inhibitor, SP 600125. VEGF-C induced JNK-dependent nuclear translocation of c-Jun. Furthermore, chromatin immunoprecipitation and reporter assays revealed that VEGF-C enhanced c-Jun binding to the cyclic adenosine 3',5'-monophosphate-response element of the COX-2 promoter and induced COX-2 expression. In sum, the data herein highlight the pathogenic role of VEGF-C in leukemia via regulation of angiogenesis through upregulation of COX-2.

  • 20. Concepcion Cruz-Santos, Maria
    et al.
    Aragon-Raygoza, Alejandro
    Espinal-Centeno, Annie
    Arteaga-Vazquez, Mario
    Cruz-Hernandez, Andres
    Bako, Laszlo
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    Cruz-Ramirez, Alfredo
    The Role of microRNAs in Animal Cell Reprogramming2016In: Stem Cells and Development, ISSN 1547-3287, E-ISSN 1557-8534, Vol. 25, no 14, p. 1035-1049Article, review/survey (Refereed)
    Abstract [en]

    Our concept of cell reprogramming and cell plasticity has evolved since John Gurdon transferred the nucleus of a completely differentiated cell into an enucleated Xenopus laevis egg, thereby generating embryos that developed into tadpoles. More recently, induced expression of transcription factors, oct4, sox2, klf4, and c-myc has evidenced the plasticity of the genome to change the expression program and cell phenotype by driving differentiated cells to the pluripotent state. Beyond these milestone achievements, research in artificial cell reprogramming has been focused on other molecules that are different than transcription factors. Among the candidate molecules, microRNAs (miRNAs) stand out due to their potential to control the levels of proteins that are involved in cellular processes such as self-renewal, proliferation, and differentiation. Here, we review the role of miRNAs in the maintenance and differentiation of mesenchymal stem cells, epimorphic regeneration, and somatic cell reprogramming to induced pluripotent stem cells.

  • 21. Cruz-Ramírez, Alfredo
    et al.
    Díaz-Triviño, Sara
    Blilou, Ikram
    Grieneisen, Verônica A.
    Sozzani, Rosangela
    Zamioudis, Christos
    Miskolczi, Pál
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Department of Forest Genetics and Plant Physiology, Umeå Plant Science Center, Swedish University of Agricultural Sciences, Umeå, Sweden.
    Nieuwland, Jeroen
    Benjamins, René
    Dhonukshe, Pankaj
    Caballero-Pérez, Juan
    Horvath, Beatrix
    Long, Yuchen
    Mähönen, Ari Pekka
    Zhang, Hongtao
    Xu, Jian
    Murray, James A. H.
    Benfey, Philip N.
    Bako, Laszlo
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Department of Forest Genetics and Plant Physiology, Umeå Plant Science Center, Swedish University of Agricultural Sciences, Umeå, Sweden.
    Marée, Athanasius F. M.
    Scheres, Ben
    A Bistable Circuit Involving SCARECROW-RETINOBLASTOMA Integrates Cues to Inform Asymmetric Stem Cell Division2012In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 150, no 5, p. 1002-1015Article in journal (Refereed)
    Abstract [en]

    In plants, where cells cannot migrate, asymmetric cell divisions (ACDs) must be confined to the appropriate spatial context. We investigate tissue-generating asymmetric divisions in a stem cell daughter within the Arabidopsis root. Spatial restriction of these divisions requires physical binding of the stem cell regulator SCARECROW (SCR) by the RETINOBLASTOM-RELATED (RBR) protein. In the stem cell niche, SCR activity is counteracted by phosphorylation of RBR through a cyclinD6;1-CDK complex. This cyclin is itself under transcriptional control of SCR and its partner SHORT ROOT (SHR), creating a robust bistable circuit with either high or low SHR-SCR complex activity. Auxin biases this circuit by promoting CYCD6;1 transcription. Mathematical modeling shows that ACDs are only switched on after integration of radial and longitudinal information, determined by SHR and auxin distribution, respectively. Coupling of cell-cycle progression to protein degradation resets the circuit, resulting in a "flip flop" that constrains asymmetric cell division to the stem cell region.

  • 22. Daste, Frederic
    et al.
    Walrant, Astrid
    Holst, Mikkel R.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Gadsby, Jonathan R.
    Mason, Julia
    Lee, Ji-Eun
    Brook, Daniel
    Mettlen, Marcel
    Larsson, Elin
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Lee, Steven F.
    Lundmark, Richard
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Gallop, Jennifer L.
    Control of actin polymerization via the coincidence of phosphoinositides and high membrane curvature2017In: Journal of Cell Biology, ISSN 0021-9525, E-ISSN 1540-8140, Vol. 216, no 11, p. 3745-3765Article in journal (Refereed)
    Abstract [en]

    The conditional use of actin during clathrin-mediated endocytosis in mammalian cells suggests that the cell controls whether and how actin is used. Using a combination of biochemical reconstitution and mammalian cell culture, we elucidate a mechanism by which the coincidence of PI(4,5)P-2 and PI(3)P in a curved vesicle triggers actin polymerization. At clathrin-coated pits, PI(3) P is produced by the INPP4A hydrolysis of PI(3,4)P-2, and this is necessary for actin-driven endocytosis. Both Cdc42.guanosine triphosphate and SNX9 activate N-WASP-WIP-and Arp2/3-mediated actin nucleation. Membrane curvature, PI(4,5)P-2, and PI(3) P signals are needed for SNX9 assembly via its PX-BAR domain, whereas signaling through Cdc42 is activated by PI(4,5)P-2 alone. INPP4A activity is stimulated by high membrane curvature and synergizes with SNX9 BAR domain binding in a process we call curvature cascade amplification. We show that the SNX9-driven actin comets that arise on human disease-associated oculocerebrorenal syndrome of Lowe (OCRL) deficiencies are reduced by inhibiting PI(3) P production, suggesting PI(3) P kinase inhibitors as a therapeutic strategy in Lowe syndrome.

  • 23.
    Dingeldein, Artur Peter Günther
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Pokorna, Sarka
    Lidman, Martin
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Sparrman, Tobias
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Sachl, Radek
    Hof, Martin
    Gröbner, Gerhard
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Apoptotic Bax at Oxidatively Stressed Mitochondrial Membranes: Lipid Dynamics and Permeabilization2017In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 112, no 10, p. 2147-2158Article in journal (Refereed)
    Abstract [en]

    Mitochondria are crucial compartments of eukaryotic cells because they function as the cellular power plant and play a central role in the early stages of programmed cell death (apoptosis). To avoid undesired cell death, this apoptotic pathway is tightly regulated by members of the Bcl-2 protein family, which interact on the external surface of the mitochondria, i.e., the mitochondrial outer membrane (MOM), and modulate its permeability to apoptotic factors, controlling their release into the cytosol. A growing body of evidence suggests that the MOM lipids play active roles in this permeabilization process. In particular, oxidized phospholipids (OxPls) formed under intracellular stress seem to directly induce apoptotic activity at the MOM. Here we show that the process of MOM pore formation is sensitive to the type of OxPls species that are generated. We created MOM-mimicking liposome systems, which resemble the cellular situation before apoptosis and upon triggering of oxidative stress conditions. These vesicles were studied using P-31 solid-state magic-angle-spinning nuclear magnetic resonance spectroscopy and differential scanning calorimetry, together with dye leakage assays. Direct polarization and cross-polarization nuclear magnetic resonance experiments enabled us to probe the heterogeneity of these membranes and their associated molecular dynamics. The addition of apoptotic Bax protein to OxPls-containing vesicles drastically changed the membranes' dynamic behavior, almost completely negating the previously observed effect of temperature on the lipids' molecular dynamics and inducing an ordering effect that led to more cooperative membrane melting. Our results support the hypothesis that the mitochondrion-specific lipid cardiolipin functions as a first contact site for Bax during its translocation to the MOM in the onset of apoptosis. In addition, dye leakage assays revealed that different OxPls species in the MOM-mimicking vesicles can have opposing effects on Bax pore formation.

  • 24.
    Domeij, Siw
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    The laryngeal mucosa and the superior laryngeal nerve of the rat: an immunohistochemical and electron microscopic study1990Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Neuropeptides are present in nerve fibers of the upper and lower airways. Local release of these substances may be of importance for the pathophysiology of airway disorders and may play a role in responses to different stimuli. However, little is known about the distribution of neuropeptides in the larynx. The superior laryngeal nerve is one of the vagal branches supplying the larynx. The aim of the present study was to investigate the fiber composition of this nerve and to analyse the distribution of different neuropeptides and mast cells in the larynx.

    The internal and the external branches of the superior laryngeal nerve had a similar number and size of the nerve fibers. Numerous unmyelinated fibers were evenly distributed in the branches. A large majority of the fibers were sensory myelinated and unmyelinated fibers; only a few of the myelinated fibers of the external branch ( 2-10 %) were motor. About a quarter of the unmyelinated fibers of the internal and the external branches had their cell bodies in the brainstem, and single myelinated and unmyelinated fibers emanated from the superior cervical ganglion. In every superior laryngeal nerve examined one to three spherical paraganglia were observed. These paraganglia contained cells which were similar to the type I and type II cells found in the carotid body and the paraganglia of the recurrent laryngeal nerve. Thin-walled sinusoidal blood vessels which were sometimes fenestrated were also present

    The laryngeal mucosa was supplied with nerve fibers exhibiting substance P- and calcitonin gene-related peptide-like immunoreactivity with regional differences in the distribution. The laryngeal side of the epiglottis and the ventral recess were richly supplied, and the vocal cords showed no evidence of immunoreactive nerve fibers. The distribution of connective tissue mast cells and mucosal mast cells/globular leucocytes was similar to that of nerve fibers displaying substance P- and calcitonin gene-related peptide-like immunoreactivity. These cells were found in close approximation to nerve fibers.

    Acetylcholinesterase-positive ganglionic cells in the larynx showed vasoactive intestinal polypeptide-, neuropeptide Y-and enkephalin-like immunoreactivity. Neuropeptide Y-like immunoreactivity was co-localized with tyrosine-hydroxylase/dopamine beta-hydroxylase-like immunoreactivity in nerve fibers in some blood vessel walls. Enkephalin-like immunoreactivity was rarely found in this location and co-localization with tyrosine- hydroxylase-like immunoreactivity was not detected. In glands and some blood vessel walls neuropeptide Y- and enkephalin-like immunoreactivity were localized in nerve fibers showing a positive acetylcholinesterase reaction and vasoactive intestinal polypeptide-like immunoreactivity. Thus, this indicates that neuropeptide Y is present in both the sympathetic and parasympathetic nervous systems, while enkephalin and vasoactive intestinal polypeptide are confined to the parasympathetic nervous system in the rat larynx.

    The present study shows that the superior laryngeal nerve is mainly sensory, and the study also provides a morphological basis for neuropeptide effects in laryngeal physiology/pathophysiology.

  • 25.
    Eklöf, Jan
    Institutionen för skoglig genetik och växtfysiologi, Sveriges lantbruksuniversitet, 901 83 Umeå.
    Control of lateral root development in Arabidopsis thaliana2001Licentiate thesis, comprehensive summary (Other academic)
  • 26.
    Fick, James
    et al.
    Department of Applied Physics, University of Eastern Finland, Kuopio, Finland.
    Huttu, Mari
    Department of Applied Physics, University of Eastern Finland, Kuopio, Finland.
    Lammi, Mikko
    Department of Applied Physics, University of Eastern Finland, Kuopio, Finland.
    Korhonen, Rami
    Department of Applied Physics, University of Eastern Finland, Kuopio, Finland.
    In vitro glycation of articular cartilage alters the biomechanical response of chondrocytes in a depth-dependent manner2014In: Osteoarthritis and Cartilage, ISSN 1063-4584, E-ISSN 1522-9653, Vol. 22, no 10, p. 1410-1418Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To determine if increasing cartilage cross-links through in vitro glycation of cartilage explants can alter the biomechanical response of chondrocytes to compressive deformation.

    METHOD: Bovine osteochondral explants were either incubated with cell culture solution supplemented with (n = 7) or without (n = 7) ribose for 42 h in order to induce glycation. Deformation-induced changes in cell volume, dimensions and local tissue strains were determined through confocal laser scanning microscopy (CLSM) and the use of a custom built micro-compression device. Osteochondral explants were also utilized to demonstrate changes in depth-wise tissue properties, biomechanical tissue properties and cross-links such as pentosidine (Pent), hydroxylysyl pyridinoline (HP) and lysyl pyridinoline (LP).

    RESULTS: The ribose treated osteochondral samples experienced reduced cell volume deformation in the upper tissue zone by ∼ 8% (P = 0.005), as compared the control samples, through restricting cell expansion. In the deeper tissue zone, cell volume deformation was increased by ∼ 12% (P < 0.001) via the transmission of mechanical signals further into the tissue depth. Biomechanical testing of the ribose treated osteochondral samples demonstrated an increase in the equilibrium and dynamic strain dependent moduli (P < 0.001 and P = 0.008, respectively). The biochemical analysis revealed an increase in Pent cross-links (P < 0.001). Depth-wise tissue property analyses revealed increased levels of carbohydrate content, greater levels of fixed charge density and an increased carbohydrate to protein ratio from 6 to 16%, 55-100% and 72-79% of the normalized tissue thickness (from the surface), respectively, in the ribose-treated group (P < 0.05).

    CONCLUSION: In vitro glycation alters the biomechanical response of chondrocytes in cartilage differently in upper and deeper zones, offering possible insights into how aging could alter cell deformation behavior in cartilage.

  • 27.
    Florea, Cristina
    et al.
    Department of Applied Physics, University of Eastern Finland, Kuopio, Finland.
    Tanska, Petri
    Department of Applied Physics, University of Eastern Finland, Kuopio, Finland.
    Mononen, Mika
    Department of Applied Physics, University of Eastern Finland, Kuopio, Finland.
    Qu, Chengjuan
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Lammi, Mikko
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). School of Public Health, Health Science Center of Xi’an Jiaotong University, Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, Xi’an, China.
    Laasanen, Mikko
    School of Engineering and Technology, Savonia University of Applied Sciences, Kuopio, Finland.
    Korhonen, Rami
    Department of Applied Physics, University of Eastern Finland, Kuopio, Finland; Diagnostic Imaging Center, Kuopio University Hospital, Kuopio, Finland.
    A combined experimental atomic force microscopy-based nanoindentation and computational modeling approach to unravel the key contributors to the time-dependent mechanical behavior of single cells2017In: Biomechanics and Modeling in Mechanobiology, ISSN 1617-7959, E-ISSN 1617-7940, Vol. 16, no 1, p. 297-311, article id 27554263Article in journal (Refereed)
    Abstract [en]

    Cellular responses to mechanical stimuli are influenced by the mechanical properties of cells and the surrounding tissue matrix. Cells exhibit viscoelastic behavior in response to an applied stress. This has been attributed to fluid flow-dependent and flow-independent mechanisms. However, the particular mechanism that controls the local time-dependent behavior of cells is unknown. Here, a combined approach of experimental AFM nanoindentation with computational modeling is proposed, taking into account complex material behavior. Three constitutive models (porohyperelastic, viscohyperelastic, poroviscohyperelastic) in tandem with optimization algorithms were employed to capture the experimental stress relaxation data of chondrocytes at 5 % strain. The poroviscohyperelastic models with and without fluid flow allowed through the cell membrane provided excellent description of the experimental time-dependent cell responses (normalized mean squared error (NMSE) of 0.003 between the model and experiments). The viscohyperelastic model without fluid could not follow the entire experimental data that well (NMSE = 0.005), while the porohyperelastic model could not capture it at all (NMSE = 0.383). We also show by parametric analysis that the fluid flow has a small, but essential effect on the loading phase and short-term cell relaxation response, while the solid viscoelasticity controls the longer-term responses. We suggest that the local time-dependent cell mechanical response is determined by the combined effects of intrinsic viscoelasticity of the cytoskeleton and fluid flow redistribution in the cells, although the contribution of fluid flow is smaller when using a nanosized probe and moderate indentation rate. The present approach provides new insights into viscoelastic responses of chondrocytes, important for further understanding cell mechanobiological mechanisms in health and disease.

  • 28.
    Francis, Matthew
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    The pathogenic Yersiniae: advances in the understanding of physiology and virulence2013In: Frontiers in Cellular and Infection Microbiology, ISSN 2235-2988, Vol. 3, no 51, p. 2p. 1-2Article, review/survey (Refereed)
  • 29.
    Francis, Monika K.
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Holst, Mikkel R.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Vidal-Quadras, Maite
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Henriksson, Sara
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Santarella-Mellwig, Rachel
    Sandblad, Linda
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Lundmark, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Endocytic membrane turnover at the leading edge is driven by a transient interaction between Cdc42 and GRAF12015In: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 128, no 22, p. 4183-4195Article in journal (Refereed)
    Abstract [en]

    Changes in cell morphology require coordination of plasma membrane turnover and cytoskeleton dynamics, processes that are regulated by Rho GTPases. Here, we describe how a direct interaction between the Rho GTPase Cdc42 and the GTPase activating protein (GAP) GRAF1, facilitate rapid cell surface turnover at the leading edge. Both Cdc42 and GRAF1 were required for fluid phase uptake and regulated the generation of transient GRAF1-coated endocytic carriers, distinct from clathrin coated vesicles. GRAF1 was found to transiently assemble at discrete Cdc42-enriched punctae at the plasma membrane resulting in a corresponding decrease in Cdc42 microdomain association. However, Cdc42 captured in its active state was, via a GAP domain mediated interaction, localised together with GRAF1 on accumulated internal structures derived from the cell surface. Correlative fluorescence and electron tomography microscopy revealed that these structures were clusters of small membrane carriers affected in their endosomal processing. We conclude that a transient interaction between Cdc42 and GRAF1 drives endocytic turnover and controls the transition essential for endosomal maturation of plasma membrane internalised by this mechanism.

  • 30.
    Frithz-Lindsten, Elisabet
    et al.
    Department of Microbiology, Defence Research Establishment, S-901 82, Umeå, Sweden.
    Holmström, Anna
    Department of Microbiology, Defence Research Establishment, S-901 82, Umeå, Sweden.
    Jacobsson, Lars
    Department of Microbiology, Defence Research Establishment, S-901 82, Umeå, Sweden.
    Soltani, Mehnam
    Department of Microbiology, Defence Research Establishment, S-901 82, Umeå, Sweden.
    Olsson, Jan
    Department of Microbiology, Defence Research Establishment, S-901 82, Umeå, Sweden.
    Rosqvist, Roland
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Forsberg, Åke
    Department of Microbiology, Defence Research Establishment, S-901 82, Umeå, Sweden.
    Functional conservation of the effector protein translocators PopB/YopB and PopD/YopD of Pseudomonas aeruginosa and Yersinia pseudotuberculosis.1998In: Molecular Microbiology, ISSN 0950-382X, E-ISSN 1365-2958, Vol. 29, no 5, p. 1155-1165Article in journal (Refereed)
    Abstract [en]

    Virulent Yersinia species cause systemic infections in rodents, and Y. pestis is highly pathogenic for humans. Pseudomonas aeruginosa, on the other hand, is an opportunistic pathogen, which normally infects only compromised individuals. Surprisingly, these pathogens both encode highly related contact-dependent secretion systems for the targeting of toxins into eukaryotic cells. In Yersinia, YopB and YopD direct the translocation of the secreted Yop effectors across the target cell membrane. In this study, we have analysed the function of the YopB and YopD homologues, PopB and PopD, encoded by P. aeruginosa. Expression of the pcrGVHpopBD operon in defined translocation-deficient mutants (yopB/yopD) of Yersinia resulted in complete complementation of the cell contact-dependent, YopE-induced cytotoxicity of Y. pseudotuberculosis on HeLa cells. We demonstrated that the complementation fully restored the ability of Y. pseudotuberculosis to translocate the effector molecules YopE and YopH into the HeLa cells. Similar to YopB, PopB induced a lytic effect on infected erythrocytes. The lytic activity induced by PopB could be prevented if the erythrocytes were infected in the presence of sugars larger than 3 nm in diameter, indicating that PopB induced a pore of similar size compared with that induced by YopB. Our findings show that the contact-dependent toxin-targeting mechanisms of Y. pseudotuberculosis and P. aeruginosa are conserved at the molecular level and that the translocator proteins are functionally interchangeable. Based on these similarities, we suggest that the translocation of toxins such as ExoS, ExoT and ExoU by P. aeruginosa across the eukaryotic cell membrane occurs via a pore induced by PopB.

  • 31. Fülöp, Katalin
    et al.
    Tarayre, Sylvie
    Kelemen, Zsolt
    Horváth, Gábor
    Kevei, Zoltán
    Nikovics, Krisztina
    Bakó, László
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Biological Research Center; Hungarian Academy of Sciences; Szeged, Hungary.
    Brown, Spencer
    Kondorosi, Adam
    Kondorosi, Eva
    Arabidopsis anaphase-promoting complexes: multiple activators and wide range of substrates might keep APC perpetually busy2005In: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 4, no 8, p. 1084-1092Article in journal (Refereed)
    Abstract [en]

    The anaphase-promoting complex (APC), a multisubunit E3 ubiquitin ligase, is an essential regulator of the cell cycle from metaphase until S phase in yeast and metazoans. APC mediates degradation of numerous cell cycle-related proteins, including mitotic cyclins and its activation and substrate-specificity are determined by two adaptor proteins, Cdc20 and Cdh1. Plants have multiple APC activators and the Cdh1-type proteins, in addition, are represented by two subclasses, known as Ccs52A and Ccs52B. The Arabidopsis genome contains five cdc20 genes as well as ccs52A1, ccs52A2 and ccs52B.In Schizosaccharomyces pombe, expression of the three Atccs52 genes elicited distinct phenotypes supporting nonredundant function of the AtCcs52 proteins. Consistent with these activities, the AtCcs52 proteins were able to bind both to the yeast and the Arabidopsis APCs. In synchronized Arabidopsis cell cultures the cdc20 transcripts were present from early G2 until the M-phase exit, ccs52B from G2/M to M while ccs52A1 and ccs52A2 were from late M until early G2, suggesting consecutive action of these APC activators in the plant cell cycle. The AtCcs52 proteins interacted with different subsets of mitotic cyclins, in accordance with their expression profiles, either in free- or CDK-bound forms. Expression of most APC subunits was constitutive, whereas cdc27a and cdc27b, corresponding to two forms of apc3, and ubc19 and ubc20 encoding E2-C type ubiquitin-conjugating enzymes displayed differences in their cell cycle regulation. These data indicate the existence of numerous APC(Cdc20/Ccs52/Cdc27) forms in Arabidopsis, which in conjunction with different E2 enzymes might have distinct or complementary functions at distinct stages of the cell cycle.

  • 32. Galluzzi, Lorenzo
    et al.
    Vitale, Ilio
    Senovilla, Laura
    Olaussen, Ken Andre
    Pinna, Guillaume
    Eisenberg, Tobias
    Goubar, Aicha
    Martins, Isabelle
    Michels, Judith
    Kratassiouk, Gueorgui
    Carmona-Gutierrez, Didac
    Scoazec, Marie
    Vacchelli, Erika
    Schlemmer, Frederic
    Kepp, Oliver
    Shen, Shensi
    Tailler, Maximilien
    Niso-Santano, Mireia
    Morselli, Eugenia
    Criollo, Alfredo
    Adjemian, Sandy
    Jemaa, Mohamed
    Chaba, Kariman
    Pailleret, Claire
    Michaud, Mickael
    Pietrocola, Federico
    Tajeddine, Nicolas
    Rouge, Thibault de La Motte
    Araujo, Natalia
    Morozova, Nadya
    Robert, Thomas
    Ripoche, Hugues
    Commo, Frederic
    Besse, Benjamin
    Validire, Pierre
    Fouret, Pierre
    Robin, Angelique
    Dorvault, Nicolas
    Girard, Philippe
    Gouy, Sebastien
    Pautier, Patricia
    Jaegemann, Nora
    Nickel, Ann-Christin
    Marsili, Sabrina
    Paccard, Caroline
    Servant, Nicolas
    Hupe, Philippe
    Behrens, Carmen
    Behnam-Motlagh, Parviz
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Kohno, Kimitoshi
    Cremer, Isabelle
    Damotte, Diane
    Alifano, Marco
    Midttun, Oivind
    Ueland, Per Magne
    Lazar, Vladimir
    Dessen, Philippe
    Zischka, Hans
    Chatelut, Etienne
    Castedo, Maria
    Madeo, Frank
    Barillot, Emmanuel
    Thomale, Juergen
    Wistuba, Ignacio Ivan
    Sautes-Fridman, Catherine
    Zitvogel, Laurence
    Soria, Jean-Charles
    Harel-Bellan, Annick
    Kroemer, Guido
    Prognostic Impact of Vitamin B6 Metabolism in Lung Cancer2012In: CELL REPORTS, ISSN 2211-1247, Vol. 2, no 2, p. 257-269Article in journal (Refereed)
    Abstract [en]

    Patients with non-small cell lung cancer (NSCLC) are routinely treated with cytotoxic agents such as cisplatin. Through a genome-wide siRNA-based screen, we identified vitamin B6 metabolism as a central regulator of cisplatin responses in vitro and in vivo. By aggravating a bioenergetic catastrophe that involves the depletion of intracellular glutathione, vitamin B6 exacerbates cisplatin-mediated DNA damage, thus sensitizing a large panel of cancer cell lines to apoptosis. Moreover, vitamin B6 sensitizes cancer cells to apoptosis induction by distinct types of physical and chemical stress, including multiple chemotherapeutics. This effect requires pyridoxal kinase (PDXK), the enzyme that generates the bioactive form of vitamin B6. In line with a general role of vitamin B6 in stress responses, low PDXK expression levels were found to be associated with poor disease outcome in two independent cohorts of patients with NSCLC. These results indicate that PDXK expression levels constitute a biomarker for risk stratification among patients with NSCLC.

  • 33.
    Gardeström, Per
    et al.
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    Igamberdiev, Abir U.
    The origin of cytosolic ATP in photosynthetic cells2016In: Physiologia Plantarum: An International Journal for Plant Biology, ISSN 0031-9317, E-ISSN 1399-3054, Vol. 157, no 3, p. 367-379Article, review/survey (Refereed)
    Abstract [en]

    In photosynthetically active cells, both chloroplasts and mitochondria have the capacity to produce ATP via photophosphorylation and oxidative phosphorylation, respectively. Thus, theoretically, both organelles could provide ATP for the cytosol, but the extent, to which they actually do this, and how the process is regulated, both remain unclear. Most of the evidence discussed comes from experiments with rapid fractionation of isolated protoplasts subjected to different treatments in combination with application of specific inhibitors. The results obtained indicate that, under conditions where ATP demand for photosynthetic CO2 fixation is sufficiently high, the mitochondria supply the bulk of ATP for the cytosol. In contrast, under stress conditions where CO2 fixation is severely limited, ATP will build up in chloroplasts and it can then be exported to the cytosol, by metabolite shuttle mechanisms. Thus, depending on the conditions, either mitochondria or chloroplasts can supply the bulk of ATP for the cytosol. This supply of ATP is discussed in relation to the idea that mitochondrial functions may be tuned to provide an optimal environment for the chloroplast. By balancing cellular redox states, mitochondria can contribute to an optimal photosynthetic capacity.

  • 34.
    Gekara, Nelson O.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    DNA damage-induced immune response: Micronuclei provide key platform2017In: Journal of Cell Biology, ISSN 0021-9525, E-ISSN 1540-8140, Vol. 216, no 10, p. 2999-3001Article in journal (Other academic)
    Abstract [en]

    DNA damage-induced activation of the cytoplasmic DNA sensor cGAS influences the outcome of infections, autoinflammation, and cancer. Recent studies by Harding et al. (2017. Nature. http://dx.doi.org/10.1038/nature23470), Mackenzie et al. (2017. Nature. http://dx.doi.org/10.1038/nature23449), and Bartsch et al. (2017. Human Molecular Genetics. https://doi.org/10.1093/hmg/ddx283) demonstrate a role for micronuclei formation in DNA damage-induced immune activation.

  • 35. Geoghegan, Fintan
    et al.
    Buckland, Robert J.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Rogers, Eric T.
    Khalifa, Karima
    O'Connor, Emma B.
    Rooney, Mary F.
    Behnam-Motlagh, Parviz
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Nilsson, Torbjörn K.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Porter, Richard K.
    Bioenergetics of acquired cisplatin resistant H1299 non-small cell lung cancer and P31 mesothelioma cells2017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 55, p. 94711-94725Article in journal (Refereed)
    Abstract [en]

    Acquired cisplatin resistance is a common feature of tumours following cancer treatment with cisplatin and also of non-small cell lung cancer (H1299) and mesothelioma (P31) cell lines exposed to cisplatin. To elucidate the cellular basis of acquired cisplatin resistance, a comprehensive bioenergetic analysis was undertaken. We demonstrate that cellular oxygen consumption was significantly decreased in cisplatin resistant cells and that the reduction was primarily due to reduced mitochondrial activity as a result of reduced mitochondrial abundance. The differential mitochondrial abundance was supported by data showing reduced sirtuin 1 (SIRT1), peroxisome-proliferator activator receptor-gamma co-activator 1-alpha (PGC1 alpha), sirtuin 3 (SIRT3) and mitochondrial transcription factor A (TFAM) protein expression in resistant cells. Consistent with these data we observed increased reactive oxygen species (ROS) production and increased hypoxia inducible factor 1-alpha (HIF1 alpha) stabilization in cisplatin resistant cells when compared to cisplatin sensitive controls. We also observed an increase in AMP kinase subunit alpha 2 (AMPK alpha 2) transcripts and protein expression in resistant H1299 cells. mRNA expression was also reduced for cisplatin resistant H1299 cells in these genes, however the pattern was not consistent in resistant P31 cells. There was very little change in DNA methylation of these genes, suggesting that the cells are not stably reprogrammed epigenetically. Taken together, our data demonstrate reduced oxidative metabolism, reduced mitochondrial abundance, potential for increased glycolytic flux and increased ROS production in acquired cisplatin resistant cells. This suggests that the metabolic changes are a result of reduced SIRT3 expression and increased HIF-1 alpha stabilization.

  • 36. Gnanasundram, Sivakumar Vadivel
    et al.
    Pyndiah, Slovenie
    Daskalogianni, Chrysoula
    Armfield, Kate
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Wilson, Joanna B.
    Fåhraeus, Robin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences. Inserm UMRS1162, Equipe Labellisée la Ligue Contre le Cancer, Institut de Génétique Moléculaire, Université Paris 7, Hôpital St. Louis, 75010, Paris, France; RECAMO, Masaryk Memorial Cancer Institute, Zluty kopec 7, 65653, Brno, Czech Republic.
    PI3Kδ delta activates E2F1 synthesis in response to mRNA translation stress2017In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 2103Article in journal (Refereed)
    Abstract [en]

    The c-myc oncogene stimulates ribosomal biogenesis and protein synthesis to promote cellular growth. However, the pathway by which cells sense and restore dysfunctional mRNA translation and how this is linked to cell proliferation and growth is not known. We here show that mRNA translation stress in cis triggered by the gly-ala repeat sequence of Epstein–Barr virus (EBV)-encoded EBNA1, results in PI3Kδ-dependent induction of E2F1 mRNA translation with the consequent activation of c-Myc and cell proliferation. Treatment with a specific PI3Kδ inhibitor Idelalisib (CAL-101) suppresses E2F1 and c-Myc levels and causes cell death in EBNA1-induced B cell lymphomas. Suppression of PI3Kδ prevents E2F1 activation also in non-EBV-infected cells. These data illustrate an mRNA translation stress–response pathway for E2F1 activation that is exploited by EBV to promote cell growth and proliferation, offering new strategies to treat EBV-carrying cancers.

  • 37.
    Gouveia-Figueira, Sandra
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Bosson, Jenny A.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Unosson, Jon
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Behndig, Annelie F.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Nording, Malin
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Fowler, Christopher
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Relative and absolute reliability of measures of linoleic acid-derived oxylipins in human plasma2015In: Prostaglandins & other lipid mediators, ISSN 1098-8823, E-ISSN 2212-196X, Vol. 121, no Part B, p. 227-233Article in journal (Refereed)
    Abstract [en]

    Modern analytical techniques allow for the measurement of oxylipins derived from linoleic acid in biological samples. Most validatory work has concerned extraction techniques, repeated analysis of aliquots from the same biological sample, and the influence of external factors such as diet and heparin treatment upon their levels, whereas less is known about the relative and absolute reliability of measurements undertaken on different days. A cohort of nineteen healthy males were used, where samples were taken at the same time of day on two occasions, at least 7 days apart. Relative reliability was assessed using Lin's concordance correlation coefficients (CCC) and intraclass correlation coefficients (ICC). Absolute reliability was assessed by Bland-Altman analyses. Nine linoleic acid oxylipins were investigated. ICC and CCC values ranged from acceptable (0.56 [13-HODE]) to poor (near zero [9(10)- and 12(13)-EpOME]). Bland-Altman limits of agreement were in general quite wide, ranging from ±0.5 (12,13-DiHOME) to ±2 (9(10)-EpOME; log10 scale). It is concluded that relative reliability of linoleic acid-derived oxylipins varies between lipids with compounds such as the HODEs showing better relative reliability than compounds such as the EpOMEs. These differences should be kept in mind when designing and interpreting experiments correlating plasma levels of these lipids with factors such as age, body mass index, rating scales etc.

  • 38.
    Gouveia-Figueira, Sandra
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Nording, Malin L.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Validation of a tandem mass spectrometry method using combined extraction of 37 oxylipins and 14 endocannabinoid-related compounds including prostamides from biological matrices2015In: Prostaglandins & other lipid mediators, ISSN 1098-8823, E-ISSN 2212-196X, Vol. 121, no Part A, p. 110-121Article in journal (Refereed)
    Abstract [en]

    There is a clinical need for more relevant coverage of bioactive lipids using smaller sample volumes. Therefore, we have validated a tandem mass spectrometry method for combined solid phase extraction of 37 compounds in the oxylipin (OxL) and 14 in the endocannabinoid (eCB) metabolome, as well as prostamides. The limits of quantification (LOQ) for compounds in the eCB metabolome were in the range 0.5-1000fg on column, intraday accuracy and precision ranges (%) were 83-125 and 0.3-17, respectively, and interday accuracy and precision ranges (%) were 80-119 and 1.2-20, respectively, dependent upon the compound and the concentration studied. Corresponding values for OxL were 0.5fg-4.2pg on column (LOQ), 85-115% (inter- and intraday accuracy) and <5% (precision). The combined extraction method was successfully applied to tissues, cell extracts, human plasma and milk samples. A deeper study of levels in elk, pig and cow brain, as well as cow heart and liver revealed tissue and species-specific elevation of eicosanoids: arachidonate diols, 20-HETE and 12(S)-HEPE (cow liver), LTB4 (cow brain), and monohydroxy metabolites (HETEs), epoxides and 5-oxo-ETE in elk brain, which might be caused by factors of stress and/or post-mortem reactions in the tissues.

  • 39.
    Grabbe, Caroline
    et al.
    Goethe University, Frankfurt am Main, Germany.
    Dikic, Ivan
    Goethe University, Frankfurt am Main, Germany.
    Cell biology: going global on ubiquitin2008In: Science, ISSN 0036-8075, E-ISSN 1095-9203, ISSN 1095-9203, Vol. 322, no 5903, p. 872-873Article in journal (Refereed)
  • 40.
    Granholm, Susanne
    Umeå University, Faculty of Medicine, Odontology.
    The calcitonin gene family of peptides: receptor expression and effects on bone cells2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The calcitonin gene family of peptides consists of calcitonin (CT), two calcitonin gene related peptides (α-CGRP, β-CGRP), adrenomedullin (ADM), amylin (AMY), three calcitonin receptor activating peptides (CRSP1-3) and intermedin/adrenomedullin2 (IMD). These peptides bind to one of two G protein -coupled receptors, the calcitonin receptor (CTR) or the calcitonin receptor-like receptor (CRLR). The receptor specificity to different ligands is dependent on the formation of a complex with one of three receptor activity-modifying proteins (RAMP1-3).

    The aim of this study was to analyse effects of this family of peptides on the formation of osteoclasts and bone resorption, and the expression of the receptor components in bone cells.

    CT inhibited the formation of multinucleated osteoclasts in spleen cell cultures and in bone marrow macrophage cultures (BMM) without affecting a number of genes important for osteoclast differentiation, activity or fusion of osteoclast progenitor cells. All members of the CT family, except ADM, inhibited osteoclastogenesis in BMM. The inhibitory effect seemed to involve activation of both protein kinase A and the exchange protein directly activated by cyclic AMP (Epac) signalling. BMM expressed the CRLR, RAMP1-3 and the receptor component protein (RCP). AMY, ADM, CGRP and IMD, but not CRSP and CT, increased cyclic AMP (cAMP) levels in these cells, indicating the presence of functional receptors. Stimulation of BMM with RANKL gradually increased the levels of CTR mRNA as well as the capacity of the cells to respond to the stimulation by CRSP and CT. The response to stimulation of ADM was, on the contrary, decreased by RANKL. Stimulation of RANKL caused a transiently enhanced CRLR mRNA expression and transiently decreased RAMP1, but did not affect RAMP2, RAMP3, or RCP mRNA. However, RANKL did not affect protein levels of CRLR or RAMP1-3. CT, CGRP, AMY, ADM, IMD and CRSP all down regulated the CTR mRNA, but none of the peptides caused any effects on the expression of CRLR or any of the RAMPs.

    All members of the CT family, except ADM, rapidly and transiently, inhibited bone resorption in mouse calvarial bones. CT, CGRP, AMY and CRSP also significantly stimulated cAMP formation in the calvaria. cAMP analogues specifically stimulating the PKA or the Epac pathways did not cause inhibition of bone resorption in the calvaria. An unspecific cAMP analogue, stimulating both pathways did, however, cause inhibition.

    Analyses of an osteoblastic cell line, MC3T3-E1, showed that these cells express the mRNA for CRLR and all three RAMP proteins.

    In conclusion, the results of this thesis show that all peptides in CT family of peptides, except ADM, inhibit of bone resorption and osteoclast formation and that these effects involve the adenylate cyclase-cAMP pathway. Furthermore, expressions of CRLR and RAMP1-3 mRNA have been demonstrated on osteoclasts, as well as in an osteoblastic cell line.

  • 41.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Mechanisms of alloxan diabetogenicity1981Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Suspensions of pancreatic islet cells from ob/ob-mice were incubated with Trypan Blue. Microscope photometry showed that apparently viable cells excluded the dye completely, whereas the nuclei of non-viable cells accumulated Trypan Blue by a saturable process. Alloxan rapidly increased the permeability of the plasma membrane in mouse 3-cells; the exclusion of Trypan Blue is a valid and useful measure of islet cell viability following alloxan exposure.

    The diabetogenic action of alloxan may be mediated by hydroxyl radicals. In several biological systems hydroxyl radicals are formed by an iron-catalyzed reaction between superoxide anion radicals and hydrogen peroxide. To test whether this applies to alloxan diabetogenicity, the effects of superoxide dismutase, catalase, scavengers of hydroxyl radicals, and metal ion chelators were tested (a) in a cell-free radical-generating system and (b) on islets and islet-cells exposed to alloxan In vitro. The effect of longtime-circulating superoxide dismutase injected prior to alloxan was tested on mice in vivo.

    Luminol chemiluminescence was used to monitor alloxan-dependent radical production. Accumulation of 8^Rb+ and exclusion of Trypan Blue were used as cell viability criteria in isolated mouse islets and islet-cells. Blood glucose was determined to monitor the development of diabetes in living animals.

    Superoxide dismutase, catalase, scavengers of hydroxyl radicals, and metal ion chelators inhibited the alloxan-dependent chemiluminescence and decreased the toxic effects on Rb+ accumulation or Trypan Blue exclusion in islets and islet-cells. Superoxide dismutase, linked to polyethylene glycol and injected 12 hours before alloxan, largely prevented the development of alloxan diabetes.

    Alloxan toxicity _in vitro and in vivo seems to depend on the formation of superoxide radicals and hydrogen peroxide which in turn form the noxious hydroxyl radical via an iron-catalyzed Haber-Weiss reaction.

    As free radicals and hydrogen peroxide can be formed by other chemicals and during inflammation, and inflammation may accompany the outbreak of human diabetes, studies on the beneficiary effects of superoxide dismutase and other scavengers of free radicals in other forms of diabetes seem warranted.

  • 42.
    Grebe, Markus
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Out of the shade and into the light2011In: Nature Cell Biology, ISSN 1465-7392, E-ISSN 1476-4679, Vol. 13, no 4, p. 347-349Article in journal (Refereed)
    Abstract [en]

    Plants reach for the sun by avoiding the shade and by directly growing towards the light. Two studies now suggest that the polar relocation of PIN3, a transporter directing the flow of the plant hormone auxin, drives both growth processes. PIN3 repolarization occurs downstream of shade perception through phytochrome photoreceptors, whereas blue light perceived by phototropin initiates polar recycling of PIN3 and growth towards the light.

  • 43.
    Grebe, Markus
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Plant biology: Unveiling the Casparian strip.2011In: Nature, ISSN 1476-4687, Vol. 473, no 7347, p. 294-5Article in journal (Refereed)
  • 44.
    Hall, Michael
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Wagner, Raik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Lam, Xuan Tam
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Funk, Christiane
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Persson, Karina
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    The HhoA protease from Synechocystis sp. PCC 6803: novel insights into structure and activity regulation2017In: Journal of Structural Biology, ISSN 1047-8477, E-ISSN 1095-8657, Vol. 198, no 3, p. 147-153Article in journal (Refereed)
    Abstract [en]

    Proteases play a vital role in the removal of proteins, which become damaged due to temperature or oxidative stress. Important to this process in the cyanobacterium Synechocystis sp. PCC6803 is the family of Deg/HtrA proteases; HhoA (sll1679), HhoB (sll1427) and HtrA (slr1204). While previous studies have elucidated the structures of Deg/HtrA proteases from Escherichia coli and from the chloroplast of the higher plant Arabidopsis thaliana, no structural data have been available for any Deg/HtrA protease from cyanobacteria, the evolutionary ancestor of the chloroplast. To gain a deeper insight into the molecular mechanisms and regulation of these proteins we have solved the structure of the Synechocystis HhoA protease in complex with a co-purified peptide by X-ray crystallography. HhoA assembles into stable trimers, mediated by its protease domain and further into a cage-like hexamer by a novel interaction between the PDZ domains of opposing trimers. Each PDZ domain contains two loops for PDZ-PDZ formation: interaction clamp one and two (IC1, IC2). IC1 interacts with IC2 on the opposing PDZ domain and vice versa. Our structure shows a peptide bound to a conserved groove on the PDZ domain and the properties of this pocket suggest that it binds substrate proteins as well as the neo C-termini of cleaved substrates. In agreement with previous studies showing the proteolytic activity of HhoA to be activated by Ca2+ or Mg2+, binding of divalent metal ions to the central channel of the trimer by the L1 activation loop was observed.

  • 45. Hartmann, Laura
    et al.
    Pedrotti, Lorenzo
    Weiste, Christoph
    Fekete, Agnes
    Schierstaedt, Jasper
    Göttler, Jasmin
    Kempa, Stefan
    Krischke, Markus
    Dietrich, Katrin
    Mueller, Martin J
    Vicente-Carbajosa, Jesus
    Hanson, Johannes
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Department of Molecular Plant Physiology, Utrecht University, The Netherlands .
    Dröge-Laser, Wolfgang
    Crosstalk between Two bZIP Signaling Pathways Orchestrates Salt-Induced Metabolic Reprogramming in Arabidopsis Roots2015In: The Plant Cell, ISSN 1040-4651, E-ISSN 1532-298X, Vol. 27, no 8, p. 2244-2260Article in journal (Refereed)
    Abstract [en]

    Soil salinity increasingly causes crop losses worldwide. Although roots are the primary targets of salt stress, the signaling networks that facilitate metabolic reprogramming to induce stress tolerance are less understood than those in leaves. Here, a combination of transcriptomic and metabolic approaches was performed in salt-treated Arabidopsis thaliana roots, which revealed that the group S1 basic leucine zipper transcription factors bZIP1 and bZIP53 reprogram primary C- and N-metabolism. In particular, gluconeogenesis and amino acid catabolism are affected by these transcription factors. Importantly, bZIP1 expression reflects cellular stress and energy status in roots. In addition to the well-described abiotic stress response pathway initiated by the hormone abscisic acid (ABA) and executed by SnRK2 (Snf1-RELATED-PROTEIN-KINASE2) and AREB-like bZIP factors, we identify a structurally related ABA-independent signaling module consisting of SnRK1s and S1 bZIPs. Crosstalk between these signaling pathways recruits particular bZIP factor combinations to establish at least four distinct gene expression patterns. Understanding this signaling network provides a framework for securing future crop productivity.

  • 46. He, Hanzi
    et al.
    Willems, Leo
    Batushansky, Albert
    Fait, Aaron
    Hanson, Johannes
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Department of Molecular Plant Physiology, Utrecht University, NL-3584 CH Utrecht, The Netherlands.
    Nijveen, Harm
    Hilhorst, Henk W M
    Bentsink, Leónie
    Effects of Parental Temperature and Nitrate on Seed Performance are Reflected by Partly Overlapping Genetic and Metabolic Pathways2016In: Plant and Cell Physiology, ISSN 0032-0781, E-ISSN 1471-9053, Vol. 57, no 3, p. 473-487Article in journal (Refereed)
    Abstract [en]

    Seed performance is affected by the seed maturation environment and previously, we have shown that temperature, nitrate and light intensity were the most influential environmental factors affecting seed performance. Seeds developed in these environments were selected to assess the underlying metabolic pathways, using a combination of transcriptomics and metabolomics. These analyses revealed that the effects of the temperature and nitrate parental environments were reflected by partly overlapping genetic and metabolic networks, as indicated by similar changes in metabolites and transcripts expression levels. Nitrogen-metabolism related metabolites (asparagine, GABA and allantoin) were significantly decreased in both low temperature (15°C) and low nitrate (N0) maturation environments. Correspondingly, nitrogen-metabolism genes (ALLANTOINASE, NITRATE REDUCTASE 1, NITRITE REDUCTASE 1 and NITRILASE 4) were differentially regulated in the low temperature and nitrate maturation environments, as compared with control conditions. High light intensity during seed maturation increased galactinol content, and displayed a high correlation with seed longevity. Low light had a genotype-specific effect on cell surface encoding genes in the DELAY OF GERMINATION 6-Near Isogenic Line (NILDOG6). Overall, the integration of phenotypes, metabolites and transcripts led to new insights in the regulation of seed performance.

  • 47.
    Hemmingsson, Oskar
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Kao, Gautam
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Still, Maria
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    ASNA-1 activity modulates sensitivity to cisplatin2010In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 70, no 24, p. 10321-10328Article in journal (Refereed)
    Abstract [en]

    Cancer can be cured by platinum based chemotherapy but resistance is a major cause of treatment failure. Here we present the nematode Caenorhabditis elegans as a model to study interactions between the platinum drug cisplatin and signaling pathways in vivo. Null mutations in a single gene, asna-1, makes worms hypersensitive to cisplatin. The metalloregulated ATPase ASNA-1 promotes insulin secretion and membrane insertion of tail-anchored proteins. Using structural data from ASNA-1 homologs, we identify specific ASNA-1 mutants that are sensitive to cisplatin while still able to promote insulin signaling. Mutational analysis reveals that hypersensitivity of ASNA-1 mutants to cisplatin remains in absence of CEP-1/p53 or apoptosis. Human ASNA1 can substitute for the worm gene, indicating a conserved function. Cisplatin sensitivity is not affected by decreased insulin signaling in wild type nematodes or restored insulin signaling in asna-1 mutants. These findings provide a functional insight into ASNA-1, demonstrate that C. elegans can be used to characterize cisplatin resistance mechanisms and propose that rationally designed drugs against ASNA-1 can sensitize cancer cells to cisplatin.

  • 48. Hua, Kuo-Tai
    et al.
    Tan, Ching-Ting
    Johansson, Gunnar
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Umeå University.
    Lee, Jang-Ming
    Yang, Pei-Wen
    Lu, Hsin-Yi
    Chen, Chi-Kuan
    Su, Jen-Liang
    Chen, Poshen B
    Wu, Yu-Ling
    Chi, Chia-Chun
    Kao, Hsin-Jung
    Shih, Hou-Jung
    Chen, Min-Wei
    Chien, Ming-Hsien
    Chen, Pai-Sheng
    Lee, Wei-Jiunn
    Cheng, Tsu-Yao
    Rosenberger, George
    Chai, Chee-Yin
    Yang, Chih-Jen
    Huang, Ming-Shyan
    Lai, Tsung-Ching
    Chou, Teh-Ying
    Hsiao, Michael
    Kuo, Min-Liang
    N-α-acetyltransferase 10 protein suppresses cancer cell metastasis by binding PIX proteins and inhibiting Cdc42/Rac1 activity.2011In: Cancer Cell, ISSN 1535-6108, E-ISSN 1878-3686, Vol. 19, no 2, p. 218-31Article in journal (Refereed)
    Abstract [en]

    N-α-acetyltransferase 10 protein, Naa10p, is an N-acetyltransferase known to be involved in cell cycle control. We found that Naa10p was expressed lower in varieties of malignancies with lymph node metastasis compared with non-lymph node metastasis. Higher Naa10p expression correlates the survival of lung cancer patients. Naa10p significantly suppressed migration, tumor growth, and metastasis independent of its enzymatic activity. Instead, Naa10p binds to the GIT-binding domain of PIX, thereby preventing the formation of the GIT-PIX-Paxillin complex, resulting in reduced intrinsic Cdc42/Rac1 activity and decreased cell migration. Forced expression of PIX in Naa10-transfected tumor cells restored the migration and metastasis ability. We suggest that Naa10p functions as a tumor metastasis suppressor by disrupting the migratory complex, PIX-GIT- Paxillin, in cancer cells.

  • 49.
    Huch, Susanne
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Müller, Maren
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Muppavarapu, Mridula
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Gommlich, Jessie
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Balagopal, Vidya
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Nissan, Tracy
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    The decapping activator Edc3 and the Q/N-rich domain of Lsm4 function together to enhance mRNA stability and alter mRNA decay pathway dependence in Saccharomyces cerevisiae2016In: Biology Open, ISSN 2046-6390, Vol. 5, no 10, p. 1388-1399Article in journal (Refereed)
    Abstract [en]

    The rate and regulation of mRNA decay are major elements in the proper control of gene expression. Edc3 and Lsm4 are two decapping activator proteins that have previously been shown to function in the assembly of RNA granules termed P bodies. Here, we show that deletion of edc3, when combined with a removal of the glutamine/asparagine rich region of Lsm4 (edc3Δ lsm4ΔC) reduces mRNA stability and alters pathways of mRNA degradation. Multiple tested mRNAs exhibited reduced stability in the edc3Δ lsm4ΔC mutant. The destabilization was linked to an increased dependence on Ccr4-mediated deadenylation and mRNA decapping. Unlike characterized mutations in decapping factors that either are neutral or are able to stabilize mRNA, the combined edc3Δ lsm4ΔC mutant reduced mRNA stability. We characterized the growth and activity of the major mRNA decay systems and translation in double mutant and wild-type yeast. In the edc3Δ lsm4ΔC mutant, we observed alterations in the levels of specific mRNA decay factors as well as nuclear accumulation of the catalytic subunit of the decapping enzyme Dcp2. Hence, we suggest that the effects on mRNA stability in the edc3Δ lsm4ΔC mutant may originate from mRNA decay protein abundance or changes in mRNPs or alternatively may imply a role for P bodies in mRNA stabilization.

  • 50.
    Höglund, Andreas
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Strömvall, Kerstin
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Plym Forshell, Linus
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Nilsson, Jonas A
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Chk2 deficiency in Myc overexpressing lymphoma cells elicits a synergistic lethal response in combination with PARP inhibition.2011In: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 10, no 20, p. 3598-3607Article in journal (Refereed)
    Abstract [en]

    Myc is a transcription factor frequently found deregulated in human cancer. The Myc- mediated cellular transformation process is associated with fast proliferative cells and inherent genomic instability, giving rise to malignant, invasive neoplasms with poor prognosis for survival. Transcription-independent functions of Myc include stimulation of replication. Excessive Myc expression stimulates a replication-associated DNA damage response that signal via the phosphoinositide 3-kinase (PI3K) related protein kinases (PIKKs) ATM and ATR. These in turn activate the DNA damage transducers Chk1 and Chk2. Here, we show that Myc can stimulate Chek2 transcript indirectly in vitro, as well as in B cells of !-Myc transgenic mice or in the intestine of ApcMin mice. However, Chk2 is dispensable for Myc’s ability to transform cells in vitro and for the survival of established lymphoma cells from !-Myc transgenic mice. Chk2 deficiency induces polyploidy and slow growth but the cells are viable and protected against DNA damage. However, inhibition of both Chk1/Chk2 with AZD7762 induces cell death and significantly delays disease progression of transplanted lymphoma cells in vivo. DNA damage recruits PARP family members to sites of DNA breaks that in turn facilitate the induction of DNA repair. Strikingly, combining Chk2 and PARP inhibition elicits a synergistic lethal response in the context of Myc overexpression. Our data indicates that only certain types of chemotherapy would give rise to a synergistic lethal response in combination with specific Chk2 inhibitors, which will be important if Chk2 inhibitors enter the clinic.

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