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  • 1.
    Abdulamir, Dalia
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Evaluation of the Role of Histidines Regarding the Self-assembly and Fibrillar Stability of Amyloid βeta2015Independent thesis Basic level (degree of Bachelor), 10 poäng / 15 hpOppgave
  • 2.
    Adhikari, Deepak
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Signaling pathways in the development of female germ cells2014Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Primordial follicles are the first small follicles to appear in the mammalian ovary. Women are born with a fixed number of primordial follicles in the ovaries. Once formed, the pool of primordial follicles serves as a source of developing follicles and oocytes. The first aim of this thesis was to investigate the functional role of the intra-oocyte signaling pathways, especially the phosphatidylinositol-3 kinase (PI3K) and mammalian target of rapamycin complex 1 (mTORC1) pathways in the regulation of primordial follicle activation and survival. We found that a primordial follicle remains dormant when the PI3K and mTORC1 signaling in its oocyte is activated to an appropriate level, which is just sufficient to maintain its survival, but not sufficient for its growth initiation. Hyperactivation of either of these signaling pathways causes global activation of the entire pool of primordial follicles leading to the exhaustion of all the follicles in young adulthood in mice. Mammalian oocytes, while growing within the follicles, remain arrested at prophase I of meiosis. Oocytes within the fully-grown antral follicles resume meiosis upon a preovulatory surge of leutinizing hormone (LH), which indicates that LH mediates the resumption of meiosis. The prophase I arrest in the follicle-enclosed oocyte is the result of low maturation promoting factor (MPF) activity, and resumption of meiosis upon the arrival of hormonal signals is mediated by activation of MPF. MPF is a complex of cyclin dependent kinase 1 (Cdk1) and cyclin B1, which is essential and sufficient for entry into mitosis. Although much of the mitotic cell cycle machinery is shared during meiosis, lack of Cdk2  in mice leads to a postnatal loss of all oocytes, indicating that Cdk2 is important for oocyte survival, and probably oocyte meiosis also. There have been conflicting results earlier about the role of Cdk2 in metaphase II arrest of Xenopus  oocytes. Thus the second aim of the thesis was to identify the specific Cdk that is essential for mouse oocyte meiotic maturation. We generated mouse models with oocytespecific deletion of Cdk1  or Cdk2  and studied the specific requirements of Cdk1 and Cdk2 during resumption of oocyte meiosis. We found that only Cdk1 is essential and sufficient for the oocyte meiotic maturation. Cdk1 does not only phosphorylate the meiotic phosphoproteins during meiosis resumption but also phosphorylates and suppresses the downstream protein phosphatase 1, which is essential for protecting the Cdk1 substrates from dephosphorylation.

  • 3.
    Adhikari, Deepak
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Flohr, Gilian
    Hogeschool Leiden, Zernikedreef 11,2333 CK Leiden, The Netherlands.
    Gorre, Nagaraju
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Shen, Yan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Yang, Hairu
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Lundin, Eva
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Lan, Zijian
    University of Louisville Health Sciences Center, Louisville, Kentucky, USA.
    Liu, Kui
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Disruption of Tsc2 in oocytes leads to overactivation of the entire pool of primordial follicles2009Inngår i: Molecular human reproduction, ISSN 1360-9947, E-ISSN 1460-2407, Vol. 15, nr 12, 765-770 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    To maintain the length of reproductive life in a woman, it is essential that most of her ovarian primordial follicles are maintained in a quiescent state to provide a continuous supply of oocytes. However, our understanding of the molecular mechanisms that control the quiescence and activation of primordial follicles is still in its infancy. In this study, we provide some genetic evidence to show that the tumor suppressor tuberous sclerosis complex 2 (Tsc2), which negatively regulates mammalian target of rapamycin complex 1 (mTORC1), functions in oocytes to maintain the dormancy of primordial follicles. In mutant mice lacking the Tsc2 gene in oocytes, the pool of primordial follicles is activated prematurely due to elevated mTORC1 activity in oocytes. This results in depletion of follicles in early adulthood, causing premature ovarian failure (POF). Our results suggest that the Tsc1-Tsc2 complex mediated suppression of mTORC1 activity is indispensable for maintenance of the dormancy of primordial follicles, thus preserving the follicular pool, and that mTORC1 activity in oocytes promotes follicular activation. Our results also indicate that deregulation of Tsc/mTOR signaling in oocytes may cause pathological conditions of the ovary such as infertility and POF.

  • 4.
    Adhikari, Deepak
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Liu, Kui
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Molecular mechanisms underlying the activation of mammalian primordial follicles2009Inngår i: Endocrine reviews, ISSN 0163-769X, E-ISSN 1945-7189, Vol. 30, nr 5, 438-464 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In humans and other mammalian species, the pool of resting primordial follicles serves as the source of developing follicles and fertilizable ova for the entire length of female reproductive life. One question that has intrigued biologists is: what are the mechanisms controlling the activation of dormant primordial follicles. Studies from previous decades have laid a solid, but yet incomplete, foundation. In recent years, molecular mechanisms underlying follicular activation have become more evident, mainly through the use of genetically modified mouse models. As hypothesized in the 1990s, the pool of primordial follicles is now known to be maintained in a dormant state by various forms of inhibitory machinery, which are provided by several inhibitory signals and molecules. Several recently reported mutant mouse models have shown that a synergistic and coordinated suppression of follicular activation provided by multiple inhibitory molecules is necessary to preserve the dormant follicular pool. Loss of function of any of the inhibitory molecules for follicular activation, including PTEN (phosphatase and tensin homolog deleted on chromosome 10), Foxo3a, p27, and Foxl2, leads to premature and irreversible activation of the primordial follicle pool. Such global activation of the primordial follicle pool leads to the exhaustion of the resting follicle reserve, resulting in premature ovarian failure in mice. In this review, we summarize both historical and recent results on mammalian primordial follicular activation and focus on the up-to-date knowledge of molecular networks controlling this important physiological event. We believe that information obtained from mutant mouse models may also reflect the molecular machinery responsible for follicular activation in humans. These advances may provide a better understanding of human ovarian physiology and pathophysiology for future clinical applications.

  • 5.
    Adhikari, Deepak
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Liu, Kui
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    mTOR signaling in the control of activation of primordial follicles2010Inngår i: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 9, nr 9, 1673-1674 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 6.
    Adhikari, Deepak
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Zheng, Wenjing
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Shen, Yan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Gorre, Nagaraju
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Hämäläinen, Tuula
    Cooney, Austin J
    Huhtaniemi, Ilpo
    Lan, Zi-Jian
    Liu, Kui
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Tsc/mTORC1 signaling in oocytes governs the quiescence and activation of primordial follicles2010Inngår i: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 19, nr 3, 397-410 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    To maintain the female reproductive lifespan, the majority of ovarian primordial follicles are preserved in a quiescent state in order to provide ova for later reproductive life. However, the molecular mechanism that maintains the long quiescence of primordial follicles is poorly understood. Here we provide genetic evidence to show that the tumor suppressor tuberous sclerosis complex 1 (Tsc1), which negatively regulates mammalian target of rapamycin complex 1 (mTORC1), functions in oocytes to maintain the quiescence of primordial follicles. In mutant mice lacking the Tsc1 gene in oocytes, the entire pool of primordial follicles is activated prematurely due to elevated mTORC1 activity in the oocyte, ending up with follicular depletion in early adulthood and causing premature ovarian failure (POF). We further show that maintenance of the quiescence of primordial follicles requires synergistic, collaborative functioning of both Tsc and PTEN (phosphatase and tensin homolog deleted on chromosome 10) and that these two molecules suppress follicular activation through distinct ways. Our results suggest that Tsc/mTORC1 signaling and PTEN/PI3K (phosphatidylinositol 3 kinase) signaling synergistically regulate the dormancy and activation of primordial follicles, and together ensure the proper length of female reproductive life. Deregulation of these signaling pathways in oocytes results in pathological conditions of the ovary, including POF and infertility.

  • 7.
    Adhikari, Deepak
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Zheng, Wenjing
    Univ Gothenburg, Dept Chem & Mol Biol, SE-40530 Gothenburg, Sweden.
    Shen, Yan
    Univ Gothenburg, Dept Chem & Mol Biol, SE-40530 Gothenburg, Sweden.
    Gorre, Nagaraju
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Ning, Yao
    Univ Gothenburg, Dept Chem & Mol Biol, SE-40530 Gothenburg, Sweden.
    Halet, Guillaume
    Univ Rennes 1, CNRS, UMR 6061, Inst Genet & Dev Rennes, F-35043 Rennes, France .
    Kaldis, Philipp
    NUS, A STAR, IMCB, Singapore 138673, Singapore.
    Liu, Kui
    Univ Gothenburg, Dept Chem & Mol Biol, SE-40530 Gothenburg, Sweden.
    Cdk1, but not Cdk2, is the sole Cdk that is essential and sufficient to drive resumption of meiosis in mouse oocytes2012Inngår i: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 21, nr 11, 2476-2484 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Mammalian oocytes are arrested at the prophase of meiosis I during fetal or postnatal development, and the meiosis is resumed by the preovulatory surge of luteinizing hormone. The in vivo functional roles of cyclin-dependent kinases (Cdks) during the resumption of meiosis in mammalian oocytes are largely unknown. Previous studies have shown that deletions of Cdk3, Cdk4 or Cdk6 in mice result in viable animals with normal oocyte maturation, indicating that these Cdks are not essential for the meiotic maturation of oocytes. In addition, conventional knockout of Cdk1 and Cdk2 leads to embryonic lethality and postnatal follicular depletion, respectively, making it impossible to study the functions of Cdk1 and Cdk2 in oocyte meiosis. In this study, we generated conditional knockout mice with oocyte-specific deletions of Cdk1 and Cdk2. We showed that the lack of Cdk1, but not of Cdk2, leads to female infertility due to a failure of the resumption of meiosis in the oocyte. Re-introduction of Cdk1 mRNA into Cdk1-null oocytes largely resumed meiosis. Thus, Cdk1 is the sole Cdk that is essential and sufficient to drive resumption of meiosis in mouse oocytes. We also found that Cdk1 maintains the phosphorylation status of protein phosphatase 1 and lamin A/C in oocytes in order for meiosis resumption to occur.

  • 8.
    Aguilar, Ximena
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Blomberg, Jeanette
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Brännström, Kristoffer
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Olofsson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Schleucher, Jurgen
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Björklund, Stefan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Interaction Studies of the Human and Arabidopsis thaliana Med25-ACID Proteins with the Herpes Simplex Virus VP16-and Plant-Specific Dreb2a Transcription Factors2014Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 5, e98575- s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Mediator is an evolutionary conserved multi-protein complex present in all eukaryotes. It functions as a transcriptional coregulator by conveying signals from activators and repressors to the RNA polymerase II transcription machinery. The Arabidopsis thaliana Med25 (aMed25) ACtivation Interaction Domain (ACID) interacts with the Dreb2a activator which is involved in plant stress response pathways, while Human Med25-ACID (hMed25) interacts with the herpes simplex virus VP16 activator. Despite low sequence similarity, hMed25-ACID also interacts with the plant-specific Dreb2a transcriptional activator protein. We have used GST pull-down-, surface plasmon resonance-, isothermal titration calorimetry and NMR chemical shift experiments to characterize interactions between Dreb2a and VP16, with the hMed25 and aMed25-ACIDs. We found that VP16 interacts with aMed25-ACID with similar affinity as with hMed25-ACID and that the binding surface on aMed25-ACID overlaps with the binding site for Dreb2a. We also show that the Dreb2a interaction region in hMed25-ACID overlaps with the earlier reported VP16 binding site. In addition, we show that hMed25-ACID/Dreb2a and aMed25-ACID/Dreb2a display similar binding affinities but different binding energetics. Our results therefore indicate that interaction between transcriptional regulators and their target proteins in Mediator are less dependent on the primary sequences in the interaction domains but that these domains fold into similar structures upon interaction.

  • 9.
    Aksenova, Anna
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Muñoz, Iván
    Volkov, Kirill
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Ariño, Joaquín
    Mironova, Ludmila
    The HAL3-PPZ1 dependent regulation of nonsense suppression efficiency in yeast and its influence on manifestation of the yeast prion-like determinant [ISP(+)].2007Inngår i: Genes to Cells, ISSN 1356-9597, E-ISSN 1365-2443, Vol. 12, nr 4, 435-546 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The efficiency of stop codons read-through in yeast is controlled by multiple interactions of genetic and epigenetic factors. In this study, we demonstrate the participation of the Hal3-Ppz1 protein complex in regulation of read-through efficiency and manifestation of non-Mendelian anti-suppressor determinant [ISP(+)]. Over-expression of HAL3 in [ISP(+)] strain causes nonsense suppression, whereas its inactivation displays as anti-suppression of sup35 mutation in [isp(-)] strain. [ISP(+)] strains carrying hal3Delta deletion cannot be cured from [ISP(+)] in the presence of GuHCl. Since Hal3p is a negative regulatory subunit of Ppz1 protein phosphatase, consequences of PPZ1 over-expression and deletion are opposite to those of HAL3. The observed effects are mediated by the catalytic function of Ppz1 and are probably related to the participation of Ppz1 in regulation of eEF1Balpha elongation factor activity. Importantly, [ISP(+)] status of yeast strains is determined by fluctuation in Hal3p level, since [ISP(+)] strains have less Hal3p than their [isp(-)] derivatives obtained by GuHCl treatment. A model considering epigenetic (possibly prion) regulation of Hal3p amount as a mechanism underlying [ISP(+)] status of yeast cell is suggested.

  • 10.
    Aksenova, Anna
    et al.
    Department of Biology, Tufts University, Medford, Massachusetts, United States of America.
    Volkov, Kirill
    School of Biology, Georgia Institute of Technology, Atlanta, Georgia, United States of America.
    Maceluch, Jaroslaw
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Pursell, Zachary F
    Department of Biochemistry, Tulane University Health Sciences Center, New Orleans, Louisiana, United States of America.
    Rogozin, Igor B
    National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, United States of America.
    Kunkel, Thomas A
    Laboratory of Molecular Genetics and Laboratory of Structural Biology, National Institute of Environmental Health Sciences, National Institutes of Heath, Department of Health and Human Services, Research Triangle Park, North Carolina, United States of America.
    Pavlov, Youri I
    Eppley Institute for Research in Cancer, Department of Biochemistry and Molecular Biology, and Department of Microbiology and Pathology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
    Johansson, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Mismatch repair-independent increase in spontaneous mutagenesis in yeast lacking non-essential subunits of DNA polymerase ε2010Inngår i: PLoS genetics, ISSN 1553-7404, Vol. 6, nr 11, e1001209- s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Yeast DNA polymerase ε (Pol ε) is a highly accurate and processive enzyme that participates in nuclear DNA replication of the leading strand template. In addition to a large subunit (Pol2) harboring the polymerase and proofreading exonuclease active sites, Pol ε also has one essential subunit (Dpb2) and two smaller, non-essential subunits (Dpb3 and Dpb4) whose functions are not fully understood. To probe the functions of Dpb3 and Dpb4, here we investigate the consequences of their absence on the biochemical properties of Pol ε in vitro and on genome stability in vivo. The fidelity of DNA synthesis in vitro by purified Pol2/Dpb2, i.e. lacking Dpb3 and Dpb4, is comparable to the four-subunit Pol ε holoenzyme. Nonetheless, deletion of DPB3 and DPB4 elevates spontaneous frameshift and base substitution rates in vivo, to the same extent as the loss of Pol ε proofreading activity in a pol2-4 strain. In contrast to pol2-4, however, the dpb3Δdpb4Δ does not lead to a synergistic increase of mutation rates with defects in DNA mismatch repair. The increased mutation rate in dpb3Δdpb4Δ strains is partly dependent on REV3, as well as the proofreading capacity of Pol δ. Finally, biochemical studies demonstrate that the absence of Dpb3 and Dpb4 destabilizes the interaction between Pol ε and the template DNA during processive DNA synthesis and during processive 3' to 5'exonucleolytic degradation of DNA. Collectively, these data suggest a model wherein Dpb3 and Dpb4 do not directly influence replication fidelity per se, but rather contribute to normal replication fork progression. In their absence, a defective replisome may more frequently leave gaps on the leading strand that are eventually filled by Pol ζ or Pol δ, in a post-replication process that generates errors not corrected by the DNA mismatch repair system.

  • 11.
    Alanentalo, Tomas
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Hörnblad, Andreas
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Mayans, Sofia
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Nilsson, Anna Karin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Sharpe, James
    Larefalk, Åsa
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Ahlgren, Ulf
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Holmberg, Dan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Quantification and 3-D imaging of the insulitis-induced destruction of β-cells in murine type 1 diabetes2010Inngår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 59, nr 7, 1756-1764 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: The aim of this study was to refine the information regarding the quantitative and spatial dynamics of infiltrating lymphocytes and remaining beta-cell volume during the progression of type 1 diabetes in the NOD mouse model of the disease.

    Research design and methods: Using an ex vivo technique, optical projection tomography (OPT), we quantified and assessed the 3D spatial development and progression of insulitis and beta-cell destruction in pancreas from diabetes prone NOD and non-diabetes prone congenic NOD.H-2b mice between 3 and 16 weeks of age.

    Results: Together with results showing the spatial dynamics of the insulitis process we provide data of beta-cell volume distributions down to the level of the individual islets and throughout the pancreas during the development and progression of type 1 diabetes. Our data provide evidence for a compensatory growth potential of the larger insulin(+) islets during the later stages of the disease around the time point for development of clinical diabetes. This is in contrast to smaller islets, which appear less resistant to the autoimmune attack. We also provide new information on the spatial dynamics of the insulitis process itself, including its apparently random distribution at onset, the local variations during its further development, and the formation of structures resembling tertiary lymphoid organs at later phases of insulitis progression.

    Conclusions: Our data provides a powerful tool for phenotypic analysis of genetic and environmental effects on type 1 diabetes etiology as well as for evaluating the potential effect of therapeutic regimes.

  • 12. Alcocer, M. J. C.
    et al.
    Murtagh, G. J.
    Mirotti, L.
    Brans, A.
    Harnett, W.
    Rundqvist, Louise
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Larsson, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    The allergenicity of 2S plant albumins2011Inngår i: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 41, nr 12, 1827-1827 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 13. Alcocer, Marcos
    et al.
    Rundqvist, Louise
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Larsson, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Ber e 1 protein: the versatile major allergen from Brazil nut seeds.2012Inngår i: Biotechnology letters, ISSN 0141-5492, E-ISSN 1573-6776, Vol. 34, nr 4, 597-610 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Due mainly to its extremely high content of sulphur amino acids, Ber e 1 protein, the major allergen from Brazil nut, has attracted much scientific and press attention. Ber e 1 was the main target protein in early biotechnology transgenic work, in early processing studies of plant storage proteins, in plant vacuolar targeting studies and as the main protein in early nutritional supplementation experiments. Ber e 1 was also one of the first food allergens to be unintentionally transferred from one plant to another and was involved in the first reported case of systemic allergic reaction caused by a food allergen transferred in semen. In this review, many of the Ber e 1 unique biotechnological and structural functions are discussed with a particular emphasis on its use as model protein for studies of intrinsic allergenicity of food proteins.

  • 14. Aleshkov, S B
    et al.
    Fa, M
    Karolin, J
    Strandberg, L
    Johansson, L B
    Wilczynska, M
    Ny, Tor
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Biochemical and biophysical studies of reactive center cleaved plasminogen activator inhibitor type 1. The distance between P3 and P1' determined by donor-donor fluorescence energy transfer.1996Inngår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 271, nr 35, 21231-8 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Plasminogen activator inhibitor type 1 (PAI-1) is a fast acting inhibitor of plasminogen activators (PAs). In accordance with other serpins, PAI-1 is thought to undergo a conformational change upon reactive center cleavage. In this study we have developed methods to produce and purify reactive center cleaved wild-type PAI-1 and characterized this molecular form of PAI-1 by biochemical and biophysical methods. Incubation with Sepharose-bound trypsin caused cleavage only at the P1-P1' bond in the reactive center and resulted in 39- and 4-kDa polypeptides, strongly held together by noncovalent interactions. Circular dichroism measurements suggest that the reactive center cleavage triggers larger conformational changes than the conversion from the active to the latent form. Cleaved PAI-1 did not bind to either PAs or vitronectin but retained the heparin-binding capacity. To study the structure of cleaved PAI-1 by polarized fluorescence spectroscopy and to measure intramolecular distances, we used cysteine substitution mutants to which extrinsic fluorescence probes were attached. These studies revealed increasing orientational freedom of probes in the P3 and P1' positions upon cleavage. Distance measurements based on fluorescence energy transfer between probes in positions P3 and P1' indicate that these residues are separated by at least 68 +/- 10 A in cleaved PAI-1.

  • 15.
    Al-Furoukh, Natalie
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Ianni, Alessandro
    Nolte, Hendrik
    Hölper, Soraya
    Krüger, Marcus
    Wanrooij, Sjoerd
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Braun, Thomas
    ClpX stimulates the mitochondrial unfolded protein response (UPRmt) in mammalian cells2015Inngår i: Biochimica et Biophysica Acta. Molecular Cell Research, ISSN 0167-4889, E-ISSN 1879-2596, Vol. 1853, nr 10, 2580-2591 s.Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 16. Andersen, Gorm
    et al.
    Björnberg, Olof
    Polakova, Silvia
    Pynyaha, Yuriy
    Rasmussen, Anna
    Møller, Kasper
    Hofer, Anders
    Umeå universitet, Medicinsk fakultet, Medicinsk kemi och biofysik.
    Moritz, Thomas
    Sandrini, Michael Paolo Bastner
    Merico, Anna-Maria
    Compagno, Concetta
    Akerlund, Hans-Erik
    Gojković, Zoran
    Piskur, Jure
    A second pathway to degrade pyrimidine nucleic acid precursors in eukaryotes.2008Inngår i: Journal of Molecular Biology, ISSN 1089-8638, Vol. 380, nr 4, 656-66 s.Artikkel i tidsskrift (Annet vitenskapelig)
  • 17. Andersson, J
    et al.
    Westman, M
    Hofer, Anders
    Umeå universitet, Medicinsk fakultet, Medicinsk kemi och biofysik.
    Sjoberg, B M
    Allosteric regulation of the class III anaerobic ribonucleotide reductase from bacteriophage T4.2000Inngår i: Journal of Biological Chemistry, ISSN 0021-9258, Vol. 275, nr 26, 19443-8 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 18.
    Andersson, Jesper
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Low frequency of sequence variants in EEF1A1 in clear cell Renal Cell Carcinoma2014Independent thesis Basic level (degree of Bachelor), 10 poäng / 15 hpOppgave
  • 19.
    Andersson, Jesper
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Role of pro-inflammatory S100A8 and S100A9 proteins in the neuro-inflammatory amyloid cascade in traumatic brain injury and age-dependent diseases2016Independent thesis Advanced level (degree of Master (Two Years)), 20 poäng / 30 hpOppgave
  • 20.
    Andersson, Simon
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    The role of RPA and MRN complex as sensors of DNA damage. A studie of aRPA and tRPA´s interaction with DNA and MRN subunits.2014Independent thesis Advanced level (professional degree), 20 poäng / 30 hpOppgave
  • 21. Aspholm, Marina
    et al.
    Kalia, Awdhesh
    Ruhl, Stefan
    Schedin, Staffan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för tillämpad fysik och elektronik.
    Arnqvist, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Lindén, Sara
    Sjöström, Rolf
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Gerhard, Markus
    Semino-Mora, Cristina
    Dubois, Andre
    Unemo, Magnus
    Danielsson, Dan
    Teneberg, Susann
    Lee, Woo-Kon
    Berg, Douglas E
    Borén, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Helicobacter pylori adhesion to carbohydrates.2006Inngår i: Methods in enzymology, ISSN 0076-6879, Vol. 417, 293-339 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 22. Aspholm, Marina
    et al.
    Olfat, Farzad O
    Nordén, Jenny
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Sondén, Berit
    Lundberg, Carina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Sjöström, Rolf
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Altraja, Siiri
    Odenbreit, Stefan
    Haas, Rainer
    Wadström, Torkel
    Engstrand, Lars
    Semino-Mora, Cristina
    Liu, Hui
    Dubois, André
    Teneberg, Susann
    Arnqvist, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Borén, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    SabA is the H. pylori hemagglutinin and is polymorphic in binding to sialylated glycans.2006Inngår i: PLoS Pathog, ISSN 1553-7374, Vol. 2, nr 10, e110- s.Artikkel i tidsskrift (Fagfellevurdert)
  • 23.
    Aspholm-Hurtig, Marina
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Oral mikrobiologi.
    Dailide, Giedrius
    Lahmann, Martina
    Kalia, Awdhesh
    Ilver, Dag
    Roche, Niamh
    Vikström, Susanne
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Oral mikrobiologi.
    Sjöström, Rolf
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Oral mikrobiologi. Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Lindén, Sara
    Bäckström, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Oral mikrobiologi.
    Lundberg, Carina
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Oral mikrobiologi.
    Arnqvist, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Oral mikrobiologi. Umeå universitet, Medicinska fakulteten, Molekylärbiologi (Teknat- och Medfak). Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Mahdavi, Jafar
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Oral mikrobiologi.
    Nilsson, Ulf J
    Velapatiño, Billie
    Gilman, Robert H
    Gerhard, Markus
    Alarcon, Teresa
    López-Brea, Manuel
    Nakazawa, Teruko
    Fox, James G
    Correa, Pelayo
    Dominguez-Bello, Maria Gloria
    Perez-Perez, Guillermo I
    Blaser, Martin J
    Normark, Staffan
    Carlstedt, Ingemar
    Oscarson, Stefan
    Teneberg, Susann
    Berg, Douglas E
    Borén, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Oral mikrobiologi.
    Functional adaptation of BabA, the H. pylori ABO blood group antigen binding adhesin.2004Inngår i: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 305, nr 5683, 519-522 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Adherence by Helicobacter pylori increases the risk of gastric disease. Here, we report that more than 95% of strains that bind fucosylated blood group antigen bind A, B, and O antigens (generalists), whereas 60% of adherent South American Amerindian strains bind blood group O antigens best (specialists). This specialization coincides with the unique predominance of blood group O in these Amerindians. Strains differed about 1500-fold in binding affinities, and diversifying selection was evident in babA sequences. We propose that cycles of selection for increased and decreased bacterial adherence contribute to babA diversity and that these cycles have led to gradual replacement of generalist binding by specialist binding in blood group O-dominant human populations.

  • 24. Asturias, Francisco J
    et al.
    Cheung, Iris K
    Sabouri, Nasim
    Umeå universitet, Medicinsk fakultet, Medicinsk kemi och biofysik.
    Chilkova, Olga
    Umeå universitet, Medicinsk fakultet, Medicinsk kemi och biofysik.
    Wepplo, Daniel
    Johansson, Erik
    Umeå universitet, Medicinsk fakultet, Medicinsk kemi och biofysik.
    Structure of Saccharomyces cerevisiae DNA polymerase epsilon by cryo-electron microscopy.2006Inngår i: Nature Structural & Molecular Biology, ISSN 1545-9993, E-ISSN 1545-9985, Vol. 13, nr 1, 35-43 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 25.
    Augusti, Angela
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Betson, Tatiana R.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Schleucher, Jurgen
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Deriving correlated climate and physiological signals from deuterium isotopomers in tree rings2008Inngår i: Chemical Geology, ISSN 0009-2541, E-ISSN 1872-6836, Vol. 252, nr 1-2, 1-8 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    he deuterium (D) abundance of tree-ring cellulose archives past climatic conditions, but previous attempts to access this archive have led to conflicting results. Based on an overview of D fractionation mechanisms in plants, we explain why past measurements of D abundance yield unreliable paleo signals. Our data show that variation in D abundance among the C–H groups (isotopomer variation) of tree-ring cellulose is generally greater than variation in D abundance due to climatic influences. A comparison of the D isotopomer abundances of soluble sugars of annual plants and of trees, and of tree-ring cellulose shows that an “isotopomer pattern” of the C3 photosynthetic pathway is transmitted from soluble sugars to tree-ring cellulose. Differences in this pattern between oaks and conifers appear to be related to differences in metabolism. Furthermore, the patterns are modified by hydrogen isotope exchange between C–H groups and source water during cellulose synthesis. Based on these results, we propose a strategy to simultaneously reconstruct climate signals and signals related to tree physiology from D isotopomers of tree rings. Combination of climate signals and physiological signals may allow the detection of century-time-scale adaptations of trees to past environmental change, and help to forecast future adaptations.

  • 26.
    Augusti, Angela
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik.
    Betson, Tatiana R.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Schleucher, Jürgen
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Deuterium isotopomers record a CO2 response of plants in leaves and tree ringsManuskript (Annet (populærvitenskap, debatt, mm))
  • 27.
    Augusti, Angela
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Betson, Tatiana R
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Schleucher, Jürgen
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Hydrogen exchange during cellulose synthesis distinguishes climatic and biochemical isotope fractionations in tree rings.2006Inngår i: New Phytologist, ISSN 0028-646X, E-ISSN 1469-8137, Vol. 172, nr 3, 490-499 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    • The abundance of the hydrogen isotope deuterium (D) in tree rings is an attractive record of climate; however, use of this record has proved difficult so far, presumably because climatic and physiological influences on D abundance are difficult to distinguish.

    • Using D labelling, we created a D gradient in trees. Leaf soluble sugars of relatively low D abundance entered cellulose synthesis in stems containing strongly D-labelled water. We used nuclear magnetic resonance (NMR) spectroscopy to quantify D in the C-H groups of leaf glucose and of tree-ring cellulose.

    • Ratios of D abundances of individual C-H groups of leaf glucose depended only weakly on leaf D labelling, indicating that the D abundance pattern was determined by physiological influences. The D abundance pattern of tree-ring cellulose revealed C-H groups that exchanged strongly (C(2)-H) or weakly (C(6)-H2) with water during cellulose synthesis.

    • We propose that strongly exchanging C-H groups of tree-ring cellulose adopt a climate signal stemming from the D abundance of source water. C-H groups that exchange weakly retain their D abundance established in leaf glucose, which reflects physiological influences. Combining both types of groups may allow simultaneous reconstruction of climate and physiology from tree rings.

  • 28. Augusti, Angela
    et al.
    Schleucher, Jürgen
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    The ins and outs of stable isotopes in plants.2007Inngår i: New Phytologist, ISSN 0028-646X, E-ISSN 1469-8137, Vol. 174, nr 3, 473-475 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 29. Azevedo, M
    et al.
    Eriksson, Sara
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Mendes, N
    Serpa, J
    Figueiredo, C
    Resende, LP
    Ruvoën-Clouet, N
    Haas, R
    Borén, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Le Pendu, J
    David, L
    Infection by Helicobacter pylori expressing the BabA adhesin is influenced by the secretor phenotype2008Inngår i: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 215, nr 3, 308-316 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Helicobacter pylori (Hp) infects half the world's population and causes diverse gastric lesions, from gastritis to gastric cancer. Our aim was to evaluate the significance of secretor and Lewis status in infection and in vitro adherence by Hp expressing BabA adhesin. We enrolled 304 Hp-infected individuals from Northern Portugal. Gastric biopsies, blood and saliva were collected. Polymerase chain reaction (PCR) and immunofluorescence were used to detect BabA+ Hp in gastric biopsies. In vitro adherence by a BabA expressing Hp strain to gastric biopsies was performed. Secretor status was identified by Ulex, a lectin that recognizes secretor-dependent glycan structures in saliva and in gastric mucosa, and by Lewis(a/b) antibodies, and indirectly by identification of an inactivating mutation in the FUT2 gene (G428A). BabA status of infecting Hp was associated with CagA and VacAs1 (p < 0.05), intercellular localization of Hp (p < 0.01) and the presence of intestinal metaplasia (p < 0.05) and degenerative alterations (p < 0.005) in the biopsies. BabA was associated (p < 0.05) with Ulex staining of gastric biopsies and, although not significantly, to absence of homozygosity for FUT2 G428A inactivating polymorphism. In vitro Hp adherence was higher in cases wild-type or heterozygous for FUT2 G428A mutation (p < 0.0001), cases staining for Ulex (p < 0.0001) and a(-)b+ and a(-)b(-) secretor phenotypes (p < 0.001). In conclusion, BabA+ Hp infection/adhesion is secretor-dependent and associated with the severity of gastric lesions.

  • 30. Bagnato, Paola
    et al.
    Castagnino, Alessia
    Cortese, Katia
    Bono, Maria
    Grasso, Silvia
    Bellese, Grazia
    Daniele, Tiziana
    Lundmark, Richard
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    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 cells2017Inngår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, nr 36, 60109-60122 s.Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 31. Balciunas, Darius
    et al.
    Hallberg, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Björklund, Stefan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Ronne, Hans
    Functional interactions within yeast mediator and evidence of differential subunit modifications2003Inngår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 278, nr 6, 3831-3839 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    It is possible to recruit RNA polymerase II to a target promoter and, thus, activate transcription by fusing Mediator subunits to a DNA binding domain. To investigate functional interactions within Mediator, we have tested such fusions of the lexA DNA binding domain to Med1, Med2, Gal11, Srb7, and Srb10 in wild type, med1, med2, gal11, sin4, srb8, srb10, and srb11 strains. We found that lexA-Med2 and lexA-Gal11 are strong activators that are independent of all Mediator subunits tested. lexA-Srb10 is a weak activator that depends on Srb8 and Srb11. lexA-Med1 and lexA-Srb7 are both cryptic activators that become active in the absence of Srb8, Srb10, Srb11, or Sin4. An unexpected finding was that lexA-VP16 differs from Gal4-VP16 in that it is independent of the activator binding Mediator module. Both lexA-Med1 and lexA-Srb7 are stably associated with Med4 and Med8, which suggests that they are incorporated into Mediator. Med4 and Med8 exist in two mobility forms that differ in their association with lexA-Med1 and lexA-Srb7. Within purified Mediator, Med4 is present as a phosphorylated lower mobility form. Taken together, these results suggest that assembly of Mediator is a multistep process that involves conversion of both Med4 and Med8 to their low mobility forms.

  • 32. Baldassarre, Maurizio
    et al.
    Baronio, Cesare M.
    Morozova-Roche, Ludmilla A.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Barth, Andreas
    Amyloid beta-peptides 1-40 and 1-42 form oligomers with mixed beta-sheets2017Inngår i: Chemical Science, ISSN 2041-6520, E-ISSN 2041-6539, Vol. 8, nr 12, 8247-8254 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Two main amyloid-beta peptides of different length (A beta(40) and A beta(42)) are involved in Alzheimer's disease. Their relative abundance is decisive for the severity of the disease and mixed oligomers may contribute to the toxic species. However, little is know about the extent of mixing. To study whether A beta(40) and A beta(42) co-aggregate, we used Fourier transform infrared spectroscopy in combination with C-13-labeling and spectrum calculation and focused on the amide I vibration, which is sensitive to backbone structure. Mixtures of monomeric labeled A beta(40) and unlabeled A beta(42) (and vice versa) were co-incubated for similar to 20 min and their infrared spectrum recorded. The position of the main C-13-amide I' band shifted to higher wavenumbers with increasing admixture of C-12-peptide due to the presence of C-12-amides in the vicinity of C-13-amides. The results indicate that A beta(40) and A beta(42) form mixed oligomers with a largely random distribution of A beta(40) and A beta(42) strands in their beta-sheets. The structures of the mixed oligomers are intermediate between those of the pure oligomers. There is no indication that one of the peptides forces the backbone structure of its oligomers on the other peptide when they are mixed as monomers. We also demonstrate that isotope-edited infrared spectroscopy can distinguish aggregation modulators that integrate into the backbone structure of their interaction partner from those that do not. As an example for the latter case, the pro-inflammatory calcium binding protein S100A9 is shown not to incorporate into the b-sheets of A beta(42).

  • 33. Barfeld, Stefan J
    et al.
    Fazli, Ladan
    Persson, Margareta
    Marjavaara, Lisette
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Urbanucci, Alfonso
    Kaukoniemi, Kirsi M
    Rennie, Paul S
    Ceder, Yvonne
    Chabes, Andrei
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Visakorpi, Tapio
    Mills, Ian G
    Myc-dependent purine biosynthesis affects nucleolar stress and therapy response in prostate cancer2015Inngår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 6, nr 14, 12587-12602 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The androgen receptor is a key transcription factor contributing to the development of all stages of prostate cancer (PCa). In addition, other transcription factors have been associated with poor prognosis in PCa, amongst which c-Myc (MYC) is a well-established oncogene in many other cancers. We have previously reported that the AR promotes glycolysis and anabolic metabolism; many of these metabolic pathways are also MYC-regulated in other cancers. In this study, we report that in PCa cells de novo purine biosynthesis and the subsequent conversion to XMP is tightly regulated by MYC and independent of AR activity. We characterized two enzymes, PAICS and IMPDH2, within the pathway as PCa biomarkers in tissue samples and report increased efficacy of established anti-androgens in combination with a clinically approved IMPDH inhibitor, mycophenolic acid (MPA). Treatment with MPA led to a significant reduction in cellular guanosine triphosphate (GTP) levels accompanied by nucleolar stress and p53 stabilization. In conclusion, targeting purine biosynthesis provides an opportunity to perturb PCa metabolism and enhance tumour suppressive stress responses.

  • 34.
    Basmarke-Wehelie, Rahma
    et al.
    Department of Genetics, Microbiology and Toxicology, Stockholm University, Stockholm, Swede.
    Sjolinder, Hong
    Department of Genetics, Microbiology and Toxicology, Stockholm University, Stockholm, Swede.
    Jurkowski, Wiktor
    Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
    Elofsson, Arne
    Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
    Arnqvist, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Engstrand, Lars
    Swedish Institute for Infectious Disease Control, Karolinska Institutet, Solna, Sweden .
    Hagner, Matthias
    Department of Genetics, Microbiology and Toxicology, Stockholm University, Stockholm, Sweden.
    Wallin, Elin
    Department of Genetics, Microbiology and Toxicology, Stockholm University, Stockholm, Sweden.
    Guan, Na
    Department of Genetics, Microbiology and Toxicology, Stockholm University, Stockholm, Sweden.
    Kuranasekera, Hasanthi
    Department of Genetics, Microbiology and Toxicology, Stockholm University, Stockholm, Sweden.
    Aro, Helena
    Department of Genetics, Microbiology and Toxicology, Stockholm University, Stockholm, Sweden.
    Jonsson, Ann-Beth
    Department of Genetics, Microbiology and Toxicology, Stockholm University, Stockholm, Sweden.
    The Complement Regulator CD46 Is Bactericidal to Helicobacter pylori and Blocks Urease Activity2011Inngår i: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 141, nr 3, 918-928 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background & Aims: CD46 is a C3b/C4b binding complement regulator and a receptor  for several human pathogens. We examined the interaction between CD46 and Helicobacter pylori (a bacterium that colonizes the human gastric mucosa and causes gastritis), peptic ulcers, and cancer.

    Methods: Using gastric epithelial cells, we analyzed a set of H pylori strains and mutants for their ability to interact with CD46 and/or influence CD46 expression. Bacterial interaction with full-length CD46 and small CD46 peptides was evaluated by flow cytometry, fluorescence microscopy, enzyme-linked immunosorbent assay, and bacterial survival analyses.

    Results: H pylori infection caused shedding of CD46 into the extracellular environment. A soluble form of CD46 bound to H pylori and inhibited growth, in a dose- and time-dependent manner, by interacting with urease and alkyl hydroperoxide reductase, which are essential bacterial pathogenicity-associated factors. Binding of CD46 or CD46-derived synthetic peptides blocked theurease activity and ability of bacteria to survive in acidic environments. Oral administration of one CD46 peptide eradicated H pylori from infected mice.

    Conclusions: CD46 is an antimicrobial agent that can eradicate H pylori. CD46 peptides might be developed to treat H pylori infection.

  • 35. Baumann, Anne
    et al.
    Jorge-Finnigan, Ana
    Jung-KC, Kunwar
    Sauter, Alexander
    Horvath, Istvan
    Morozova-Roche, Ludmilla A.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Martinez, Aurora
    Tyrosine Hydroxylase Binding to Phospholipid Membranes Prompts Its Amyloid Aggregation and Compromises Bilayer Integrity2016Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, 39488Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Tyrosine hydroxylase (TH), a rate-limiting enzyme in the synthesis of catecholamine neurotransmitters and hormones, binds to negatively charged phospholipid membranes. Binding to both large and giant unilamellar vesicles causes membrane permeabilization, as observed by efflux and influx of fluorescence dyes. Whereas the initial protein-membrane interaction involves the N-terminal tail that constitutes an extension of the regulatory ACT-domain, prolonged membrane binding induces misfolding and self-oligomerization of TH over time as shown by circular dichroism and Thioflavin T fluorescence. The gradual amyloid-like aggregation likely occurs through cross-beta interactions involving aggregation-prone motives in the catalytic domains, consistent with the formation of chain and ring-like protofilaments observed by atomic force microscopy in monolayer-bound TH. PC12 cells treated with the neurotoxin 6-hydroxydopamine displayed increased TH levels in the mitochondrial fraction, while incubation of isolated mitochondria with TH led to a decrease in the mitochondrial membrane potential. Furthermore, cell-substrate impedance and viability assays showed that supplementing the culture media with TH compromises cell viability over time. Our results revealed that the disruptive effect of TH on cell membranes may be a cytotoxic and pathogenic factor if the regulation and intracellular stability of TH is compromised.

  • 36.
    Berglin, Ewa
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Johansson, T
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Sundin, U
    Jidell, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk immunologi.
    Wadell, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi.
    Hallmans, Göran
    Rantapää-Dahlqvist, Solbritt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Radiological outcome in rheumatoid arthritis is predicted by presence of antibodies against cyclic citrullinated peptide before and at disease onset, and by IgA-RF at disease onset.2006Inngår i: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 65, nr 4, 453-458 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE: To evaluate the significance of antibodies against cyclic citrullinated peptide (anti-CCP) and rheumatoid factors (RFs), before the onset of rheumatoid arthritis and when presenting as early disease (baseline), for disease activity and progression. METHODS: 93 of a cohort of 138 patients with early rheumatoid arthritis (<12 months of symptoms) had donated blood before symptoms of rheumatoid arthritis (defined as pre-patients) and were identified from among blood donors within the Medical Biobank of northern Sweden. Disease activity (erythrocyte sedimentation rate (ESR), C reactive protein, joint score, global visual analogue scale) and radiological destruction in hands and feet (Larsen score) were assessed at baseline and after two years. Anti-CCP antibodies and RFs were analysed using enzyme immunoassays. HLA shared epitope (SE) alleles (DRB1*0401/0404) were identified. RESULTS: Patients with anti-CCP antibodies before disease onset had significantly higher Larsen score at baseline and after two years. In multiple regression analyses baseline values of anti-CCP/IgA-RF/IgG-RF/IgM-RF, swollen joint count, and Larsen score significantly predicted radiological outcome at two years. In logistic regression analyses, baseline values of anti-CCP antibodies/IgA-RF, therapeutic response at six months, and swollen joint count/ESR significantly predicted radiological progression after two years. The baseline titre of anti-CCP antibodies was higher in patients with radiological progression and decreased significantly in those with response to therapy. SE allele carriage was associated with a positive test for anti-CCP antibodies in pre-patients and in early rheumatoid arthritis. CONCLUSIONS: Presence of anti-CCP antibodies before disease onset is associated with more severe radiological damage. The titre of anti-CCP antibodies is related to disease severity.

  • 37. Bergström, F.
    et al.
    Hägglöf, P.
    Umeå universitet, Medicinsk fakultet, Medicinsk kemi och biofysik.
    Karolin, J.
    Ny, T.
    Johansson, L. B.-A.
    The use of site-directed fluorophore labeling and donor-donor energy migration to investigate solution structure and dynamics in proteins1999Inngår i: Proc. Natl. Acad. Sci. USA, Vol. 96, nr 22, 12477-12481 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 38. Bergström, F
    et al.
    Hägglöf, P
    Karolin, J
    Ny, Tor
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Johansson, L B
    The use of site-directed fluorophore labeling and donor-donor energy migration to investigate solution structure and dynamics in proteins.1999Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 96, nr 22, 12477-81 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The use of molecular genetics for introducing fluorescent molecules enables the use of donor-donor energy migration to determine intramolecular distances in a variety of proteins. This approach can be applied to examine the overall molecular dimensions of proteins and to investigate structural changes upon interactions with specific target molecules. In this report, the donor-donor energy migration method is demonstrated by experiments with the latent form of plasminogen activator inhibitor type 1. Based on the known x-ray structure of plasminogen activator inhibitor type 1, three positions forming the corners of a triangle were chosen. Double Cys substitution mutants (V106C-H185C, H185C-M266C, and M266C-V106C) and corresponding single substitution mutants (V106C, H185C, and M266C) were created and labeled with a sulfhydryl specific derivative of BODIPY (=the D molecule). The side lengths of this triangle were obtained from analyses of the experimental data. The analyses account for the local anisotropic order and rotational motions of the D molecules, as well as for the influence of a partial DD-labeling. The distances, as determined from x-ray diffraction, between the C(alpha)-atoms of the positions V106C-H185C, H185C-M266C, and M266C-V106C were 60.9, 30.8, and 55.1 A, respectively. These are in good agreement with the distances of 54 +/- 4, 38 +/- 3, and 55 +/- 3 A, as determined between the BODIPY groups attached via linkers to the same residues. Although the positions of the D-molecules and the C(alpha)-atoms physically cannot coincide, there is a reasonable agreement between the methods.

  • 39. Bergström, F
    et al.
    Hägglöf, P
    Karolin, J
    Ny, Tor
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Johansson, L-B
    Application of donor-donor energy migration (DDEM) for examining protein structure and function1999Inngår i: Advances in Fluorescence Sensing Technology IV: Proceedings of SPIE / [ed] Lakowicz, J.R., Spoer, S.A., Thompson, R.B., SPIE , 1999, 3602, 250-255 s.Kapittel i bok, del av antologi (Fagfellevurdert)
  • 40. Bergström, Fredrik
    et al.
    Mikhalyov, Ilya
    Hägglöf, Peter
    Wortmann, Rüdiger
    Ny, Tor
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Johansson, Lennart B A
    Dimers of dipyrrometheneboron difluoride (BODIPY) with light spectroscopic applications in chemistry and biology.2002Inngår i: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 124, nr 2, 196-204 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A ground-state dimer (denoted D(I)) exhibiting a strong absorption maximum at 477 nm (epsilon = 97 000 M(-1)cm(-1)) can form between adjacent BODIPY groups attached to mutant forms of the protein, plasminogen activator inhibitor type 1 (PAI-1). No fluorescence from excited D(I) was detected. A locally high concentration of BODIPY groups was also achieved by doping lipid phases (micelles, vesicles) with BODIPY-labeled lipids. In addition to an absorption band located at about 480 nm, a new weak absorption band is also observed at ca. 570 nm. Both bands are ascribed to the formation of BODIPY dimers of different conformation (D(I) and D(II)). Contrary to D(I) in PAI-1, the D(II) aggregates absorbing at 570 nm are emitting light observed as a broad band centered at about 630 nm. The integrated absorption band of D(I) is about twice that of the monomer, which is compatible with exciton coupling within a dimer. The Förster radius of electronic energy transfer between a BODIPY excited monomer and the ground-state dimer (D(I)()) is 57 +/- 2 A. A simple model of exciton coupling suggests that in D(I) two BODIPY groups are stacked on top of each other in a sandwich-like configuration with parallel electronic transition dipoles. For D(II) the model suggests that the S(0) --> S(1) transition dipoles are colinear. An explanation for the previously reported (J. Am. Chem. Soc. 1994, 116, 7801) exceptional light spectroscopic properties of BODIPY is also presented. These are ascribed to the extraordinary electric properties of the BODIPY chromophore. First, changes of the permanent electric dipole moment (Delta(mu) approximately -0.05 D) and polarizability (-26 x 10(-40) C m(2) V(-1)) between the ground and the first excited states are small. Second, the S(0) <--> S(1) electronic transition dipole moments are perpendicular to Delta(mu).

  • 41.
    Bergström, Fredrik
    et al.
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Mikhalyov, Ilya
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Hägglöf, Peter
    Medicinsk fakultet, Medicinsk kemi och biofysik.
    Wortmann, Rüdiger
    Ny, Tor
    Medicinsk fakultet, Medicinsk kemi och biofysik.
    Johansson, Lennart B-Å
    Dimers of Dipyrrometheneboron Difluoride (BODIPY) with Light Spectroscopic Applications in Chemistry and Biology2002Inngår i: Journal of the American Chemical Society, Vol. 124, nr 2, 196-204 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A ground-state dimer (denoted DI) exhibiting a strong absorption maximum at 477 nm ( = 97 000 M-1cm-1) can form between adjacent BODIPY groups attached to mutant forms of the protein, plasminogen activator inhibitor type 1 (PAI-1). No fluorescence from excited DI was detected. A locally high concentration of BODIPY groups was also achieved by doping lipid phases (micelles, vesicles) with BODIPY-labeled lipids. In addition to an absorption band located at about 480 nm, a new weak absorption band is also observed at ca. 570 nm. Both bands are ascribed to the formation of BODIPY dimers of different conformation (DI and DII). Contrary to DI in PAI-1, the DII aggregates absorbing at 570 nm are emitting light observed as a broad band centered at about 630 nm. The integrated absorption band of DI is about twice that of the monomer, which is compatible with exciton coupling within a dimer. The Förster radius of electronic energy transfer between a BODIPY excited monomer and the ground-state dimer (DI) is 57 ± 2 Å. A simple model of exciton coupling suggests that in DI two BODIPY groups are stacked on top of each other in a sandwich-like configuration with parallel electronic transition dipoles. For DII the model suggests that the S0 S1 transition dipoles are collinear. An explanation for the previously reported (J. Am. Chem. Soc. 1994, 116, 7801) exceptional light spectroscopic properties of BODIPY is also presented. These are ascribed to the extraordinary electric properties of the BODIPY chromophore. First, changes of the permanent electric dipole moment ( -0.05 D) and polarizability (-26 × 10-40 C m2 V-1) between the ground and the first excited states are small. Second, the S0 S1 electronic transition dipole moments are perpendicular to .

  • 42.
    Betson, Tatiana
    Umeå universitet, Medicinsk fakultet, Medicinsk kemi och biofysik.
    Deuterium isotopomers as a tool in environmental research2006Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    This thesis describes the development and the use of quantitative deuterium Nuclear Magnetic Resonance spectroscopy (NMR) as a tool in two areas of environmental research: the study of long term climate-plant interactions and the source tracking of persistent organic pollutant.

    Long-term interactions between plants and climate will influence climate change during this century and beyond, but cannot be studied in manipulative experiments. We propose that long tree rings series can serve as records for tracking such interactions during past centuries.

    The abundance of the stable hydrogen isotope deuterium (D) is influenced by physical and biochemical isotope fractionations. Because the overlapping effects of these fractionations are not understood, studies of the D abundance of tree rings led to conflicting results. We hypothesized that both types of fractionations can be separated if the D abundance of individual C-H groups of metabolites can be measured, that is if individual D isotopomers are quantified.

    The first paper describes a technique for quantification of D isotopomers in tree-ring cellulose by NMR. The technique showed that the D isotopomers distribution (DID) was non-random. Therefore, the abundance of each isotopomer potentially contains individual information which suggests an explanation for the conflicting results obtained by measuring the overall D abundance (dD).

    In the second paper, this technique was used to study hydrogen isotope exchange during cellulose synthesis in tree rings. This revealed that some C-H positions exchange strongly with xylem water, while others do not. This means that the exchanging C-H positions should acquire the D abundance of source water, which is determined by physical fractionations, while non-exchanging C-H positions of tree-ring cellulose should retain biochemical fractionations from the leaf level. Therefore, the abundance of the corresponding D isotopomers should contain information about climate and physiology. When analysing tree-ring series, the DIDs should reflect information about temperature, transpiration and regulation of photosynthesis.

    In the third paper, we showed that CO2 concentration during photosynthesis determines a specific abundance ratio of D isotopomers. This dependence was found in metabolites of annual plants, and in tree-ring cellulose. This result shows that D isotopomers of tree-ring series may be used to detect long-term CO2 fertilisation effects. This information is essential to forecast adaptations of plants to increasing CO2 concentrations on time scales of centuries.

    In the fourth paper, the source of persistent organic pollutants in the environment was tracked using DID measurements. The dD values of two compounds of related structures were not enough to show indisputably that they did not originate from the same source. However, the DIDs of the common part between the two compounds proved that they did not originate from the same source. These results underline the superior discriminatory power of DIDs, compared to dD measurements.

    The versatility of DID measurements makes them a precious tool in addressing questions that can not be answered by dD measurements.

  • 43.
    Betson, Tatiana R
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Augusti, Angela
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Schleucher, Jürgen
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Quantification of deuterium isotopomers of tree-ring cellulose using nuclear magnetic resonance.2006Inngår i: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 78, nr 24, 8406-8411 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Stable isotopes in tree rings are important tools for reconstruction of past climate. Deuterium (D) is of particular interest since it may contain climate signals and report on tree physiology. Measurements of the D/H ratio of tree-ring cellulose have proven difficult to interpret, presumably because the D/H ratio of the whole molecule blends the abundances of the seven D isotopomers of cellulose. Here we present a method to measure the abundance of the D isotopomers of tree-ring cellulose by nuclear magnetic resonance spectroscopy (NMR). The method transforms tree-ring cellulose into a glucose derivative that gives highly resolved, quantifiable deuterium NMR spectra. General guidelines for measurement of D isotopomers by NMR are described. The transformation was optimized for yield and did not alter the original D isotopomer abundances, thus, conserving the original signals recorded in wood cellulose. In the tree-ring samples tested, the abundances of D isotopomers varied by approximately ±10% (2% standard error). This large variability can only be caused by biochemistry processes and shows that more information is present in D isotopomer abundances, compared to the D/H ratio. Therefore, measurements of the D isotopomer distribution of tree rings may be used to obtain information on long-term adaptations to environmental changes and past climate change.

  • 44. Betson, Tatiana R.
    et al.
    Augusti, Angela
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Schleucher, Jürgen
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Quantifying deuterium isotopomers of cellulose using Nuclear Magnetic Resonance2006Inngår i: Analytical Chemistry, Vol. 78, nr 24, 8406-8411 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 45. Bicsak, T A
    et al.
    Cajander, S B
    Peng, X R
    Ny, Tor
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    LaPolt, P S
    Lu, J K
    Kristensen, P
    Tsafriri, A
    Hsueh, A J
    Tissue-type plasminogen activator in rat oocytes: expression during the periovulatory period, after fertilization, and during follicular atresia.1989Inngår i: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 124, nr 1, 187-94 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The regulation of tissue-type plasminogen activator (tPA) in rat oocytes during the periovulatory period, in early embryos, and in oocytes during induced follicular atresia was studied using a quantitative chromogenic substrate assay. Oocytes and early embryos were collected from three ovulation models: 1) intact immature female rats treated with PMSG, followed by hCG 48 h later; 2) hypophysectomized immature rats treated with PMSG, followed by a GnRH agonist (GnRHa) 56 h later; and 3) adult cyclic rats on the mornings of proestrus and estrus and up to 5 days after fertilization. In addition, follicular atresia was induced by either withdrawal of diethylstilbestrol (DES) for 2 days or injection of GnRHa for 2 days in hypophysectomized DES-implanted immature rats. Treatment with PMSG alone did not increase oocyte tPA content (5-20 microIU/oocyte) in either immature rat model, but treatment with either hCG or GnRHa induced meiotic maturation and ovulation and increased tPA activity to 80 and 140 microIU/oocyte 24 h after hCG and GnRHa treatment, respectively. Northern blot analysis of total RNA extracted from oocytes of PMSG-treated rats indicated the presence of a specific tPA message at 22S. tPA levels were low in preovulatory oocytes obtained on proestrus morning and increased in ovulated oocytes on estrus morning. After fertilization, tPA levels remained high in the embryos on days 1-4 of pregnancy, but dropped dramatically on day 5. Furthermore, oocytes from atretic follicles of hypophysectomized DES-implanted rats after either DES withdrawal or GnRHa treatment contained elevated levels of tPA, coincident with germinal vesicle breakdown (GVBD). Immunohistochemical staining revealed tPA antigen only in those oocytes that had undergone apparent meiotic maturation, as confirmed by GVBD. Thus, oocytes contain tPA mRNA and synthesize the active protease under a variety of stimuli which result in GVBD. The observed periovulatory increase in oocyte tPA activity, its maintenance until day 5 of pregnancy, and expression of tPA in nonovulatory oocytes of atretic follicles suggest diverse functions for the oocyte and embryo tPA.

  • 46.
    Björklund, Stefan
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Gustafsson, Claes M
    The mediator complex.2004Inngår i: Advances in Protein Chemistry, ISSN 0065-3233, E-ISSN 1557-8941, Vol. 67, 43-65 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 47.
    Björklund, Stefan
    et al.
    Umeå universitet, Medicinsk fakultet, Medicinsk kemi och biofysik.
    Gustafsson, Claes M
    The yeast Mediator complex and its regulation.2005Inngår i: Trends in Biochemical Sciences, ISSN 0968-0004, Vol. 30, nr 5, 240-4 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 48.
    Björklund, Stefan
    et al.
    Umeå universitet, Medicinsk fakultet, Medicinsk kemi och biofysik.
    Hjortsberg, K
    Johansson, Erik
    Umeå universitet, Medicinsk fakultet, Medicinsk kemi och biofysik.
    Thelander, Lars
    Umeå universitet, Medicinsk fakultet, Medicinsk kemi och biofysik.
    Structure and promoter characterization of the gene encoding the large subunit (R1 protein) of mouse ribonucleotide reductase.1993Inngår i: Proceedings of the National Academy of Science U S A, ISSN 0027-8424, Vol. 90, nr 23, 11322-6 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 49.
    Björklund, Stefan
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Skog, Sven
    Tribukait, Bernard
    Thelander, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    S-phase-specific expression of mammalian ribonucleotide reductase R1 and R2 subunit mRNAs1990Inngår i: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 29, nr 23, 5452-5458 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Ribonucleotide reductase in mammalian cells is composed of two nonidentical subunits, proteins R1 and R2, each inactive alone. The R1 protein is present in excess in proliferating cells, and its levels are constant during the cell cycle. Expression of the R2 protein, which is limiting for enzyme activity, is strictly S-phase-correlated. In this paper, we have used antisense RNA probes in a solution hybridization assay to measure the levels of R1 and R2 mRNA during the cell cycle in centrifugally elutriated cells and in cells synchronized by isoleucine or serum starvation. The levels of both transcripts were very low or undetectable in G0/G1-phase cells, showed a pronounced increase as cells progressed into S phase, and then declined when cells progressed into G2 + M phase. The R1 and R2 transcripts increased in parallel, starting slightly before the rise in S-phase cells, and reached the same levels. The relative lack of cell cycle dependent variation in R1 protein levels, obtained previously, may therefore simply be a consequence of the long half-life of the R1 protein. Hydroxyurea-resistant, R2-overproducing mouse TA3 cells showed the same regulation of the R1 and R2 transcripts as the parental cells, but with R2 mRNA at a 40-fold higher level.

  • 50.
    Björklund, Stefan
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Skogman, E
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Thelander, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    An S-phase specific release from a transcriptional block regulates the expression of mouse ribonucleotide reductase R2 subunit1992Inngår i: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 11, nr 13, 4953-4959 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Ribonucleotide reductase (RR) activity in mammalian cells is closely linked to DNA synthesis. The RR enzyme is composed of two non-identical subunits, proteins R1 and R2. Both proteins are required for holoenzyme activity, which is regulated by S-phase specific de novo synthesis and breakdown of the R2 subunit. In quiescent cells stimulated to proliferate and in elutriated cell populations enriched in the various cell cycle phases the R2 protein levels are correlated to R2 mRNA levels that are low in G0/G1-phase cells but increase dramatically at the G1/S border. Using an R2 promoter-luciferase reporter gene construct we demonstrate an unexpected early activation of the R2 promoter as cells pass from quiescence to proliferation. However, due to a transcriptional block, this promoter activation only results in very short R2 transcripts until cells enter the S-phase, when full-length R2 transcripts start to appear. The position for the transcriptional block was localized to a nucleotide sequence approximately 87 bp downstream from the first exon/intron boundary by S1 nuclease mapping of R2 transcripts from modified in vitro nuclear run-on experiments. These results identify blocking of transcription as a mechanism to control cell cycle regulated gene expression.

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