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  • 301.
    Johnsson, Anna-Karin
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Profilin and actin localizes to Synaptotagmin-induced filopodia2007Other (Other (popular science, discussion, etc.))
    Abstract [en]

    We are interested in the dynamics of the microfilament system at the leading edge. Our main focus is to explore how profilin:actin is transported to actin polymer forming sites at the inner leaflet of the plasma membrane. As a model system to study this process we are overexpressing synaptotagmin 1 in mammalian cells. This leads to a dramatic change in cell morphology with numerous oversized filopodia beeing formed. In addition to using this effect as a model system we are also interested in characterizing the mechanism responsible for this process. We have seen that the synaptotagmin 1 induced filopodia stain positively for profilin and actin and that they are enriched in the phosphatidylinositol lipid PIP2. Through cotransfection with a dominant negative form of Cdc42 we have indications that the formation of these filopodia is dependent on this small Rho GTPase.

    ASCB/ECF-möte i Dijon 27-30 juni 2007

  • 302.
    Johnsson, Anna-Karin
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    The Actin Filament System: Its Involvement in Cell Migration and Neurotransmitter Release2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The microfilament system consists of actin filaments as the major component and is regulated by a number of actin binding proteins. It is juxtaposed to the plasma membrane where it forms a dense cortical weave from where it pervades into the cell interior. This filament system has multiple roles and participates in virtually all motile processes where its dynamic activities depend on receptor mediated signaling leading to constant polymerizations and depolymerizations. These activities are now also known to affect gene regulation. This thesis discusses these dynamic reorganizations of the microfilament system and how components are supplied to support these motile processes. The focus is on profilin/profilin:actin, actin polymerization and the localization of the transcripts of these proteins.

    The localization of profilin mRNA was examined in relation to the distribution of β-actin mRNA using fluorescent in situ hybridization. It was concluded that both these mRNAs localize to sites of massive actin polymerization called dorsal ruffles albeit the data obtained suggests that this localization must be dependent on distinct mechanisms. Additionally signal transduction and cell motility was studied after depleting the two profilin isoforms 1 and 2. The activity of the transcription factor SRF is known to be coupled to microfilament system dynamics via the cofactor MAL which binds to actin monomers and is released upon receptor mediated actin polymerization. Depletion of profilin was seen to influence SRF dependent signaling, most likely because the lack of profilin enables more MAL to bind actin monomers thereby preventing SRF dependent transcription. Finally, it was also investigated how the synaptic vesicle protein synaptotagmin 1 which is involved in exocytosis, has a role in actin polymerization. This protein has previously been described to cause filopodia formation when ectopically expressed. A polybasic sequence motif was identified as the effector sequence for this activity and it was established that this sequence interacts with anionic lipids. It is also discussed how this sequence could have a role in neurotransmitter release and actin polymerization in the nerve synapse.

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  • 303.
    Johnsson, Anna-Karin
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Cell Biology.
    Karlsson, Roger
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Cell Biology.
    Microtubule-dependent localization of profilin I mRNA to actin polymerization sites in serum-stimulated cells2010In: European Journal of Cell Biology, ISSN 0171-9335, E-ISSN 1618-1298, Vol. 89, no 5, p. 394-401Article in journal (Refereed)
    Abstract [en]

    Specific localization of messenger RNA (mRNA) appears to be a general mechanism to accumulate certain proteins to subcellular compartments for participation in local processes, thereby maintaining cell polarity under strict spatiotemporal control. Transportation of mRNA with associated protein components (RNP granules) by the actin microfilament or the microtubule systems is one important mechanism to achieve this locally distributed protein production. Here we provide evidence for a microtubule-dependent localization of mRNA encoding the actin regulatory protein profilin to sites in mouse embryonic fibroblasts, which express enhanced actin polymerization.

  • 304.
    Johnsson, Anna-Karin
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Cell Biology.
    Karlsson, Roger
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Cell Biology.
    Synaptotagmin 1 causes phosphatidyl inositol lipid-dependent actin remodeling in cultured non-neuronal and neuronal cells2012In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 318, no 2, p. 114-126Article in journal (Refereed)
    Abstract [en]

    Here we demonstrate that a dramatic actin polymerizing activity caused by ectopic expression of the synaptic vesicle protein synaptotagmin 1 that results in extensive filopodia formation is due to the presence of a lysine rich sequence motif immediately at the cytoplasmic side of the transmembrane domain of the protein. This polybasic sequence interacts with anionic phospholipids in vitro, and, consequently, the actin remodeling caused by this sequence is interfered with by expression of a phosphatidyl inositol (4,5)-bisphosphate (PIP2)-targeted phosphatase, suggesting that it intervenes with the function of PIP2-binding actin control proteins. The activity drastically alters the behavior of a range of cultured cells including the neuroblastoma cell line SH-SY5Y and primary cortical mouse neurons, and, since the sequence is conserved also in synaptotagmin 2, it may reflect an important fine-tuning role for these two proteins during synaptic vesicle fusion and neurotransmitter release.

  • 305.
    Jönsson, Gun
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Apoptosis regulation in bladder cancer and multiple sclerosis2003Doctoral thesis, comprehensive summary (Other academic)
  • 306.
    Jörgensen, Johanna A
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Zadravec, Damir
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Jacobsson, Anders
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Norepinephrine and rosiglitazone synergistically induce Elovl3 expression in brown adipocytes2007In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 293, no 5, p. E1159-68Article in journal (Refereed)
    Abstract [en]

    The Elovl3 gene, which putatively encodes for a protein involved in the elongation of saturated and monounsaturated fatty acids in the C20–C24 range, is expressed in murine liver, skin, and brown adipose tissue (BAT). In BAT, Elovl3 is dramatically upregulated during tissue activation in response to cold exposure, and functional data imply that ELOVL3 is a critical enzyme for lipid accumulation in brown adipocytes during the early phase of tissue recruitment. The activation of BAT is controlled by sympathetic nerve activity and norepinephrine release. By using primary cultures of brown adipocytes, we show here that the induced Elovl3 gene expression is synergistically regulated by norepinephrine and the peroxisome proliferator-activated receptor (PPAR) γ ligand rosiglitazone. In addition, the potency of rosiglitazone to induce Elovl3 expression was several orders of magnitude higher than for the PPARα and PPARδ ligands WY-14643 and L-165041, respectively. The maximal increase in mRNA level by norepinephrine and rosiglitazone is achieved by induced transcription as well as increased mRNA stability, and the whole process requires novel protein synthesis. We conclude that norepinehrine and PPARγ, despite having different roles in brown adipocyte activation and differentiation, cooperate in expanding the intracellular lipid pool by synergistically stimulating Elovl3 expression.

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    FULLTEXT01
  • 307.
    Kabilan, Lalitha
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    T-cell regulation of immune responses to the Plasmodium falciparum antigen Pf155/RESA1990Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Plasmodium falciparum is the cause of the most severe malaria inhumans. Due to the rapid resurgence of malaria in many parts of theworld extensive efforts have been made during the last few years todefine several P.falciparum antigens for inclusion in a vaccine. Onesuch antigen, generally considered to be a candidate for inclusion in asubunit vaccine against the asexual blood stages of the parasite isPfl55/RESA. Several antibody-binding structures (B-cell epitopes) ofthe molecule have recently been identified. However, immunogens for asubunit (malaria) vaccine should also contain T-cell activating sitesderived from the parasite in order to induce good secondary responsesafter natural boosting.For this reason, we have investigated Pfl55/RESA for its T-cellactivating capacity. Here we have shown, in Pfl55/RESA seropositivedonors, that the antigen induced production of anti-Pfl55/RESAantibodies in vitro is T-cell dependent, implying that Pfl55/RESAcontains T-helper cell stimulating epitopes. We have also shown thatsynthetic peptides representing sequences from the amino-acid repeatregions of Pfl55/RESA stimulate T-cells from P.falciparum-primed donorsto proliferate, to release IFN-7 and/or to synthesize IL-4. The resultssuggest the presence of several T-cell epitopes in the conserved repeatregions of Pfl55/RESA. In individual donors, there was no correlationbetween these different activities. Rather, they were negativelyassociated, suggesting that they have exhibited by functionallydistinct T-cells perhaps similar to the TH1 and TH2 cells found inmice. The results also demonstrate the importance of examining multipleparameters of T-cell activation when estimating the proportion ofindividuals responding to any particular epitope. However, induction ofIL-4 was seen in donors who had elevated concentrations of serumantibodies to the peptide used for T-cell activation. These resultssuggest that IL-4 producing cells have a role in the induction of theformation of Pfl55/RESA specific antibodies.To measure the actual number of cells secreting IFN-7 in vitro inresponse to Pfl55/RESA peptides, a single cell assay (ELISPOT) wasdeveloped. The results show that small numbers of antigen specificIFN-7 producing cells could be detected by ELISPOT even in the absenceof detectable levels of IFN-7 secreted into the culture supernatant.Thus, the Elispot makes it possible to estimate the frequency of Tcellsproducing different lymphokines even when cell numbers arelimited. As it requires only small volumes of blood and is relativelysimple, it is a useful assay for large scale epidemiological studies ofT-cell responsiveness in malaria or other diseases.

  • 308.
    Kaneko, Akira
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    A community-directed strategy for sustainable malaria elimination on islands: Short-term MDA integrated with ITNs and robust surveillance2010In: Acta Tropica, ISSN 0001-706X, E-ISSN 1873-6254, Vol. 114, no 3, p. 177-183Article in journal (Refereed)
    Abstract [en]

    In the Asia Pacific sites with low and unstable transmission, elimination should be feasible with existing tools. On Aneityum island, Vanuatu both Plasmodium falciparum and Plasmodium vivax malaria were eliminated in 1991 after implementation of a combined intervention package, including mass drug administration (MDA) and insecticide-treated bed nets (ITNs), with high degree of community involvement. Subsequently, community-based surveillance and vector control measures have kept. By reviewing the experiences of the Aneityum project, I intended to examine the roles of community in malaria elimination. To be successful, the program should transfer major intervention components from the external donor-directed initiative to the community-directed approach. Scaling up of community involvement from simple participation to social participation, where communities involve in health planning functions is necessary from malaria control to malaria elimination.

  • 309.
    Kegel, Andreas
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Silencing and DNA double-strand break repair in budding yeast2006Doctoral thesis, monograph (Other academic)
    Abstract [en]

    Transcriptional silencing that makes large chromosomal domains inaccessible for the transcriptional apparatus is nucleated at DNA elements called silencers. In K.lactis a 102bp HMLα silencer was defined revealing three distinct protein-binding regions (A, B, and C) that were required for silencing of HMLα. The B-sequence was a binding-site for the transcription factor Reb1. Temperature sensitive reb1 alleles displayed silencing defects at the restrictive temperature. In addition, point mutations in the B-sequence abolished both Reb1-binding and silencer function. Silencing in the related yeast S.cerevisiae does not require Reb1 indicating that silencer-binding proteins diverge rapidly in hemiascomysetous species.

    Yeast strains lacking Sir2, Sir3 or Sir4 display a defect in the DNA double-strand break repair pathway, called nonhomologous end joining (NHEJ). We identified the first haploid-specific gene (NEJ1) involved in DSB repair and demonstrated that the NHEJ defect of sir mutants was largely attributable to the transcriptional repression of NEJ1. Cells lacking Nej1 initially slowed down the 5´to 3´DNA degradation rate at a DSB suggesting that Nej1 has a direct role in end joining repair. The localization of Nej1 to the nucleus and a direct molecular interaction with the NHEJ protein Lif1 supported this notion. Indirect participation of Nej1 in end joining by regulating the transport or stability of Lif1 was excluded.

    In K.lactis integration of exogenous DNA via illegitimate recombination (IR) occurred with a high frequency and was completely dependent on the NHEJ pathway. NHEJ was capable of efficient repair of a wide variety of DNA ends and both haploid and diploid cells performed NHEJ with the same efficiency. Furthermore, IR preferentially took place within intergenic regions and ribosomal DNA. A rad52 mutant had no affect on targeting preference for IGRs indicating that DSBs in ORFs were not primarily repaired by homologous recombination (HR). Introduction of an ectopic DSB preferentially targeted IR to this site. Thus, we suggest that IR occurs at DSBs and by analysing IR-events spontaneously arising mitotic DSBs can be mapped.

  • 310. Kegel, Andreas
    et al.
    Martinez, Paula
    Carter, Sidney
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Äström, Stefan
    Genome wide distribution of illegitimate recombination events in Kluyveromyces lactis2006In: Nucleic Acids Research, ISSN 1362-4962, Vol. 34, no 5, p. 1633-1645Article in journal (Refereed)
  • 311. Keller, Pernille
    et al.
    Gburcik, Valentina
    Petrovic, Natasa
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Physiology.
    Gallagher, Iain J.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Physiology.
    Cannon, Barbara
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Physiology.
    Timmons, James A.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Physiology.
    Gene-chip studies of adipogenesis-regulated microRNAs in mouse primary adipocytes and human obesity2011In: BMC Endocrine Disorders, E-ISSN 1472-6823, Vol. 11, p. 7-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Adipose tissue abundance relies partly on the factors that regulate adipogenesis, i.e. proliferation and differentiation of adipocytes. While components of the transcriptional program that initiates adipogenesis is well-known, the importance of microRNAs in adipogenesis is less well studied. We thus set out to investigate whether miRNAs would be actively modulated during adipogenesis and obesity.

    METHODS: Several models exist to study adipogenesis in vitro, of which the cell line 3T3-L1 is the most well known, albeit not the most physiologically appropriate. Thus, as an alternative, we produced EXIQON microarray of brown and white primary murine adipocytes (prior to and following differentiation) to yield global profiles of miRNAs.

    RESULTS: We found 65 miRNAs regulated during in vitro adipogenesis in primary adipocytes. We evaluated the similarity of our responses to those found in non-primary cell models, through literature data-mining. When comparing primary adipocyte profiles, with those of cell lines reported in the literature, we found a high degree of difference in 'adipogenesis' regulated miRNAs suggesting that the model systems may not be accurately representing adipogenesis. The expression of 10 adipogenesis-regulated miRNAs were studied using real-time qPCR and then we selected 5 miRNAs, that showed robust expression, were profiled in subcutaneous adipose tissue obtained from 20 humans with a range of body mass indices (BMI, range = 21-48, and all samples have U133+2 Affymetrix profiles provided). Of the miRNAs tested, mir-21 was robustly expressed in human adipose tissue and positively correlated with BMI (R2 = 0.49, p < 0.001).

    CONCLUSION: In conclusion, we provide a preliminary analysis of miRNAs associated with primary cell in vitro adipogenesis and demonstrate that the inflammation-associated miRNA, mir-21 is up-regulated in subcutaneous adipose tissue in human obesity. Further, we provide a novel transcriptomics database of EXIQON and Affymetrix adipocyte profiles to facilitate data mining.

  • 312. Kiesler, E
    et al.
    Miralles, F
    Östlund, A-K
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Visa, N
    Department of Molecular Biology and Functional Genomics.
    The Hrp65 self-interaction is mediated by an evolutionarily conserved domain and is required for nuclear import of Hrp65 isoforms that lack a nuclear localization signal2003In: Journal of Cell Science, Vol. 116, p. 3949-3956Article in journal (Refereed)
  • 313.
    Kiesler, Eva
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Miralles, Franscesc
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Östlund Farrants, Ann-Kristin
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Visa, Neus
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    The Hrp65 self-interaction is mediated by an evolutionarily conserved domain and is required for nuclear import of Hrp65 isoforms that lack a nuclear localization signal2003In: Journal of Cell Science, ISSN 1477-9137, Vol. 116, no 19, p. 3949-3956Article in journal (Refereed)
    Abstract [en]

    Hrp65, an evolutionary conserved RNA-binding protein from the midge Chironomus tentans, has a conserved DBHS (Drosophila behavior, human splicing) domain that is also present in several mammalian proteins. In a yeast two-hybrid screening we found that Hrp65 can interact with itself. Here we confirm the Hrp65 self-interaction by in vitro pull-down experiments and map the sequences responsible for the interaction to a region that we refer to as the protein-binding domain located within the DBHS domain. We also show that the protein-binding domains of Drosophila NonA and human PSF, two other proteins with conserved DBHS domains, bind to Hrp65 in the yeast two-hybrid system. These observations indicate that the protein-binding domain can mediate homodimerization of Hrp65 as well as heterodimerization between different DBHS-containing proteins. Moreover, analyses of recombinant Hrp65 by gel-filtration chromatography show that Hrp65 can not only dimerize but also oligomerize into complexes of at least three to six molecules. Furthermore, we have analyzed the functional significance of the Hrp65 self-interaction in cotransfection assays, and our results suggest that the interaction between different Hrp65 isoforms is crucial for their intracellular localization.

  • 314. Kis, Loránd L.
    et al.
    Gerasimcik, Natalija
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Cell Biology. Vilnius University .
    Salamon, Daniel
    Persson, Emma K.
    Nagy, Noémi
    Klein, George
    Severinson, Eva
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Cell Biology.
    Klein, Eva
    The STAT6 signaling pathway activated by the cytokines IL-4 and IL-13 induces expression of the Epstein-Barr virus-encoded protein LMP-1 in absence of EBNA-2: implications for the type II EBV latent gene expression in Hodgkin lymphoma2011In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 117, no 1, p. 165-174Article in journal (Refereed)
    Abstract [en]

    In line with the B-lymphotropic nature of EBV, the virus is present in several types of B cell lymphomas. EBV expresses a different set of latent genes in the associated tumors, such as EBNA-1 and LMPs (type II latency) in the classical Hodgkin lymphomas (cHL). We have previously reported that exposure of the in vitro EBV-converted, HL-derived cell line KMH2-EBV to CD40-ligand and IL-4 induced the expression of LMP-1. Here we show that exposure to IL-4 or IL-13 alone induced LMP-1 in the absence of EBNA-2. The induction of LMP-1 by IL-4 and IL-13 was mediated by the signal transducer STAT6 and a newly defined high-affinity STAT6-binding site in the LMP-1 promoter. IL-4 induced LMP-1 also in Burkitt lymphoma-derived lines and in tonsillar B cells infected with the EBNA-2-deficient EBV strain P3HR-1. Furthermore, co-culture of EBV-carrying BL cells with activated CD4(+) T cells resulted in the induction of LMP-1 in the absence of EBNA-2. As the Hodgkin/Reed-Sternberg are known to secrete IL-13, to have constitutively activated STAT6, and to be closely surrounded by CD4+ T cells, these mechanisms may be involved in the expression of LMP-1 in the EBV-positive cHLs.

  • 315.
    Klaude, Maria
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Chemical carcinogenesis by dimethylnitrosamine: the influence of nutritional status of age1986Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Dimethylnitrosamine (DMN) is a potent carcinogen in a variety of animal species. Nitrosamines are widely spread in the environment and many populations of the world are continuously exposed to low doses of them. Dietary deficiency might strongly influence the capacity of the body to metabolize and excrete chemical carcinogens. DMN is mainly metabolized in the liver giving rise to alkylating species which can react with cellular components such as proteins and nucleic acids. The alkylation of the DNA molecule is thought to lead to the carcinogenic transformations caused by DMN.

    In this study the effects of DMN metabolism among nuclear components were studied in relation to diet and age and also between different tissues in mice.

    The alkylation of DNA and chromatin proteins was non-randomly distributed within liver nuclei in DMN-treated mice. Chromatin regions enriched in transcriptional activity were more accessible to the alkylating species derived from DMN than less active parts of the chromatin organization. This correlated with the inhibition by DMN of RNA polymerase II-mediated transcription activity which was most pronounced in the transcriptionally active chromatin regions.

    Dietary shortage in essential amino acids enhanced the level of the promutagenic lesion 0-methylguanine in liver DNA after a single dose of DMN. The deficient diets also resulted in a decreased level of the enzyme, Og-methylguanine-DNA methyl transferase, responsible for the repair of 0-methylguanine. There were age-related differences in the level of the repair enzyme in animals fed an adequate amount of essential amino acids, with adult mice having twice the level of subadult mice. After dietary deficiency the amount of the repair enzyme decreased to the same level in both age groups. A continuous exposure to DMN potentiated the increase in 0-methylguanine and the decrease of its repair enzyme in animals fed amino acid deficient diets.

    Age-related, tissue-specific differences in the capacity to metabolize DMN were observed. Subadult mice fed the control diet had higher levels of 7-methylguanine in kidney and lung compared with adults. In response to dietary deficiency increased levels of 7-methylguanine were found in the lung of both age groups and in the kidneys of the adult animals alone.

  • 316.
    Knutsson Jenvert, Rose-Marie
    et al.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Holmberg Schiavone, Lovisa
    Characterization of the tRNA and ribosome-dependent pppGpp-synthesis by recombinant stringent factor from Escherichia coli2005In: FEBS Journal, ISSN 1742-464X, Vol. 272, no 3, p. 685-695Article in journal (Refereed)
  • 317.
    Kobayashi, Tsutomu
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Zadravec, Damir
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Jacobsson, Anders
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    ELOVL2 overexpression enhances triacylglycerol synthesis in 3T3-L1 and F442A cells.2007In: FEBS Letters, ISSN 0014-5793, Vol. 581, no 17, p. 3157-63Article in journal (Refereed)
    Abstract [en]

    Elongation of very long-chain fatty acids (ELOVL) members were overexpressed in two preadipocyte cell lines, ELOVL2 and ELOVL3 in 3T3-L1 cells, and ELOVL1–3 in F442A cells. Cells overexpressing ELOVL2, whose preferred substrates are arachidonic acid (AA, C20:4n−6) and eicosapentaenoic acid (EPA, C20:5n−3), showed an enhanced triacylglycerol (TAG) synthesis and subsequent accumulation of lipid droplets. Incorporation of fatty acid (FA) but not of glucose into TAG was enhanced by ELOVL2-overexpression. Two lipogenic genes encoding diacylglycerol acyltransferase-2 (DGAT2) and fatty acid-binding protein-4 (FABP4, aP2) were induced in ELOVL2-overexpressing cells, whereas no such effect was seen on the fatty acid synthase (FAS) gene.

  • 318.
    Koho, Hannu
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Antigens associated with human urinary bladder carcinoma: identification and functional studies1990Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The primary aim of this study was to identify antigens associated with themalignant state of human urinary bladder carcinoma cells. Characterization ofsuch tumor-associated antigens should provide clues to the molecularmechanisms of tumorigenesis, as well as leading to possible clinical applications,such as immunodiagnosis and immunotherapy.Five novel cell-surface glycoproteins were identified by monoclonalantibodies raised against bladder carcinoma cells. Four of these were selectivelyexpressed by malignant urothelial cells. One of the antigens was also identified asa differentiation antigen on B-lymphocytes, and has subsequently beendesignated CD40 in accordance with international nomenclature. This andanother antigen, 8F4, are putative growth factor receptors. Functional studiesshowed that these two antigens, CD40 and 8F4, are phosphoproteins. The 8F4antigen also displayed protein kinase activity, similar to many growth factorreceptors and receptor-like oncogene products. The CD40 antigen has anestablished role in the growth regulation of B-lymphocytes, as demonstrated bythe capacity of anti-CD40 antibodies to stimulate growth of preactivated Blymphocytes.Molecular cloning has also identified the antigen as a putativegrowth factor receptor related to the NGF-receptor. Structural analysis of theCD40 gene in bladder carcinoma cell lines by cDNA cloning and DNA sequencinganalysis showed no differences from the CD40 gene expressed in B cells. Theover-expression of CD40 in bladder carcinomas is not likely associated withstructural changes in the transcribed portion of the gene. Possible reasons for theover-expression are discussed. Expression of antigens was affected by interferongammatreatment, in that three antigens (CD40, 8F4, and 4E8) were up-regulatedand one (2F6) was down-regulated. Although the identified antigens areassociated with malignancy, their role in the transformation process remains tobe investigated. In this respect, molecular cloning is an important tool forfunctional characterization of the other antigens and should also reveal whetherthere are additional receptors among them. It will also be of interest to examinethe possible involvement of these antigens in tumor invasion and metastasis.

  • 319. Kota, Jhansi
    et al.
    Gilstring, C Fredrik
    Ljungdahl, Per O
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Membrane chaperone Shr3 assists in folding amino acid permeases preventing precocious ERAD.2007In: J Cell Biol, ISSN 0021-9525, Vol. 176, no 5, p. 617-28Article in journal (Refereed)
  • 320. Kota, Jhansi
    et al.
    Melin-Larsson, Monika
    Ljungdahl, Per O
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Forsberg, Hanna
    Ssh4, Rcr2 and Rcr1 affect plasma membrane transporter activity in Saccharomyces cerevisiae.2007In: Genetics, ISSN 0016-6731, Vol. 175, no 4, p. 1681-94Article in journal (Refereed)
  • 321. Kramarova, Ludmila I
    et al.
    Bronnikov, Gennady E
    Ignat'ev, Dmitry A
    Cannon, Barbara
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Adrenergic receptor density in brown adipose tissue of active and hibernating hamsters and ground squirrels.2007In: Comp Biochem Physiol A Mol Integr Physiol, ISSN 1095-6433, Vol. 146, no 3, p. 408-14Article in journal (Refereed)
  • 322.
    Kramarova, Tatiana
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Limiting factors in ATP synthesis2006Doctoral thesis, monograph (Other academic)
    Abstract [en]

    The aim of the present study was to investigate the biosynthesis of the ATP synthase in various tissues, and to test hypotheses about possible models of activation of several mitochondrial proteins, the ATP/ADP translocase and UCPs, that could utilize the proton gradient, thus bypassing the ATP synthase.

    We have examined the role of the expression of the P1 isoform of the c-Fo subunit in the biogenesis of ATP synthase in brown adipose tissue. Our findings point to a role for the c-Fo subunit in defining the final content of the ATP synthase in brown adipose tissue.

    We have analyzed sequences in the 3’UTR of the β subunit F1-ATPase mRNA that are important for formation of RNA-protein complexes. We could detect protein complexes that bind to two different sequence regions of the 3’UTR, one being the poly(A) tail and an adjacent region), and the other being a sequence stretch at the 3’ end of the 3’UTR able to form a stem-loop structure, which is evolutionarily conserved throughout mammalian species.

    We investigated a role of the ATP/ADP carrier (ANT) in fatty acid-induced uncoupling in brown-fat mitochondria. We conclude that the ANT cannot substitute for UCP1 in fatty acid uncoupling in brown-fat mitochondria from mice lacking UCP1. We propose that the two ANT isoforms mediate proton translocation under different conditions.

    We have investigated a role of UCP1 in defence against oxidative stress. We found that products of oxidative stress (4-HNE) could neither reactivate purine nucleotide-inhibited UCP1, nor induce additional activation of innately active UCP1 in brown-fat mitochondria from UCP1(+/+) and UCP1(-/-) mice. We conclude that UCP1 is not involved in defence against oxidative stress.

    We evaluated possible uncoupling activity of UCP3 in skeletal muscle from warm- and cold-acclimated UCP1(+/+) and UCP1(-/-) mice. We conclude that no evidence exists for a higher UCP3-mediated uncoupling activity; a high UCP3 content in cold-acclimated UCP1(-/-) mice could possibly be linked to improved fatty acid oxidative capacity.

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  • 323.
    Kramarova, Tatiana V
    et al.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Antonicka, Hana
    Houstek, Josef
    Cannon, Barbara
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    A sequence predicted to form a stem-loop is proposed to be required for formation of an RNA-protein complex involving the 3'UTR of beta-subunit F0F1-ATPase mRNA.2008In: Biochim Biophys Acta, ISSN 0006-3002, Vol. 1777, no 7-8, p. 747-57Article in journal (Refereed)
  • 324. Kramarova, Tatiana V
    et al.
    Shabalina, Irina G
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Andersson, Ulf
    Westerberg, Rolf
    Carlberg, Inger
    Houstek, Josef
    Nedergaard, Jan
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Cannon, Barbara
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Mitochondrial ATP synthase levels in brown adipose tissue are governed by the c-Fo subunit P1 isoform.2007In: FASEB J, ISSN 1530-6860Article in journal (Refereed)
  • 325.
    Kramarova, Tatiana V.
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Shabalina, Irina G.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Andersson, Ulf
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Westerberg, Rolf
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Carlberg, Inger
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Houstek, Josef
    Nedergaard, Jan
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Cannon, Barbara
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Mitochondrial ATP synthase levels in brown adipose tissue are governed by the c-Fo subunit P1 isoform2008In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 22, no 1, p. 55-63Article in journal (Refereed)
    Abstract [en]

    Despite the significance of mitochondrial ATP synthase for mammalian metabolism, the regulation of the amount of ATP synthase in mammalian systems is not understood. As brown adipose tissue mitochondria contain very low amounts of ATP synthase, relative to respiratory chain components, they constitute a physiological system that allows for examination of the control of ATP synthase assembly. To examine the role of the expression of the P1-isoform of the c-F-o subunit in the biogenesis of ATP synthase, we made transgenic mice that express the P1-c subunit isoform under the promoter of the brown adipose tissue-specific protein UCP1. In the resulting UCP1p1 transgenic mice, total P1-c subunit mRNA levels were increased; mRNA levels of other F1F(o)-ATPase subunits were unchanged. In isolated brown-fat mitochondria, protein levels of the total c-Fo subunit were increased. Remarkably, protein levels of ATP synthase subunits that are part of the F-1-ATPase complex were also increased, as was the entire Complex V. Increased ATPase and ATP synthase activities demonstrated an increased functional activity of the F1Fo-ATPase. Thus, the levels of the c-F-o subunit P1-isoform are crucial for defining the final content of the ATP synthase in brown adipose tissue. The level of c-F-o subunit may be a determining factor for F1Fo-ATPase assembly in all higher eukaryotes.-Kramarova, T. V., Shabalina, I. G., Andersson, U., Westerberg, R., Carlberg, I., Houstek, J., Nedergaard, J., Cannon, B. Mitochondrial ATP synthase levels in brown adipose tissue are governed by the c-F-o subunit P1 isoform.

  • 326. Krauss-Etschmann, Susanne
    et al.
    Bush, Andrew
    Bellusci, Saverio
    Brusselle, Guy G.
    Erik K. Dahlén, Sven
    Dehmel, Stefan
    Eickelberg, Oliver
    Gibson, Greg
    Hylkema, Machteld N.
    Knaus, Petra
    Königshoff, Melanie
    Lloyd, Clare M.
    Macciarini, Paolo
    Mailleux, Arnaud
    Marsland, Benjamin J.
    Postma, Dirkje S.
    Roberts, Graham
    Samakovlis, Christos
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Stocks, Janet
    Vandesompele, Joke
    Wjst, Matthias
    Holloway, John
    Of flies, mice and men: a systematic approach to understanding the early life origins of chronic lung disease2013In: Thorax, ISSN 0040-6376, E-ISSN 1468-3296, Vol. 68, no 4, p. 380-384Article, review/survey (Refereed)
    Abstract [en]

    Despite intensive research efforts, the aetiology of the majority of chronic lung diseases (CLD) in both, children and adults, remains elusive. Current therapeutic options are limited, providing only symptomatic relief, rather than treating the underlying condition, or preventing its development in the first place. Thus, there is a strong and unmet clinical need for the development of both, novel effective therapies and preventative strategies for CLD. Many studies suggest that modifications of prenatal and/or early postnatal lung development will have important implications for future lung function and risk of CLD throughout life. This view represents a fundamental change of current pathophysiological concepts and treatment paradigms, and holds the potential to develop novel preventative and/or therapeutic strategies. However, for the successful development of such approaches, key questions, such as a clear understanding of underlying mechanisms of impaired lung development, the identification and validation of relevant preclinical models to facilitate translational research, and the development of concepts for correction of aberrant development, all need to be solved. Accordingly, a European Science Foundation Exploratory Workshop was held where clinical, translational and basic research scientists from different disciplines met to discuss potential mechanisms of developmental origins of CLD, and to identify major knowledge gaps in order to delineate a roadmap for future integrative research.

  • 327.
    Kuang, Wen
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Developmental Biology.
    Genetic and Functional Analysis of Cell Adhesion in Muscle1998Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Skeletal muscle is one of the most abundant tissues in the body, and its main function is to generate the force for movement. The mature muscle cell is a giant, elongated, multinucleated cell surrounded by a specialized, extracellular matrix (ECM), the basement membrane (BM). The BM in muscle, as in other tissues, is composed of laminin, type IV collagen, entactin/nidogen and heparan sulphate proteoglycan. One major component of the BM in muscle is laminin-2, which is composed of a heavy chain laminina2 and two light chains,b1 and lamining1. Laminin-2 is predominantly expressed in skeletal muscle and peripheral nerve but is also found in other tissues.

    Cell adhesion to the basement membrane is mediated by cell surface receptors, which thereby link the BM to the cytoskeleton. This linkage is thought to be important for generating the force required for movement. Mutations in adhesion molecules in muscle cause muscular dystrophy, proving the importance of cell adhesion in muscle.

    In order to analyze the molecular mechanisms of cell adhesion in muscle, we have analyzed laminin-2 and two other muscle adhesion proteins, laminina-sarcoglycan and tetranectin, in muscle development and regeneration. Most importantly, we have developed in vitro and in vivo models for laminin-2 deficient muscular dystrophy.

    We generated several lines of mutant embryonic stem (ES) cell with disruption of the laminin- laminina2 chain gene. We found that homozygous null mutant ES cells differentiate normally in vitro, giving rise to cardiomyocytes, myotubes, and smooth muscle cells in addition to many other cell types. However, the myotubes that are formed are unstable. They detach, collapse, and degenerate, a process which is initiated at the appearance of the mature, contractile phenotype of the cells. We propose that the detachment and death of contracting myotubes in vitro has its counterpart in vivo, and that contraction-induced myofiber damage, along with the lack of survival cues provided by laminin-2/merosin, is a significant contribution to muscle degeneration in merosin-deficient muscular dystrophy.

    We used laminin laminina2 mutant mice to study the expression of laminin-2 in development and regeneration using the lacZ gene as a reporter for the lama2 gene. We found that the lacZ/lama2 gene is highly expressed in the early stages of myogenesis and is down regulated when myogenesis is completed. Most importantly, the gene is up-regulated early in muscle regeneration, suggesting that laminin-2 plays an important role in this process. Despite the prominent expression of lama2 in normal development, laminina2 null mutant mice have no obvious developmental defect. Instead, they develop muscular dystrophy two weeks after birth. We found extensive apoptosis in null mutant mice, and this cell death is dramatically reduced in mice in which laminin-2 expression is restored in skeletal muscle by expression of a wild type LAMA2 transgene. Most of the apoptotic cells in null mutant mice are newly formed myofibers, suggesting that laminin-2 is needed for maturation and survival of regenerated myotubes. The apparent abortive muscle regeneration in laminin-2 deficiency suggests that the severe disease of MCMD is caused by insufficient regeneration after muscle damage.

    We have expressed a human LAMA2 transgene under the regulation of a muscle-specific creatine kinase promoter in mice with complete or partial deficiency of merosin. The transgene restored the synthesis and localization of laminin-2 in skeletal muscle, and greatly improved muscle morphology and integrity and the health and longevity of the mice. However, the transgenic mice share with the non-transgenic dystrophic mice a progressive lameness of hind legs, suggesting a nerve defect. These results indicate that the absence of merosin in tissues other than the muscle, such as nervous tissue, is a critical component of MCMD.

    We have cloned and characterized, a-sarcoglycan/adhalin, a member of the dystrophin associated sarcoglycan complex in muscle. We showed that a-sarcoglycan is expressed very late in myogenic differentiation both in vitro and in vivo. In fact, the expression is associated with the capacity of muscle cells to contract. The sarcoglycans may therefore have a role in muscle contraction. We also analyzed an ECM-associated molecule, tetranectin. We showed that expression of tetranectin is closely associated with skeletal muscle development and regeneration, and with muscle cell differentiation in vitro.

    In summary, our studies show the importance of laminin-2 in skeletal muscle. We have provided new information on three markers for different stages of myogenic differentiation, laminin laminina2, laminina-sarcoglycan, and tetranectin. In addition, our studies contribute to a better understanding of the mechanism of human disease caused by laminin-2 deficiency.

  • 328.
    Kulane, Asli
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    In Vitro Studies of Factors Potentially Affecting Plasmodium Falciparum Infection: (Heparin and Anti-P. falciparum Immune Responses)1997Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Plasmodium falciparum malaria is considered one of the major infectious diseases in humans, with regard to mortality and morbidity. Growing resistance of malaria to most anti-malaria drugs and of the Anopheles mosquitoes to insecticides have resulted in a global resurgence of the disease. Therefore, the need to explore drugs with possible antimalarial effects or the development of vaccines against malaria are considered a high priority for control of the disease. In this thesis, the antimalarial effect of heparin and the identification of T- and B-cell epitopes in P. falciparum vaccine candidate antigens, Pf155/RESA and Pf332 have been addressed.

    Heparin, a drug included in the supportive or ancillary treatment of cerebral malaria, was tested for its anti-parasitic effect on the blood stages of P. falciparum malaria in vitro. Heparin was cleaved into fragments differing in molecular weight and in their affinity for antithrombin III. Both unfractionated heparin and heparin fractions inhibited the merozoite invasion into red blood cells. The mechanism by which heparin acts is not clear. However, the inhibition was reversible by washing heparin-treated P. falciparum cultures indicating a direct effect of heparin. The sensitivity of laboratory strains and/or fresh isolates obtained from individuals residing in malaria endemic areas was compared. Although varying in sensitivity none of the samples tested was found to be resistant to heparin and its derivates. A fraction of heparin with low affinity for antithrombin III was the most potent inhibitor of merozoite invasion. The fraction with low affinity for antithrombin III is devoid of anticoagulant activity, suggesting a potential role of this fraction for the treatment of malaria.

    For the development of subunit vaccines it is important to identify and characterise epitopes which activate relevant B- and T-cell functions. In this study we have investigated two putative malaria vaccine candidate antigens, Pf155/RESA and Pf332, for T- and B-cell reactive epitopes. A large number of donors had antibodies against the Pf155/RESA sequence 186-206. For the Pf332 derived fragment, EB200, the donors also exhibited high antibody levels in their plasma. In our studies we have measured multi parameters of T-cell activation (proliferation, IFN-g and/or IL-4 production). Peptides corresponding to the N-terminal region of Pf155 or to EB200, stimulated peripheral blood mononuclear cells from P. falciparum-immune donors to proliferate, to induce secretion of IFN-g and/or IL-4. In individual donors the cellular immune responses to the peptides varied considerably. However, there was no clear association between proliferation and production of the cytokines investigated. This lack of association underlines the importance of including multiple parameters when analysing T-cell responses to defined epitopes.

    In conclusion, the non-repeat region of Pf155/RESA and the EB200 fragment of Pf332 contains several B-cell epitopes as well as several epitopes inducing functionally distinct T-cell responses, which should be a useful tool for inclusion in a subunit malaria vaccine as well as in future immuno-epidemiological studies.

  • 329. Kusi, Kwadwo A
    et al.
    Gyan, Ben A
    Goka, Bamenla Q
    Dodoo, Daniel
    Obeng-Adjei, George
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Akanmori, Bartholomew D
    Adjimani, Jonathan P
    Levels of soluble CD163 and severity of malaria in children in Ghana.2008In: Clinical and Vaccine Immunology, ISSN 1556-6811, E-ISSN 1556-679X, Vol. 15, no 9, p. 1456-60Article in journal (Refereed)
  • 330.
    Kuusela, Pertti
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Physiology.
    Effects of norepinephrine and insulin on brown adipose tissue lipid metabolism1996Doctoral thesis, comprehensive summary (Other academic)
  • 331.
    Larsson, Anna-Karin
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Early life cytokines, viral infections and IgE-mediated allergic disease2006Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: The reasons why some individuals become IgE-sensitised and allergic are largely unknown, though genetic- and early life environmental factors seem to be of importance.

    Objective: The overall aim of this thesis was to investigate the relationship between IgE-sensitisation and allergic disease, viral infections, genetic markers and early life cytokines.

    Results: IgE-sensitised children were found to have reduced numbers of IL-12 producing cord blood mononuclear cells (CBMC), whereas children diagnosed with eczema were found to have reduced numbers of IFN-γ producing CBMC. When dividing the children into early onset of IgE-sensitisation and late onset of IgE-sensitisation we found that the children with an early onset had low numbers of PHA-induced IL-4, IL-12 and IFN-γ secreting CBMC. At the age of two there was a general exacerbation of cytokine responses in the IgE-sensitised children, and the results were similar for the children with early onset IgE-sensitisation. Children with a late onset IgE-sensitisation were more similar to the non-sensitised children, but with a specific increase in the response to cat allergen (IL-4 and IFN-γ). The mothers of IgE-sensitised children, were just as their children, found to have an exaggerated cytokine response as compared to mothers of non-sensitised children. Maternal responses correlated well to the responses seen in the child, though the samples were taken two years after delivery.

    Cytomegalovirus (CMV) infection in early life was associated to reduced numbers of IL-4, and increased numbers of IFN-γ producing cells at the age of two. No association between CMV seropositivity and IgE-sensitisation was seen. Epstein-Barr virus (EBV) infection, on the other hand, was inversely correlated with IgE –sensitisation, whereas no statistically significant association to cytokine production could be seen.

    We also showed that the IL12B 1188 C-allele was associated to having a positive skin prick test at the age of two. The rare alleles of the three SNPs investigated (IL12B 1188C, IL12RB1132C and IRF1 1688A) were all associated to low IL-12 production at birth.

    Conclusions: Our results indicate that allergic diseases are complex traits, and that both the genetic and the cytokine background differ between the different allergic diseases. We can also conclude that the time of onset seem to play a role when investigating IgE-sensitisation, and that perhaps early and late onset IgE-sensitisation have partly different causes. CMV and EBV infection early in life are associated to a protective cytokine profile and to protection from IgE-sensitisation, respectively, again indicating the heterogeneity and the complexity of allergic diseases.

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  • 332.
    Larsson, Anna-Karin
    et al.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Nilsson, Caroline
    Höglind, Ankie
    Sverremark-Ekström, Eva
    Lilja, Gunnar
    Troye-Blomberg, Marita
    Relationship between maternal and child cytokine responses to allergen and phytohaemagglutinin 2 years after delivery2005In: Clinical and Experimental Immunology, ISSN 0009-9104, Vol. 144, no 3, p. 801-808Article in journal (Refereed)
  • 333.
    Larsson, Anna-Karin
    et al.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Vafa, Manijeh
    Montgomery, Scott M
    van Tuyl, Miranda
    Nilsson, Caroline
    Höglind, Ankie
    Gabrielsson, Susanne
    Lilja, Gunnar
    Troye-Blomberg, Marita
    The IL12B 1188 C-allele associate with low interleukin-12 and to a positive skin prick testManuscript (Other academic)
  • 334.
    Larsson, Håkan
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Profilactin and the regulation of actin assembly and disassembly1985Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Actin filament assembly and disassembly are believed to be fundamental steps in the mechanism of cell motility in non-muscle cells. Profilactin is a complex between monomeric actin and a small protein, profilin, which inhibits the polymerization of the actin. It is assumed that profilactin is an unpolymerized storage form of actin in the cell and that profilin is of central importance to the regulation of actin physiology. Previously, biochemical characterization of calf spleen profilactin has been difficult because of a disturbing variability in the stability between different preparations of the complex.

    This thesis demonstrates that the major reason for the variation in the stability of profilactin was the presence of minute amounts of contaminating protein factors that affect actin polymerization, presumably by binding specifically to one of the ends of the actin polymer. Conditions for the removal of these contaminating factors have been worked out and for the isolation of intact homogeneous profilin and actin. It is shown that the properties of the reconstituted complex are essentially the same as those of the isolated 'native' complex. The effects of profilin on spleen actin assembly and disassembly have been studied and apparent dissociation constants have been determined for the spleen complex as well as for the heterologous complex formed between spleen profilin and actin isolated from rabbit skeletal muscle. Finally, it has been shown that the spleen proteins, both separately and as a complex, specifically interact with detergents and the hydrophobic probe DPH.

  • 335.
    Larsson, Sofia L.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Structural and functional studies of the ribosomes: a closer look at expansion segments and translational dynamics in eukaryotes2001Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The ribosome is the basic machinery for protein synthesis in all living cells. In the last decade, there has been an explosion of structural information on the ribosome. The eukaryotic ribosome is larger than the prokaryotic counterpart and contains several extra features, even though they have similar core structures. The major size and shape differences are due to added ribosomal proteins and the eukaryote specific expansion segments in ribosomal RNA. In this thesis, the secondary structure of several expansion segments was determined in an effort to explore the structural, and possibly functional, differences between prokaryotic and eukaryotic ribosomes. An experimental modeling method was chosen, since the exclusive use of phylogenetic covariation analysis results in inconclusive structures, due to the variability of the segments. A wide range of chemical and enzymatic modification reagents was used to probe the ribosomal RNA. The experimental data was combined with phylogenetic alignments, and applied in computer modeling based on energy minimization. Secondary structure models are presented for ES15 and ES39 in 28S rRNA from mouse, rat and rabbit, in addition to wheat in the latter case. Models are also proposed for V4 in 18S rRNA from mouse and wheat. Hopefully, these models can in time be fit into the three-dimensional ribosome structures and give us an indication of the role that expansion segments play in eukaryotic protein synthesis.

    Experimental probing of the rRNA and analysis of the three-dimensional models of the ribosome has made it clear that the ribosome exhibits inherent dynamic characteristics during translation. The flexibility is especially evident during the elongation cycle. Disruption of the ability of the ribosome to progress through different conformations during elongation destroys the ribosome's capacity to add new amino acids to the growing peptide chain. For instance, the function of elongation factors eEF2 and eEF1 is affected by the ribosome inactivating proteins ricin and -sarcin, respectively. Native ribosomes were treated with these inhibitors, which resulted in modification patterns that only partially overlap. This indicates that the different effects of the two inhibitors in ribosomal function are reflected in different effects on the conformation of ribosomal RNA. This is especially true at the GTPase activating center of the ribosome, i.e. the interaction site of the elongation factors. 

  • 336.
    Lassing, Ingrid
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Cell Biology.
    Hillberg, Louise
    Karolinska institutet.
    Höglund, Anna-Stina
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Karlsson, Roger
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Cell Biology.
    Schutt, Clarence
    Princeton University.
    Lindberg, Uno
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Tropomyosin is a tetramer under physiological salt conditions.2010In: Cytoskeleton (Hoboken, N.J.), ISSN 1949-3592, Vol. 67, no 9, p. 599-607Article in journal (Refereed)
    Abstract [en]

    Tropomyosin (TM) is a coiled-coil dimer of alpha-helical peptides, which self associates in a head- to-tail fashion along actin polymers, conferring stability to the microfilaments and serving a regulatory function in acto-myosin driven force generation. While the major amount of TM is associated with filaments also in non-muscle cells, it was recently reported that there are isoform-specific pools of TM multimers (not associated with F-actin), which appear to be utilized during actin polymerization and reformed during depolymerization. To determine the size of these multimers, skeletal muscle TM was studied under different salt conditions using gel-filtration and sucrose gradient sedimentation, and compared with purified non-muscle TM 1 and 5, as well as with TM present in non-muscle cell extracts and skeletal muscle TM added to such extracts. Under physiological salt conditions TM appears as a single homogenous peak with the Stokes radius 8.2 nm and the molecular weight (mw) 130,000. The corresponding values for TM 5 are 7.7 nm and 104,000, respectively. This equals four peptides, implying that native TM is a tetramer in physiological salt. It is therefore concluded that the TM multimers are tetramers.

  • 337. Laurencikiene, Jurga
    et al.
    Tamosiunas, Vytas
    Severinson, Eva
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Regulation of epsilon germline transcription and switch region mutations by IgH locus 3' enhancers in transgenic mice.2007In: Blood, ISSN 0006-4971, Vol. 109, no 1, p. 159-67Article in journal (Refereed)
  • 338.
    Lettesjö, Helene
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Immunoregulatory factors in synovial fluid of rheumatoid arthritis patients1998Doctoral thesis, comprehensive summary (Other academic)
  • 339.
    Li, Yu
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Cell Behavior and the Role of Profilin2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Profilin is a key regulator of the microfilament system. It binds to actin monomers in a 1:1 complex, forming the profilin:actin complex, which is the major precursor of actin for filament formation in vivo. The distribution of profilin has been studied in a variety of cells. It is present not only in the cytoplasm but also in the nucleus. In the cytoplasm, it is evenly distributed in a dotted pattern, which is concentrated at the edge of advancing lamellipodia and in the perinuclear region. In the nucleus, it is localized to Speckles and Cajal bodies. However, the distribution of the profilin:actin has not been possible to establish due to the lack of specific reagents. In this thesis I present the localization of the profilin:actin complex and demonstrate the importance of profilin during cell migration.

    The distribution of the profilin:actin complex was studied using affinity purified antibodies generated against a covalently coupled variant of profilin:actin in colocalization experiments with VASP and the Arp2/3 complex. In both cases, close co-distribution with profilin:actin was found. In order to study the role of profilin in vivo in migratory cells, I used the siRNA-technique to deplete profilin from motile mouse melanoma B16 cells. The particular cell line employed expressed actin fused to green fluorescent protein, which enabled imaging of live cells. Upon profilin-deficiency severe effects on cell behavior were observed, e.g. the cells lacked the ability to form characteristic broad lamellipodia at advancing edges, instead small protruding structures were generated and extended with a significantly reduced rate compared to control cells. Observations were also made suggesting that profilin regulates the expression of actin in mammalian cells.

    A new experimental system for studies of myoblast fusion and subsequent myotube formation in vitro was also established during these studies. This will facilitate systematic studies of molecular processes connected to muscle development.

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  • 340.
    Li, Yu
    et al.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Grenklo, Staffan
    Higgins, Theresa
    Karlsson, Roger
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    The profilin:actin complex localizes to sites of dynamic actin polymerization at the leading edge of migrating cells and pathogen-induced actin tails.2008In: Eur J Cell Biol, ISSN 0171-9335, Vol. 87, no 11, p. 893-904Article in journal (Refereed)
  • 341.
    Li, Yu
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Grenklo, Staffan
    Karlsson, Roger
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Localization of the Profilin:Actin complex in Migrating cells: Co-distribution with VASP and Arp2/3Article in journal (Refereed)
  • 342.
    Li, Yu
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Johnsson, Anna-Karin
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Karlsson, Roger
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Profilin controls actin mRNA level, microfilament organization and cell migration of B16 mouse melanoma cellsManuscript (Other academic)
  • 343.
    Lilja, Tobias
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Functions of Transcriptional Co-regulators in Drosophila development2007Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    During Drosophila development, regulation of gene expression through interplay between transcriptional activators and repressors is generating complex patterns of gene expression that leads to cell differentiation. For proper control of transcription, transcription factors bind to DNA at control regions, so called Cis Regulatory Modules (CRM). Transcription factors recruit additional factors, co-regulators, that affect gene expression through interactions with the general transcription machinery, as well as affect the chromatin environment through post-translational modifications of the histone tails. In this thesis the role of transcriptional co-regulators in Drosophila development is investigated.

    This work has demonstrated the need for the transcriptional co-activator CREB binding protein (CBP) in signalling by the Transforming Growth Factor-β (TGF-β) molecules Decapentaplegic (Dpp) and Screw (Scw) in early embryos. Furthermore it is shown that the acetyl transferase activity of CBP is dispensable for this function.

    In a screen for novel regulators of gene expression in the embryo, Brakeless (Bks) was isolated as a co-repressor for the Tailless (Tll) transcription factor. This work shows that Tll function is impaired in bks mutants, that Bks and Tll bind each other in vitro and interact genetically. Bks is present on CRMs controlled by Tll and can repress transcription when tethered to DNA. Bks interacts and functions together with another co-repressor Atrophin.

    Reptin is part of several complexes including the TIP60 Histone Acetyl Transferase (HAT) complex. Work in this thesis show that Reptin and other members of the TIP60 complex function in formation of silent chromatin in Drosophila.

    Together these results show that transcriptional co-regulators function selectively in specific processes during development.

  • 344.
    Lilja, Tobias
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Aihara, Hitoshi
    Stabell, Marianne
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Nibu, Yutaka
    Mannervik, Mattias
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    The acetyltransferase activity of Drosophila CBP is dispensable for regulation of the Dpp pathway in the early embryo2007In: Developmental Biology, ISSN 0012-1606, E-ISSN 1095-564X, Vol. 305, no 2, p. 650-658Article in journal (Refereed)
    Abstract [en]

    The CBP protein is a transcriptional co-activator and histone acetyltransferase. Reduced expression of Drosophila CBP (dCBP) in the early embryo specifically impairs signaling by the TGF-β molecules Dpp and Screw (Scw). This occurs by a failure to activate transcription of the tolloid (tld) gene, which codes for a protease that generates active Dpp and Scw ligands. We show that dCBP directly regulates this gene by binding to the tld enhancer, and that tld expression can be partially rescued with a dCBP transgene. At a slightly later stage of development, Dpp/Scw signaling recovers in mutant embryos, but is unable to turn on expression of the Dpp/Scw-target gene rhomboid (rho). Interestingly, an acetyltransferase (AT)-defective dCBP transgene rescued tld and rho gene expression to an extent comparable to the wild-type transgene, whereas a transgene containing a 130 amino acid deletion rescued tld but not late rho expression. A tracheal phenotype caused by the reduced dCBP levels was also rescued more efficiently with the wild-type dCBP transgene than with this mutant transgene. Our results indicate that separate parts of the dCBP protein are required on different promoters, and that the AT activity of dCBP is dispensable for certain aspects of Dpp signaling. We discuss the similarity of these results to the role of p300/CBP in TGF-β signaling in the mouse.

  • 345.
    Lilja, Tobias
    et al.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Qi, Dai
    Stabell, Marianne
    Mannervik, Mattias
    The CBP coactivator functions both upstream and downstream of Dpp/Screw signalling in the early Drosophila embryo2003In: Developmental Biology, ISSN 0012-1606, Vol. 262, no 2, p. 294-302Article in journal (Refereed)
  • 346. Lindberg, Uno
    et al.
    Karlsson, Roger
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Lassing, Ingrid
    Schutt, Clarence E.
    Hoglund, Anna-Stina
    The microfilament system and malignancy2008In: Seminars in Cancer Biology, ISSN 1044-579X, E-ISSN 1096-3650, Vol. 18, no 1, p. 2-11Article, review/survey (Refereed)
    Abstract [en]

    Increased motile activity, increased rate of cell proliferation and removal of growth inhibiting cell-cell contacts are hallmarks of tumorigenesis. Activation of cell motility and migration is caused by activation of receptors, turning on the growth cycle. Increased expression of metalloproteinases, breaking cell:cell contacts and organ confines, allows the spread of malignant cancer cells to other sites in the organism. It has become increasingly clear that most transmembrane proteins (growth factor receptors, adhesion proteins and ion channels) are either permanently or transiently associated with the sub-membraneous system of actin microfilaments (MF), whose force generating capacity they control. Although there has been great progress in our understanding of the physiological importance of the MF-system, as will be exemplified in this issue of SCB, many aspects of actin microfilament formation and its regulation are still unclear. Redox control of the actin (MF)-system in cell motility and migration and its perturbations in pathophysiology, including cancer, is an emerging field of research. 

  • 347.
    Lindroth, Karin
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Maturation of humoral immune responses: Studies on the effects of antigen type, apoptosis and age2004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The humoral immune response is dependent on the formation of antibodies. Antibodies are produced by terminally differentiated B cells, plasma cells. Plasma cells are generated either directly from antigen challenged B cells, memory cells or from cells that have undergone the germinal center (GC) reaction. The GC is the main site for class switch, somatic hypermutation and generation of memory cells.

    Different factors, both internal and external, shape the outcome of the immune response. In this thesis, we have studied a few factors that influence the maturation of the humoral response. We have studied how age affects the response, and we show that responses against thymus dependent antigens (TD) are more affected than responses to thymus independent (TI) antigens, in concordance with the view that the T cell compartment is more affected by age than the B cell compartment. Furthermore, we demonstrate that priming early in life have a big influence on the immune response in the aged individual. Priming with a TI form of the carbohydrate dextran B512 (Dx) induces a reduction of IgG levels in later TD responses against Dx. We have evaluated possible mechanisms for this reduction. The reduction does not seem to be caused by clonal exhaustion or antibody mediated mechanisms. We also showed that the reduced TD response after TI priming can be induced against another molecule than Dx. With the hypothesis that TI antigens induce a plasma cell biased maturation of the responding B cells, we examined the presence of Blimp-1, a master regulator of plasma cell differentiation, in GCs induced by TD and TI antigen. Blimp-1 was found earlier in GCs induced by TI antigen and the staining intensity in these GCs was stronger than in TD antigen induced GCs, indicating that plasma cells might be continuously recruited from these GCs.

    B cells undergoing the GC reaction are thought to be under a strict selection pressure that removes cells with low affinity for the antigen and also cells that have acquired self-reactivity. We investigated the effect of apoptotic deficiencies on the accumulation of somatic mutations in GC B cells. In mice lacking the death receptor Fas, lpr mice, the frequency of mutations was increased but the pattern of the mutations did not differ from wild type mice. In contrast, mice over-expressing the anti-apoptotic protein Bcl-2, had a lowered frequency of mutations and the mutations introduced had other characteristics.

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  • 348.
    Lindroth, Karin
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Fernández, Carmen
    The role of Blimp-1 in the GC reaction: Differential expression of Blimp-1 upon immunization with TD and TI antigens2007In: Immunology Letters, ISSN 0165-2478, E-ISSN 1879-0542, Vol. 113, no 2, p. 70-75Article in journal (Refereed)
    Abstract [en]

    Humoral responses against thymus-dependent (TD) antigens are characterized by Ig class switch, somatic hypermutations (SHM) and generation of memory. These processes are thought to occur in the specialized environment of the germinal center (GC). Some thymus-independent (TI) antigens, such as native dextran B512 (Dx) can also induce formation of GCs, but the responses do not undergo substantial affinity maturation or induction of memory. Immunization with TI Dx affects later TD responses against the same epitope, reducing Dx specific IgG 1. We have studied if the different outcome of the TI- and TD-induced GC reaction is due to differences in plasma cell differentiation. The transcriptional repressor B lymphocyte-induced maturation protein, Blimp- 1, was used as a marker for differentiation of plasma cells. We show that TI GCs contain Blimp- I in early and mature GCs, in contrast to TD-induced GCs which strongly express Blimp- I only in established GCs. Furthermore, the intensity of the Blimp- I staining is stronger in TI GCs. In addition, we demonstrate that in TD responses after TI priming the pattern of Blimp- I expression is a mixture of both TI and TD responses. This is novel evidence since these TD Immoral responses against Dx display a TI isotype pattern.

  • 349.
    Lindroth, Karin
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Fernández Mastache, Elena
    Roos, Izaura
    González Fernández, África
    Fernández, Carmen
    Understanding thymus independent antigen induced reduction of thymus dependent immune responses2004In: Immunology, ISSN 0019-2805, E-ISSN 1365-2567, Vol. 112, no 3, p. 413-419Article in journal (Refereed)
    Abstract [en]

    Deficiencies in immune responses against polysaccharides can have direct consequences for patients, and therefore, a better understanding of these immune reactions is crucial. We have studied the immune response against the polysaccharide dextran B512 (Dx). Administration of immunogenic doses of thymus-independent (TI) Dx reduces the immunoglobulin G1 response to later challenges with a thymus-dependent (TD) form of Dx. We investigated if this suppression is a general phenomenon caused not only by Dx but also by other TI antigens, and examined possible mechanisms contributing to this unresponsiveness. We show that clonal exhaustion is not involved in modulating subsequent responses, nor is signalling via FcgammaRIIB or other antibody mediated pathways. The reduced TD response is not an exclusive Dx phenomenon; it is also induced by TI antigen oxazolone (Ox). However, responses against the hapten dinitrophenyl (DNP) are not affected, indicating that the TI priming negative effect is not a general process. This may be explained by the restricted immune response to both Dx and Ox, in contrast to the unrestricted DNP response. Our conclusion from these experiments is that the underlying mechanism for the TI-induced reduction of latter TD responses is a property of the TI activation itself.

  • 350. Lisowska, Halina
    et al.
    Deperas-Kaminska, Marta
    Haghdoost, Siamak
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Parmryd, Ingela
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Cell Biology.
    Wojcik, Andrzej
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Radiation-induced DNA damage and repair in human gammadelta and alphabeta T-lymphocytes analysed by the alkaline comet assay.2010In: Genome integrity, ISSN 2041-9414, Vol. 1, no 1, p. 8-Article in journal (Refereed)
    Abstract [en]

    ABSTRACT: It has been shown by a number of authors that the radiosensitivity of peripheral blood mononuclear cells (PBMC) is higher in cancer patients compared to healthy donors, which is interpreted as a sign of genomic instability. PBMC are composed of different cell subpopulations which are differently radiosensitive and the difference between cancer patients and healthy donors could also be due to different composition of their PBMC pools. Gamma-delta T-lymphocytes play an important role in immunosurveillance and are promising cells for immunotherapy. Their abundance is frequently reduced in cancer patients so should their sensitivity to radiation be lower than that of other T-lymphocytes, this could, at least partly explain the low radiosensitivity of PBMC from healthy individuals compared to cancer patients. The present investigation was carried out to test this. Using the alkaline comet assay we analysed the level of DNA damage and repair in isolated gammadelta T-lymphocytes, pan T-lymphocytes and in total PBMC exposed in vitro to gamma radiation. We found no difference in the level of DNA damage and the capacity of DNA repair between the T cell populations. This is the first study that addresses the question of sensitivity to radiation of gamma-delta T-cells.

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