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  • 401.
    Xu, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Evolutionary and Pharmacological Studies of NPY and QRFP Receptors2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The neuropeptide Y (NPY) system consists of 3-4 peptides and 4-7 receptors in vertebrates. It has powerful effects on appetite regulation and is involved in many other biological processes including blood pressure regulation, bone formation and anxiety. This thesis describes studies of the evolution of the NPY system by comparison of several vertebrate species and structural studies of the human Y2 receptor, which reduces appetite, to identify amino acid residues involved in peptide-receptor interactions.

    The NPY system was studied in zebrafish (Danio rerio), western clawed frog (Xenopus tropicalis), and sea lamprey (Petromyzon marinus). The receptors were cloned and functionally expressed and their pharmacological profiles were determined using the native peptides in either binding studies or a signal transduction assay. Some peptide-receptor preferences were observed, indicating functional specialization.

    A receptor family closely related to the NPY receptors, called the QRFP receptors, was investigated. A QRFP receptor was cloned from amphioxus, Branchistoma floridae, showing that the receptor arose before the origin of the vertebrates. Evolutionary studies demonstrated that the ancestral vertebrate had as many as four QRFP receptors, only one of which remains in mammals today. This correlates with the NPY receptor family, located in the same chromosomal regions, which had seven members in the ancestral vertebrate but only 4-5 in living mammals. Some vertebrates have considerably more complex NPY and QRFP receptor systems than humans and other mammals.

    Two studies investigated interactions of NPY-family peptides with the human Y2 receptor. Candidate residues, selected based on structural modeling and docking, were mutated to disrupt possible interactions with peptide ligands. The modified receptors were expressed in cultured cells and investigated by measuring binding and functional responses. Several receptor residues were found to influence peptide-receptor interactions, some of which are involved in maintaining receptor structure. In a pilot study, the kinetics of peptide-receptor interaction were found to be very slow, of the order several hours.

    In conclusion, this thesis clarifies evolutionary relationships for the complex NPY and QRFP peptide-receptor systems and improves the structural models of the human NPY-family receptors, especially Y2. These results will hopefully facilitate drug design for targeting of NPY-family receptors.

    List of papers
    1. Cloning and pharmacological characterization of the neuropeptide Y receptor Y5 in the sea lamprey, Petromyzon marinus
    Open this publication in new window or tab >>Cloning and pharmacological characterization of the neuropeptide Y receptor Y5 in the sea lamprey, Petromyzon marinus
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    2013 (English)In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 39, p. 64-70Article in journal (Refereed) Published
    Abstract [en]

    The neuropeptide Y system is known to have expanded in early vertebrate evolution. Three neuropeptide Y receptors have been proposed to have existed before the two basal vertebrate tetraploidizations, namely a VI-like, a Y2-like, and a Y5-like receptor, with their genes in the same chromosomal region. Previously we have described a VI-subfamily and a Y2-subfamily receptor in the river lamprey, Lampetra fluviatilis. Here we report the identification of a Y5 receptor in the genome of the sea lamprey, Petromyzon marinus. In phylogenetic analyses, the Y5 receptor clusters together with gnathostome Y5 receptors with high bootstrap value and shares the long intracellular loop 3. This lamprey receptor has an even longer loop 3 than the gnathostome Y5 receptors described so far, with the expansion of amino acid repeats. Functional expression in a human cell line, co-transfected with a modified human G-protein, resulted in inositol phosphate turnover in response to the three lamprey NPY-family peptides NPY, PYY and PMY at nanomolar concentrations. Our results confirm that the Y1-Y2-Y5 receptor gene triplet arose before the cyclostome-gnathostome divergence. However, it is not clear from the NPY receptors whether cyclostomes diverged from the gnathostome lineage after the first or the second tetraploidization. Duplicates resulting from the tetraploidizations exist for both Y1 and Y2 in gnathostomes, but only a single copy of Y5 has survived in all vertebrates characterized to date, making the physiological roles of Y5 interesting to explore.

    Keywords
    Lamprey, Neuropeptide Y, Peptide YY, Y5 receptor
    National Category
    Biological Sciences
    Identifiers
    urn:nbn:se:uu:diva-198074 (URN)10.1016/j.peptides.2012.11.007 (DOI)000315839300011 ()
    Available from: 2013-04-09 Created: 2013-04-08 Last updated: 2022-01-28Bibliographically approved
    2. Neuropeptide Y family receptors Y1 and Y2 from sea lamprey, Petromyzon marinus: cloning and pharmacological characterization
    Open this publication in new window or tab >>Neuropeptide Y family receptors Y1 and Y2 from sea lamprey, Petromyzon marinus: cloning and pharmacological characterization
    2015 (English)In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 222, p. 106-115Article in journal (Other academic) Published
    Abstract [en]

    The vertebrate gene family for neuropeptide Y (NPY) receptors expanded by duplication of the chromosome carrying the ancestral Y1–Y2–Y5 gene triplet. After loss of some duplicates, the ancestral jawed vertebrate had seven receptor subtypes forming the Y1 (including Y1, Y4, Y6, Y8), Y2 (including Y2, Y7) and Y5 (only Y5) subfamilies. Lampreys are considered to have experienced the same chromosome duplications as gnathostomes and should also be expected to have multiple receptor genes. However, previously only a Y4-like and a Y5 receptor have been cloned and characterized. Here we report the cloning and characterization of two additional receptors from the sea lamprey Petromyzon marinus. Sequence phylogeny alone could not with certainty assign their identity, but based on synteny comparisons of P. marinus and the Arctic lamprey, Lethenteron camtschaticum, with jawed vertebrates, the two receptors most likely are Y1 and Y2. Both receptors were expressed in human HEK293 cells and inositol phosphate assays were performed to determine the response to the three native lamprey peptides NPY, PYY and PMY. The three peptides have similar potencies in the nanomolar range for Y1. No obvious response to the three peptides was detected for Y2. Synteny analysis supports identification of the previously cloned receptor as Y4. No additional NPY receptor genes could be identified in the presently available lamprey genome assemblies. Thus, four NPY-family receptors have been identified in lampreys, orthologs of the same subtypes as in humans (Y1, Y2, Y4 and Y5), whereas many other vertebrate lineages have retained additional ancestral subtypes.

    National Category
    Evolutionary Biology Endocrinology and Diabetes
    Identifiers
    urn:nbn:se:uu:diva-233437 (URN)10.1016/j.ygcen.2015.08.005 (DOI)000366438000012 ()26255155 (PubMedID)
    Funder
    Swedish Research Council
    Available from: 2014-10-06 Created: 2014-10-05 Last updated: 2019-01-03Bibliographically approved
    3. Characterization of the neuropeptide Y system in the frog Silurana tropicalis (Pipidae): three peptides and six receptor subtypes
    Open this publication in new window or tab >>Characterization of the neuropeptide Y system in the frog Silurana tropicalis (Pipidae): three peptides and six receptor subtypes
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    2012 (English)In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 177, no 3, p. 322-331Article in journal (Refereed) Published
    Abstract [en]

    Neuropeptide Y and its related peptides PYY and PP (pancreatic polypeptide) are involved in feeding behavior, regulation of the pituitary and the gastrointestinal tract, and numerous other functions. The peptides act on a family of G-protein coupled receptors with 4-7 members in jawed vertebrates. We describe here the NPY system of the Western clawed frog Silurana (Xenopus) tropicalis. Three peptides, NPY, PYY and PP, were identified together with six receptors, namely subtypes Y1, Y2, Y4, Y5, Y7 and Y8. Thus, this frog has all but one of the ancestral seven gnathostome NPY-family receptors, in contrast to mammals which have lost 2-3 of the receptors. Expression levels of mRNA for the peptide and receptor genes were analyzed in a panel of 19 frog tissues using reverse transcriptase quantitative PCR. The peptide mRNAs had broad distribution with highest expression in skin, blood and small intestine. NPY mRNA was present in the three brain regions investigated, but PYY and PP mRNAs were not detectable in any of these. All receptor mRNAs had similar expression profiles with high expression in skin, blood, muscle and heart. Three of the receptors, Y5, Y7 and Y8, could be functionally expressed in HEK-293 cells and characterized with binding studies using the three frog peptides. PYY had the highest affinity for all three receptors (K(i) 0.042-0.34 nM). Also NPY and PP bound to the Y8 receptor with high affinity (0.14 and 0.50 nM). The low affinity of NPY for the Y5 receptor (100-fold lower than PYY) differs from mammals and chicken. This may suggest a less important role of NPY on Y5 in appetite stimulation in the frog compared with amniotes. In conclusion, our characterization of the NPY system in S. tropicalis with its six receptors demonstrates not only greater complexity than in mammals but also some interesting differences in ligand-receptor preferences.

    Keywords
    NPY, PYY, G-protein-coupled receptor, Silurana tropicalis, evolution
    National Category
    Biological Sciences
    Identifiers
    urn:nbn:se:uu:diva-129517 (URN)10.1016/j.ygcen.2012.04.027 (DOI)000306390100005 ()22565163 (PubMedID)
    Note

    Erratum in General and Comparative Endocrinology 2015:215, doi:10.1016/j.ygcen.2014.11.014.

    Available from: 2010-08-18 Created: 2010-08-18 Last updated: 2019-01-03Bibliographically approved
    4. Interactions of zebrafish peptide YYb with the neuropeptide Y-family receptors Y4, Y7, Y8a, and Y8b
    Open this publication in new window or tab >>Interactions of zebrafish peptide YYb with the neuropeptide Y-family receptors Y4, Y7, Y8a, and Y8b
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    2013 (English)In: Frontiers in Neuroscience, ISSN 1662-4548, E-ISSN 1662-453X, Vol. 7, article id 29Article in journal (Refereed) Published
    Abstract [en]

    The neuropeptide Y (NPY) system influences numerous physiological functions including feeding behavior, endocrine regulation, and cardiovascular regulation. In jawed vertebrates it consists of 3-4 peptides and 4-7 receptors. Teleost fishes have unique duplicates of NPY and PYY as well as the Y8 receptor. In the zebrafish, the NPY system consists of the peptides NPYa, PYYa, and PYYb (NPYb appears to have been lost) and at least seven NPY receptors: Y1, Y2, Y2-2, Y4, Y7, Y8a, and Y8b. Previously PYYb binding has been reported for Y2 and Y2-2. To search for peptide-receptor preferences, we have investigated PYYb binding to four of the remaining receptors and compared with NPYa and PYYa. Taken together, the most striking observations are that PYYa displays reduced affinity for Y2 (3 nM) compared to the other peptides and receptors and that all three peptides have higher affinity for Y4 (0.028-0.034 nM) than for the other five receptors. The strongest peptide preference by any receptor selectivity is the one previously reported for PYYb by the Y2 receptor, as compared to NPY and PYYa. These affinity differences may be helpful to elucidate specific details of peptide-receptor interactions. Also, we have investigated the level of mRNA expression in different organs using qPCR. All peptides and receptors have higher expression in heart, kidney, and brain. These quantitative aspects on receptor affinities and mRNA distribution help provide a more complete picture of the NPY system.

    Keywords
    Evolution, genome duplication, NPY, elephant shark
    National Category
    Natural Sciences Neurology
    Research subject
    Neuroscience
    Identifiers
    urn:nbn:se:uu:diva-205599 (URN)10.3389/fnins.2013.00029 (DOI)000346567300029 ()23508731 (PubMedID)
    Funder
    Swedish Research Council
    Available from: 2013-08-20 Created: 2013-08-20 Last updated: 2019-01-03Bibliographically approved
    5. Characterization of peptide QRFP (26RFa) and its receptor from amphioxus, Branchiostoma floridae
    Open this publication in new window or tab >>Characterization of peptide QRFP (26RFa) and its receptor from amphioxus, Branchiostoma floridae
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    2015 (English)In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 210, p. 107-113Article in journal (Refereed) Published
    Abstract [en]

    A peptide ending with RFamide (Arg-Phe-amide) was discovered independently by three different laboratories in 2003 and named 26RFa or QRFP. In mammals, a longer version of the peptide, 43 amino acids, was identified and found to bind to the orphan G protein-coupled receptor GPR103. We searched the genome database of Branchiostoma floridae (Bfl) for receptor sequences related to those that bind peptides ending with RFa or RYa (including receptors for NPFF, PRLH, GnIH, and NPY). One receptor clustered in phylogenetic analyses with mammalian QRFP receptors. The gene has 3 introns in Bfl and 5 in human, but all intron positions differ, implying that the introns were inserted independently. A QRFP-like peptide consisting of 25 amino acids and ending with RFa was identified in the amphioxus genome. Eight of the ten last amino acids are identical between Bfl and human. The prepro-QRFP gene in Bfl has one intron in the propeptide whereas the human gene lacks introns. The Bfl QRFP peptide was synthesized and the receptor was functionally expressed in human cells. The response was measured as inositol phosphate (IP) turnover. The Bfl QRFP peptide was found to potently stimulate the receptor's ability to induce IP turnover with an EC50 of 0.28nM. Also the human QRFP peptides with 26 and 43 amino acids were found to stimulate the receptor (1.9 and 5.1nM, respectively). Human QRFP with 26 amino acids without the carboxyterminal amide had dramatically lower potency at 1.3μM. Thus, we have identified an amphioxus QRFP-related peptide and a corresponding receptor and shown that they interact to give a functional response.

    Keywords
    Neuropeptide, receptor, evolution
    National Category
    Neurosciences
    Research subject
    Evolutionary Genetics; Neuroscience
    Identifiers
    urn:nbn:se:uu:diva-240039 (URN)10.1016/j.ygcen.2014.10.010 (DOI)000346886400012 ()25449662 (PubMedID)
    Available from: 2015-01-05 Created: 2015-01-05 Last updated: 2022-01-28Bibliographically approved
    6. Unexpected multiplicity of QRFP receptors in early vertebrate evolution
    Open this publication in new window or tab >>Unexpected multiplicity of QRFP receptors in early vertebrate evolution
    2014 (English)In: Frontiers in Neuroscience, ISSN 1662-4548, E-ISSN 1662-453X, Vol. 8, p. 337-Article in journal (Refereed) Published
    Abstract [en]

    The neuropeptide QRFP, also called 26RFa, and its G protein-coupled receptor GPR103 have been identified in all vertebrates investigated. In mammals, this peptide-receptor pair has been found to have several effects including stimulation of appetite. Recently, we reported that a QRFP peptide is present in amphioxus, Branchiostoma floridae, and we also identified a QRFP receptor (QRFPR) that mediates a functional response to sub-nanomolar concentrations of the amphioxus peptide as well as short and long human QRFP (Xu et al., submitted). Because the ancestral vertebrate underwent two tetraploidizations, it might be expected that duplicates of the QRFP gene and its receptor gene may exist. Indeed, we report here the identification of multiple vertebrate QRFPR genes. Three QRFPR genes are present in the coelacanth Latimeria chalumnae, representing an early diverging sarcopterygian lineage. Three QRFPR genes are present in the basal actinopterygian fish, the spotted gar. Phylogenetic and chromosomal analyses show that only two of these receptor genes are orthologous between the two species, thus demonstrating a total of four distinct vertebrate genes. Three of the QRFPR genes resulted from the early vertebrate tetraploidizations and were copied along with syntenic neuropeptide Y receptor genes. The fourth QRFPR gene may be an even older and distinct lineage. Because mammals and birds have only a single QRFPR gene, this means that three genes have been lost in these lineages, and at least one of these was lost independently in mammals and birds because it is still present in a turtle. In conclusion, these results show that the QRFP system gained considerable complexity in the early stages of vertebrate evolution and still maintains much of this in some lineages, and that it has been secondarily reduced in mammals.

    Keywords
    Neuropeptide, receptor, evolution
    National Category
    Natural Sciences
    Research subject
    Neuroscience; Evolutionary Genetics
    Identifiers
    urn:nbn:se:uu:diva-240037 (URN)10.3389/fnins.2014.00337 (DOI)000346532900001 ()25386115 (PubMedID)
    Available from: 2015-01-05 Created: 2015-01-05 Last updated: 2019-01-03Bibliographically approved
    7. Mutagenesis and Computational Modeling of Human G‑Protein-Coupled Receptor Y2 for Neuropeptide Y and Peptide YY
    Open this publication in new window or tab >>Mutagenesis and Computational Modeling of Human G‑Protein-Coupled Receptor Y2 for Neuropeptide Y and Peptide YY
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    2013 (English)In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 52, no 45, p. 7987-7998Article in journal (Refereed) Published
    Abstract [en]

    Neuropeptide Y and peptide YY receptor type 2 (Y2) is involved in appetite regulation and several other physiological processes. We have investigated the structure of the human Y2 receptor. Computational modeling of receptor–agonist interactions was used as a guide to design a series of receptor mutants, followed by binding assays using full-length and truncated peptide agonists and the Y2-specific antagonist BIIE0246. Our model suggested a hydrogen bond network among highly conserved residues Thr2.61, Gln3.32, and His7.39, which could play roles in ligand binding and/or receptor structure. In addition, the C-terminus of the peptide could make contact with residues Tyr5.38 and Leu6.51. Mutagenesis of all these positions, followed by binding assays, provides experimental support for our computational model: most of the mutants for the residues forming the proposed hydrogen bond network displayed reduced peptide agonist affinities as well as reduced hPYY3-36 potency in a functional assay. The Ala and Leu mutants of Gln3.32 and His7.39 disrupted membrane expression of the receptor. Combined with the modeling, the experimental results support roles for these hydrogen bond network residues in peptide binding as well as receptor architecture. The reduced agonist affinity for mutants of Tyr5.38 and Leu6.51 supports their role in a binding pocket surrounding the invariant tyrosine at position 36 of the peptide ligands. The results for antagonist BIIE0246 suggest several differences in interactions compared to those of the peptides. Our results lead to a new structural model for NPY family receptors and peptide binding.

    Place, publisher, year, edition, pages
    American Chemical Society (ACS), 2013
    National Category
    Natural Sciences Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-154994 (URN)10.1021/bi400830c (DOI)000330017700012 ()
    Available from: 2011-08-04 Created: 2011-06-14 Last updated: 2022-01-28Bibliographically approved
    8. Detecting ligand interactions with G protein-coupled receptors in real-time on living cells
    Open this publication in new window or tab >>Detecting ligand interactions with G protein-coupled receptors in real-time on living cells
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    2013 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 441, no 4, p. 820-824Article in journal (Refereed) Published
    Abstract [en]

    G protein-coupled receptors (GPCRs) are a large group of receptors of great biological and clinical relevance. Despite this, the tools for a detailed analysis of ligand-GPCR interactions are limited. The aim of this paper was to demonstrate how ligand binding to GPCRs can be followed in real-time on living cells. This was conducted using two model systems, the radiolabeled porcine peptide YY (pPYY) interacting with transfected human Y2 receptor (hY2R) and the bombesin antagonist RM26 binding to the naturally expressed gastrin-releasing peptide receptor (GRPR). By following the interaction over time, the affinity and kinetic properties such as association and dissociation rate were obtained. Additionally, data were analyzed using the Interaction Map method, which can evaluate a real-time binding curve and present the number of parallel interactions contributing to the curve. It was found that pPYY binds very slowly with an estimated time to equilibrium of approximately 12 h. This may be problematic in standard end-point assays where equilibrium is required. The RM26 binding showed signs of heterogeneity, observed as two parallel interactions with unique kinetic properties. In conclusion, measuring binding in real-time using living cells opens up for a better understanding of ligand interactions with GPCRs.

    Keywords
    GPCR, Real-time, LigandTracer, Interaction Map, Kinetics, Heterogeneity
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-215943 (URN)10.1016/j.bbrc.2013.10.149 (DOI)000328434800022 ()
    Note

    De två första författarna delar första författarskapet.

    Available from: 2014-01-17 Created: 2014-01-17 Last updated: 2019-01-03Bibliographically approved
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  • 402. Xu, J.
    et al.
    Eriksson, S. E.
    Cebula, M.
    Sandalova, T.
    Hedstrom, E.
    Pader, I.
    Cheng, Q.
    Myers, C. R.
    Antholine, W. E.
    Nagy, P.
    Hellman, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Selivanova, G.
    Lindqvist, Y.
    Arner, E. S. J.
    The conserved Trp114 residue of thioredoxin reductase 1 has a redox sensor-like function triggering oligomerization and crosslinking upon oxidative stress related to cell death2015In: Cell Death and Disease, ISSN 2041-4889, E-ISSN 2041-4889, Vol. 6, article id e1616Article in journal (Refereed)
    Abstract [en]

    The selenoprotein thioredoxin reductase 1 (TrxR1) has several key roles in cellular redox systems and reductive pathways. Here we discovered that an evolutionarily conserved and surface-exposed tryptophan residue of the enzyme (Trp114) is excessively reactive to oxidation and exerts regulatory functions. The results indicate that it serves as an electron relay communicating with the FAD moiety of the enzyme, and, when oxidized, it facilitates oligomerization of TrxR1 into tetramers and higher multimers of dimers. A covalent link can also be formed between two oxidized Trp114 residues of two subunits from two separate TrxR1 dimers, as found both in cell extracts and in a crystal structure of tetrameric TrxR1. Formation of covalently linked TrxR1 subunits became exaggerated in cells on treatment with the pro-oxidant p53-reactivating anticancer compound RITA, in direct correlation with triggering of a cell death that could be prevented by antioxidant treatment. These results collectively suggest that Trp114 of TrxR1 serves a function reminiscent of an irreversible sensor for excessive oxidation, thereby presenting a previously unrecognized level of regulation of TrxR1 function in relation to cellular redox state and cell death induction.

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  • 403.
    Xu, Jingxiang
    et al.
    Gannan Med Univ, Sch Basic Med, Ganzhou 341000, Peoples R China..
    Liao, Wei
    Fujian Agr & Forestry Univ, Coll Food Sci, Fuzhou 350002, Peoples R China..
    Yang, Shuxin
    Gannan Med Univ, Sch Basic Med, Ganzhou 341000, Peoples R China..
    Liu, Juan
    Gannan Med Univ, Sch Basic Med, Ganzhou 341000, Peoples R China..
    Jiang, Shiyue
    Gannan Med Univ, Sch Basic Med, Ganzhou 341000, Peoples R China..
    Liu, Yuanyuan
    Fujian Agr & Forestry Univ, Coll Food Sci, Fuzhou 350002, Peoples R China..
    El-Seedi, Hesham R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Zhao, Chao
    Fujian Agr & Forestry Univ, Coll Marine Sci, Fuzhou 350002, Peoples R China.;Fujian Agr & Forestry Univ, State Key Lab Mariculture Breeding, Key Lab Marine Biotechnol Fujian Prov, Fuzhou 350002, Peoples R China.;15 Shangxiadian Rd, Fuzhou 350002, Peoples R China..
    Ulva lactuca polysaccharide inhibits hepatocellular carcinoma growth by induces the expression of CD5L and activates complement cascade2024In: Journal of Functional Foods, ISSN 1756-4646, E-ISSN 2214-9414, Vol. 112, article id 105994Article in journal (Refereed)
    Abstract [en]

    Ulva polysaccharide (ULP) as main active ingredient of Ulva lactuca, has good pharmacological activity. This study further explored its anti-tumor mechanisms in hepatocellular carcinoma (HCC) with wet experiments and bioinformatic analyses. Results indicate that the differential proteins after ULP treatment are mainly enriched in immunomodulatory and complement pathways, among which the immune molecule CD5L and the key proteins of the membrane attack complex (MAC) are significantly upregulated, and the expression of MAC proteins are positively correlated with the expression of CD5L. Moreover, results from TIMER2.0 indicated that CD5L expression had positive correlation with CD8 + T cell infiltration in HCC, and single cell RNA-Seq analysis showed CD5L positive macrophage cells have higher expression of CFP, C1QA, C1QB, and C1QC, which are key molecular of complement cascades. Take together, the results suggest that ULP may exerts its anti-tumor activity by induces the expression of CD5L in HCC.

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  • 404. Xu, Weiping
    et al.
    Morris, Ulrika
    Aydin-Schmidt, Berit
    Msellem, Mwinyi I.
    Shakely, Deler
    Petzold, Max
    Bjorkman, Anders
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD).
    SYBR Green Real-Time PCR-RFLP Assay Targeting the Plasmodium Cytochrome B Gene - A Highly Sensitive Molecular Tool for Malaria Parasite Detection and Species Determination2015In: PLOS ONE, E-ISSN 1932-6203, Vol. 10, no 3, article id e0120210Article in journal (Refereed)
    Abstract [en]

    A prerequisite for reliable detection of low-density Plasmodium infections in malaria pre-elimination settings is the availability of ultra-sensitive and high-throughput molecular tools. We developed a SYBR Green real-time PCR restriction fragment length polymorphism assay (cytb-qPCR) targeting the cytochrome b gene of the four major human Plasmodium species (P. falciparum, P. vivax, P. malariae, and P. ovale) for parasite detection and species determination with DNA extracted from dried blood spots collected on filter paper. The performance of cytb-qPCR was first compared against four reference PCR methods using serially diluted Plasmodium samples. The detection limit of the cytb-qPCR was 1 parasite/mu l (p/mu l) for P. falciparum and P. ovale, and 2 p/mu l for P. vivax and P. malariae, while the reference PCRs had detection limits of 0.5-10 p/mu l. The ability of the PCR methods to detect low-density Plasmodium infections was then assessed using 2977 filter paper samples collected during a cross-sectional survey in Zanzibar, a malaria pre-elimination setting in sub-Saharan Africa. Field samples were defined as 'final positive' if positive in at least two of the five PCR methods. Cytb-qPCR preformed equal to or better than the reference PCRs with a sensitivity of 100% (65/65; 95% CI 94.5-100%) and a specificity of 99.9%(2910/2912; 95% CI 99.7-100%) when compared against 'final positive' samples. The results indicate that the cytb-qPCR may represent an opportunity for improved molecular surveillance of low-density Plasmodium infections in malaria pre-elimination settings.

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  • 405.
    Xu, Zhaowei
    et al.
    Binzhou Med Univ, Shandong Technol Innovat Ctr Mol Targeting & Intel, Yantai, Peoples R China.;Binzhou Med Univ, Sch Pharm, Yantai, Peoples R China..
    Liu, Shuyan
    Binzhou Med Univ, Sch Pharm, Yantai, Peoples R China..
    Feng, Chun
    Binzhou Med Univ, Shandong Technol Innovat Ctr Mol Targeting & Intel, Yantai, Peoples R China.;Binzhou Med Univ, Med Coll 2, Yantai, Peoples R China..
    Xu, Fuyi
    Binzhou Med Univ, Shandong Technol Innovat Ctr Mol Targeting & Intel, Yantai, Peoples R China.;Binzhou Med Univ, Sch Pharm, Yantai, Peoples R China..
    Kong, Demin
    Binzhou Med Univ, Sch Pharm, Yantai, Peoples R China..
    Mi, Jia
    Binzhou Med Univ, Shandong Technol Innovat Ctr Mol Targeting & Intel, Yantai, Peoples R China.;Binzhou Med Univ, Sch Pharm, Yantai, Peoples R China..
    Yang, Chunhua
    Binzhou Med Univ, Shandong Technol Innovat Ctr Mol Targeting & Intel, Yantai, Peoples R China.;Binzhou Med Univ, Sch Pharm, Yantai, Peoples R China..
    Zhang, Guilong
    Binzhou Med Univ, Shandong Technol Innovat Ctr Mol Targeting & Intel, Yantai, Peoples R China.;Binzhou Med Univ, Sch Pharm, Yantai, Peoples R China..
    Wei, Pengfei
    Binzhou Med Univ, Shandong Technol Innovat Ctr Mol Targeting & Intel, Yantai, Peoples R China.;Binzhou Med Univ, Sch Pharm, Yantai, Peoples R China..
    Orgil, Buyan-Ochir
    Univ Tennessee Hlth Sci Ctr, Memphis, TN USA..
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Binzhou Med Univ, Shandong Technol Innovat Ctr Mol Targeting & Intel, Yantai, Peoples R China..
    Tian, Geng
    Binzhou Med Univ, Shandong Technol Innovat Ctr Mol Targeting & Intel, Yantai, Peoples R China.;Binzhou Med Univ, Sch Pharm, Yantai, Peoples R China..
    Acetylation of Checkpoint suppressor 1 enhances its stability and promotes the progression of triple-negative breast cancer2022In: Cell Death Discovery, E-ISSN 2058-7716, Vol. 8, no 1, article id 474Article in journal (Refereed)
    Abstract [en]

    Checkpoint suppressor 1 (CHES1), a transcriptional regulator, had been dysregulated in many types of malignancies including breast cancer, and its expression level is strongly associated with progression and prognosis of patients. However, the underlying regulatory mechanisms of CHES1 expression in the breast cancer and the effects of post-translational modifications (PTMs) on its functional performance remain to be fully investigated. Herein, we found that CHES1 had a high abundance in triple-negative breast cancer (TNBC) and its expression was tightly associated with malignant phenotype and poor outcomes of patients. Furthermore, we confirmed that CHES1 was an acetylated protein and its dynamic modification was mediated by p300 and HDAC1, and CHES1 acetylation enhanced its stability via decreasing its ubiquitination and degradation, which resulted in the high abundance of CHES1 in TNBC. RNA-seq and functional study revealed that CHES1 facilitated the activation of oncogenic genes and pathways leading to proliferation and metastasis of TNBC. Taken together, this research established a novel regulatory role of acetylation on the stability and activity of CHES1. The results demonstrate the significance of CHES1 acetylation and underlying mechanisms in the progression of TNBC, offering new potential candidate for molecular-targeted therapy in breast cancer.

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  • 406.
    Yakymovych, Ihor
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Yakymovych, Mariya
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hamidi, Anahita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Landström, Maréne
    Department of Medical Biosciences, Pathology Section, Umeå University, SE-901 87 Umeå, Sweden..
    Heldin, Carl-Henrik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    The type II TGF-β receptor phosphorylates Tyr 182 in the type I receptor to activate downstream Src signaling2022In: Science Signaling, ISSN 1945-0877, E-ISSN 1937-9145, Vol. 15, no 760, article id eabp9521Article in journal (Refereed)
    Abstract [en]

    Transforming growth factor–β (TGF-β) signaling has important roles during embryonic development and in tissue homeostasis. TGF-β ligands exert cellular effects by binding to type I (TβRI) and type II (TβRII) receptors and induce both SMAD-dependent as well as SMAD-independent intracellular signaling pathways. Activation of the tyrosine kinase Src is one such SMAD-independent consequence of TGF-β signaling. We investigated the mechanism by which TGF-β stimulation activates Src in human and mouse cells. Before TGF-β stimulation, inactive Src was present in a complex with TβRII. Upon TGF-β1 stimulation, which induces the formation of a complex of TβRI and TβRII, TβRII phosphorylated TβRI on serine and threonine residues, which promotes TβRI kinase activity, and on Tyr182. The SH2 domain of Src bound to phosphporylated Tyr182, leading to activation of Src kinase activity. Interaction of the Src SH3 domain with a proline-rich region in TβRI also contributed to binding. TGF-β1–induced Src activation depended on the kinase activity of TβRII but not on that of TβRI, indicating that binding to TβRI activated Src through a non-enzymatic mechanism. Activated Src then phosphorylated TβRI on several tyrosine residues, which may stabilize Src binding to the receptor. In functional assays, Src activation was required for the TGF-β–induced production of fibronectin and for migration in human breast carcinoma cells and for the induction of α-smooth muscle actin (α-SMA) and actin reorganization in mouse fibroblasts. Thus, TGF-β induces Src activation by stimulating a direct interaction with TβRI that depends on tyrosine phosphorylation of TβRI by TβRII. 

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    Yakymovych, et al., Sci. Signal. 2022
  • 407. Yamamoto, Daniel L.
    et al.
    Csikasz, Robert I.
    Li, Yu
    Sharma, Gunjana
    Hjort, Klas
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Micro Structural Technology.
    Karlsson, Roger
    Bengtsson, Tore
    Myotube formation on micro-patterned glass: Intracellular organization and protein distribution in C2C12 skeletal muscle cells2008In: Journal of Histochemistry and Cytochemistry, ISSN 0022-1554, E-ISSN 1551-5044, Vol. 56, no 10, p. 881-892Article in journal (Refereed)
    Abstract [en]

    Proliferation and fusion of myoblasts are needed for the generation and repair of multinucleated skeletal muscle fibers in vivo. Studies of myocyte differentiation, cell fusion, and muscle repair are limited by an appropriate in vitro muscle cell culture system. We developed a novel cell culture technique [two-dimensional muscle syncytia (2DMS) technique] that results in formation of myotubes, organized in parallel much like the arrangement in muscle tissue. This technique is based on UV lithography-produced micro-patterned glass on which conventionally cultured C2C12 myoblasts proliferate, align, and fuse to neatly arranged contractile myotubes in parallel arrays. Combining this technique with fluorescent microscopy, we observed alignment of actin filament bundles and a perinuclear distribution of glucose transporter 4 after myotube formation. Newly formed myotubes contained adjacently located MyoD-positive and MyoD-negative nuclei, suggesting fusion of MyoD-positive and MyoD-negative cells. In comparison, the closely related myogenic factor Myf5 did not exhibit this pattern of distribution. Furthermore, cytoplasmic patches of MyoD colocalized with bundles of filamentous actin near myotube nuclei. At later stages of differentiation, all nuclei in the myotubes were MyoD negative. The 2DMS system is thus a useful tool for studies on muscle alignment, differentiation, fusion, and subcellular protein localization.

  • 408.
    Yang, Chen
    et al.
    Karolinska Inst, Dept Oncol & Pathol, Stockholm, Sweden.;Cent South Univ, Dept Gen Surg, Xiangya Hosp, Changsha, Hunan, Peoples R China.;Hunan Key Lab Precise Diag & Treatment Gastrointe, Changsha, Hunan, Peoples R China..
    Zhang, Yifan
    Karolinska Inst, Dept Oncol & Pathol, Stockholm, Sweden..
    Chen, Yi
    Karolinska Inst, Dept Oncol & Pathol, Stockholm, Sweden..
    Ragaller, Franziska
    Karolinska Inst, Dept Oncol & Pathol, Stockholm, Sweden.;Heidelberg Univ, Heidelberg, Germany.;German Canc Res Ctr, Heidelberg, Germany..
    Liu, Mingzhi
    Karolinska Inst, Dept Oncol & Pathol, Stockholm, Sweden..
    Corvigno, Sara
    Karolinska Inst, Dept Oncol & Pathol, Stockholm, Sweden..
    Dahlstrand, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Karolinska Inst, Dept Oncol & Pathol, Stockholm, Sweden..
    Carlson, Joseph
    Karolinska Inst, Dept Oncol & Pathol, Stockholm, Sweden..
    Chen, Zihua
    Cent South Univ, Dept Gen Surg, Xiangya Hosp, Changsha, Hunan, Peoples R China.;Hunan Key Lab Precise Diag & Treatment Gastrointe, Changsha, Hunan, Peoples R China..
    Nasman, Anders
    Karolinska Inst, Dept Oncol & Pathol, Stockholm, Sweden..
    Waraky, Ahmed
    Gothenburg Univ, Dept Lab Med, Gothenburg, Sweden..
    Lin, Yingbo
    Karolinska Inst, Dept Oncol & Pathol, Stockholm, Sweden..
    Larsson, Olle
    Karolinska Inst, Dept Oncol & Pathol, Stockholm, Sweden..
    Haglund, Felix
    Karolinska Inst, Dept Oncol & Pathol, Stockholm, Sweden..
    Nuclear IGF1R interact with PCNA to preserve DNA replication after DNA-damage in a variety of human cancers2020In: PLOS ONE, E-ISSN 1932-6203, Vol. 15, no 7, article id e0236291Article in journal (Refereed)
    Abstract [en]

    Nuclear IGF1R has been linked to poor outcome in cancer. We recently showed that nuclear IGF1R phosphorylates PCNA and increases DNA damage tolerance. In this paper we aimed to describe this mechanism in cancer tissue as well as in cancer cell lines. In situ proximity ligation assay identified frequent IGF1R and PCNA colocalization in many cancer types. IGF1R/PCNA colocalization was more frequently increased in tumor cells than in adjacent normal, and more prominent in areas with dysplasia and invasion. However, the interaction was often lost in tumors with poor response to neoadjuvant treatment and most metastatic lesions. In two independent cohorts of serous ovarian carcinomas and oropharyngeal squamous cell carcinomas, stronger IGF1R/PCNA colocalization was significantly associated with a higher overall survival. Ex vivo irradiation of ovarian cancer tissue acutely induced IGF1R/PCNA colocalization together with ?H2AX-foci formations. In vitro, RAD18 mediated mono-ubiquitination of PCNA during replication stress was dependent on IGF1R kinase activity. DNA fiber analysis revealed that IGF1R activation could rescue stalled DNA replication forks, but only in cancer cells with baseline IGF1R/PCNA interaction. We believe that the IGF1R/PCNA interaction is a basic cellular mechanism to increase DNA stress tolerance during proliferation, but that this mechanism is lost with tumor progression in conjunction with accumulated DNA damage and aberrant strategies to tolerate genomic instability. To exploit this mechanism in IGF1R targeted therapy, IGF1R inhibitors should be explored in the context of concomitant induction of DNA replication stress as well as in earlier clinical stages than previously tried.

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  • 409.
    Yau, Anthony C. Y.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Globisch, Maria A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Onyeogaziri, Favour
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Conze, Lei L.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Smith, Ross O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Jauhiainen, Suvi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Corada, Monica
    FIRC Inst Mol Oncol Fdn, Vasc Biol Unit, Milan, Italy..
    Orsenigo, Fabrizio
    FIRC Inst Mol Oncol Fdn, Vasc Biol Unit, Milan, Italy..
    Huang, Hua
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Herre, Melanie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Malinverno, Matteo
    FIRC Inst Mol Oncol Fdn, Vasc Biol Unit, Milan, Italy..
    Sundell, Veronica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Rezai Jahromi, Behnam
    Univ Helsinki, Dept Neurosurg, Helsinki, Finland.;Helsinki Univ Hosp, Helsinki, Finland..
    Niemela, Mika
    Univ Helsinki, Dept Neurosurg, Helsinki, Finland.;Helsinki Univ Hosp, Helsinki, Finland..
    Laakso, Aki
    Univ Helsinki, Dept Neurosurg, Helsinki, Finland.;Helsinki Univ Hosp, Helsinki, Finland..
    Garlanda, Cecilia
    Humanitas Univ, Dept Biomed Sci, Milan, Italy.;IRCCS Humanitas Res Hosp, Milan, Italy..
    Mantovani, Alberto
    Humanitas Univ, Dept Biomed Sci, Milan, Italy.;IRCCS Humanitas Res Hosp, Milan, Italy.;Queen Mary Univ London, William Harvey Res Inst, London, England..
    Lampugnani, Maria Grazia
    FIRC Inst Mol Oncol Fdn, Vasc Biol Unit, Milan, Italy.;Mario Negri Inst Pharmacol Res, I-20157 Milan, Italy..
    Dejana, Elisabetta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. FIRC Inst Mol Oncol Fdn, Vasc Biol Unit, Milan, Italy..
    Magnusson, Peetra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Inflammation and neutrophil extracellular traps in cerebral cavernous malformation (vol 79, 206, 2022)2022In: Cellular and Molecular Life Sciences (CMLS), ISSN 1420-682X, E-ISSN 1420-9071, Vol. 79, no 7, article id 388Article in journal (Refereed)
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    FULLTEXT01
  • 410.
    Yeung, Maggie
    et al.
    Karolinska Insitutet, CMB.
    Sofia, Zdunek
    Karolinska Insitutet, CMB.
    Bergmann, Olaf
    Karolinska Insitutet, CMB.
    Bernard, Samuel
    Salehpour, Mehran
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Ion Physics.
    Alkass, Kanar
    Perl, Shira
    Tisdale, John
    Possnert, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Ion Physics.
    Brundin, Lou
    Druid, Henrik
    Karolinska Insitutet, CMB.
    Frisén, Jonas
    Karolinska Insitutet, CMB.
    Dynamics of Oligodendrocyte Generation and Myelination in the Human Brain2014In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 159, no 4, p. 766-774Article in journal (Refereed)
    Abstract [en]

    The myelination of axons by oligodendrocytes has been suggested to be modulated by experience, which could mediate neural plasticity by optimizing the performance of the circuitry. We have assessed the dynamics of oligodendrocyte generation and myelination in the human brain. The number of oligodendrocytes in the corpus callosum is established in childhood and remains stable after that. Analysis of the integration of nuclear bomb test-derived 14C revealed that myelin is exchanged at a high rate, whereas the oligodendrocyte population in white matter is remarkably stable in humans, with an annual exchange of 1/300 oligodendrocytes. We conclude that oligodendrocyte turnover contributes minimally to myelin remodeling in human white matter and that this instead may be carried out by mature oligodendrocytes, which may facilitate rapid neural plasticity.

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    YeungetalOligoC14-revised
  • 411.
    Yin, Runting
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Department of Cardiology, Affiliated Hospital of Jiangsu University.
    Eger, Glenda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Sarri, Niki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rorsman, Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lennartsson, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Dual specificity phosphatase (DUSP)-4 is induced by platelet-derived growth factor -BB in an Erk1/2-, STAT3- and p53-dependent manner2019In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 519, no 3, p. 469-474Article in journal (Refereed)
    Abstract [en]

    Dual specificity phosphatase (DUSP) 4 has been described as a negative regulator of MAP kinase signaling, in particular for the ERK1/2 and JNK pathways. We found that DUSP4 expression was upregulated in response to prolonged platelet-derived growth factor (PDGF)-BB stimulation. The PDGF-BB-induced DUSP4 expression was dependent on ERK1/2, STAT3 and p53. We found that inhibition of ERK1/2 effectively reduced DUSP4 mRNA levels, whereas STAT3 was necessary for maintaining p53 expression. p53 has binding sites in the DUSP4 promoter and was found to promote DUSP4 expression.

  • 412.
    Zaghlool, Ammar
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Niazi, Adnan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Björklund, Åsa K.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Orzechowski Westholm, Jakub
    Stockholm Univ, Natl Bioinformat Infrastruct Sweden, Dept Biochem & Biophys, Sci Life Lab, Box 1031, S-17121 Solna, Sweden.
    Ameur, Adam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Feuk, Lars
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Characterization of the nuclear and cytosolic transcriptomes in human brain tissue reveals new insights into the subcellular distribution of RNA transcripts2021In: Scientific Reports, E-ISSN 2045-2322, Vol. 11, no 1, article id 4076Article in journal (Refereed)
    Abstract [en]

    Transcriptome analysis has mainly relied on analyzing RNA sequencing data from whole cells, overlooking the impact of subcellular RNA localization and its influence on our understanding of gene function, and interpretation of gene expression signatures in cells. Here, we separated cytosolic and nuclear RNA from human fetal and adult brain samples and performed a comprehensive analysis of cytosolic and nuclear transcriptomes. There are significant differences in RNA expression for protein-coding and lncRNA genes between cytosol and nucleus. We show that transcripts encoding the nuclear-encoded mitochondrial proteins are significantly enriched in the cytosol compared to the rest of protein-coding genes. Differential expression analysis between fetal and adult frontal cortex show that results obtained from the cytosolic RNA differ from results using nuclear RNA both at the level of transcript types and the number of differentially expressed genes. Our data provide a resource for the subcellular localization of thousands of RNA transcripts in the human brain and highlight differences in using the cytosolic or the nuclear transcriptomes for expression analysis.

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    FULLTEXT01
  • 413.
    Zhang, Juqing
    et al.
    Northwest A&F Univ, Coll Vet Med, Shaanxi Ctr Stem Cells Engn & Technol, Yangling 712100, Shaanxi, Peoples R China..
    Yue, Wei
    Northwest A&F Univ, Coll Vet Med, Shaanxi Ctr Stem Cells Engn & Technol, Yangling 712100, Shaanxi, Peoples R China..
    Zhou, Yaqi
    Northwest A&F Univ, Coll Life Sci, Yangling, Shaanxi, Peoples R China..
    Liao, Mingzhi
    Northwest A&F Univ, Coll Life Sci, Yangling, Shaanxi, Peoples R China..
    Chen, Xingqi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Hua, Jinlian
    Northwest A&F Univ, Coll Vet Med, Shaanxi Ctr Stem Cells Engn & Technol, Yangling 712100, Shaanxi, Peoples R China..
    Super enhancers-Functional cores under the 3D genome2021In: Cell Proliferation, ISSN 0960-7722, E-ISSN 1365-2184, Vol. 54, no 2, article id e12970Article, review/survey (Refereed)
    Abstract [en]

    Complex biochemical reactions take place in the nucleus all the time. Transcription machines must follow the rules. The chromatin state, especially the three-dimensional structure of the genome, plays an important role in gene regulation and expression. The super enhancers are important for defining cell identity in mammalian developmental processes and human diseases. It has been shown that the major components of transcriptional activation complexes are recruited by super enhancer to form phase-separated condensates. We summarize the current knowledge about super enhancer in the 3D genome. Furthermore, a new related transcriptional regulation model from super enhancer is outlined to explain its role in the mammalian cell progress.

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    fulltext
  • 414.
    Zhang, Qiang
    et al.
    Karolinska Inst, Dept Neurosci, Biomed, Stockholm, Sweden..
    Balourdas, Dimitrios-Ilias
    Goethe Univ, Inst Pharmaceut Chem, Max Laue Str 9, D-60438 Frankfurt, Germany.;Buchmann Inst Mol Life Sci, Max Laue Str 15, D-60438 Frankfurt, Germany..
    Baron, Bruno
    Inst Pasteur, Ctr Ressources & Rech Technol C2RT, Plateforme Biophys Mol, F-75015 Paris, France..
    Senitzki, Alon
    Technion Israel Inst Technol, Dept Biol, IL-32000 Haifa, Israel..
    Haran, Tali E.
    Technion Israel Inst Technol, Dept Biol, IL-32000 Haifa, Israel..
    Wiman, Klas G.
    Karolinska Inst, Bioclinicum, Dept Oncol Pathol, Stockholm, Sweden..
    Soussi, Thierry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. UPMC Univ Paris 06, Sorbonne Univ, F-75005 Paris, France..
    Joerger, Andreas C.
    Goethe Univ, Inst Pharmaceut Chem, Max Laue Str 9, D-60438 Frankfurt, Germany.;Buchmann Inst Mol Life Sci, Max Laue Str 15, D-60438 Frankfurt, Germany..
    Evolutionary history of the p53 family DNA-binding domain: insights from an Alvinella pompejana homolog2022In: Cell Death and Disease, ISSN 2041-4889, E-ISSN 2041-4889, Vol. 13, no 3, article id 214Article in journal (Refereed)
    Abstract [en]

    The extremophile Alvinella pompejana, an annelid worm living on the edge of hydrothermal vents in the Pacific Ocean, is an excellent model system for studying factors that govern protein stability. Low intrinsic stability is a crucial factor for the susceptibility of the transcription factor p53 to inactivating mutations in human cancer. Understanding its molecular basis may facilitate the design of novel therapeutic strategies targeting mutant p53. By analyzing expressed sequence tag (EST) data, we discovered a p53 family gene in A. pompejana. Protein crystallography and biophysical studies showed that it has a p53/p63-like DNA-binding domain (DBD) that is more thermostable than all vertebrate p53 DBDs tested so far, but not as stable as that of human p63. We also identified features associated with its increased thermostability. In addition, the A. pompejana homolog shares DNA-binding properties with human p53 family DBDs, despite its evolutionary distance, consistent with a potential role in maintaining genome integrity. Through extensive structural and phylogenetic analyses, we could further trace key evolutionary events that shaped the structure, stability, and function of the p53 family DBD over time, leading to a potent but vulnerable tumor suppressor in humans.

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    FULLTEXT01
  • 415.
    Zhang, Yan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ortsäter, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Martinez-Corral, Ines
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Cdh5-lineage–independent origin of dermal lymphatics shown by temporally restricted lineage tracing2022In: Life Science Alliance, E-ISSN 2575-1077, Vol. 5, no 11Article in journal (Refereed)
    Abstract [en]

    The developmental origins of lymphatic endothelial cells (LECs) have been under intense research after a century-long debate. Although previously thought to be of solely venous endothelial origin, additional sources of LECs were recently identified in multiple tissues in mice. Here, we investigated the regional differences in the origin(s) of the dermal lymphatic vasculature by lineage tracing using the pan-endothelial Cdh5-CreERT2 line. Tamoxifen-induced labeling of blood ECs at E9.5, before initiation of lymphatic development, traced most of the dermal LECs but with lower efficiency in the lumbar compared with the cervical skin. By contrast, when used at E9.5 but not at E11.5, 4-hydroxytamoxifen, the active metabolite of tamoxifen that provides a tighter window of Cre activity, revealed low labeling frequency of LECs, and lymphvasculogenic clusters in the lumbar skin in particular. Temporally restricted lineage tracing thus reveals contribution of LECs of Cdh5-lineage–independent origin to dermal lymphatic vasculature. Our results further highlight Cre induction strategy as a critical parameter in defining the temporal window for stage-specific lineage tracing during early developmental stages of rapid tissue differentiation.

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    fulltext
  • 416.
    Zhang, Yanqing
    et al.
    Tsinghua Univ, Sch Life Sci, Struct Biol Ctr, Key Lab Prot Sci,Minist Educ, Beijing 100084, Peoples R China..
    Mandava, Chandra Sekhar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology.
    Cao, Wei
    Tsinghua Univ, Sch Life Sci, Struct Biol Ctr, Key Lab Prot Sci,Minist Educ, Beijing 100084, Peoples R China..
    Li, Xiaojing
    Chinese Acad Sci, Inst Microbiol, Key Lab Pathogen Microbiol & Immunol, Beijing, Peoples R China..
    Zhang, Dejiu
    Chinese Acad Sci, Inst Biophys, Key Lab RNA Biol, Beijing 100080, Peoples R China..
    Li, Ningning
    Tsinghua Univ, Sch Life Sci, Struct Biol Ctr, Key Lab Prot Sci,Minist Educ, Beijing 100084, Peoples R China..
    Zhang, Yiudao
    Tsinghua Univ, Sch Life Sci, Struct Biol Ctr, Key Lab Prot Sci,Minist Educ, Beijing 100084, Peoples R China..
    Zhang, Xiaoxiao
    Tsinghua Univ, Sch Life Sci, Struct Biol Ctr, Key Lab Prot Sci,Minist Educ, Beijing 100084, Peoples R China..
    Qin, Yan
    Chinese Acad Sci, Inst Biophys, Key Lab RNA Biol, Beijing 100080, Peoples R China..
    Mi, Kaixia
    Chinese Acad Sci, Inst Microbiol, Key Lab Pathogen Microbiol & Immunol, Beijing, Peoples R China..
    Lei, Jianlin
    Tsinghua Univ, Sch Life Sci, Struct Biol Ctr, Key Lab Prot Sci,Minist Educ, Beijing 100084, Peoples R China..
    Sanyal, Suparna
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology.
    Gao, Ning
    Tsinghua Univ, Sch Life Sci, Struct Biol Ctr, Key Lab Prot Sci,Minist Educ, Beijing 100084, Peoples R China..
    HflX is a ribosome-splitting factor rescuing stalled ribosomes under stress conditions2015In: Nature Structural & Molecular Biology, ISSN 1545-9993, E-ISSN 1545-9985, Vol. 22, no 11, p. 906-913Article in journal (Refereed)
    Abstract [en]

    Adverse cellular conditions often lead to nonproductive translational stalling and arrest of ribosomes on mRNAs. Here, we used fast kinetics and cryo-EM to characterize Escherichia coil HflX, a GTPase with unknown function. Our data reveal that HflX is a heat shock-induced ribosome-splitting factor capable of dissociating vacant as well as mRNA-associated ribosomes with deacylated tRNA in the peptidyl site. Structural data demonstrate that the N-terminal effector domain of HflX binds to the peptidyl transferase center in a strikingly similar manner as that of the class I release factors and induces dramatic conformational changes in central intersubunit bridges, thus promoting subunit dissociation. Accordingly, loss of HflX results in an increase in stalled ribosomes upon heat shock, These results suggest a primary role of HflX in rescuing translationally arrested ribosomes under stress conditions.

  • 417.
    Zhao, Ying
    et al.
    Nanoscale Cell Biology, Max-Planck-Institute for Biophysical Chemistry, Göttingen D-37077, Germany.
    Fang, Qinghua
    Nanoscale Cell Biology, Max-Planck-Institute for Biophysical Chemistry, Göttingen D-37077, Germany.
    Sharma, Satyan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular biophysics. Uppsala University, Science for Life Laboratory, SciLifeLab. Nanoscale Cell Biology, Max-Planck-Institute for Biophysical Chemistry, Göttingen D-37077, Germany.
    Jakhanwal, Shrutee
    Department of Neurobiology, Max-Planck-Institute for Biophysical Chemistry, Göttingen D-37077, Germany.
    Jahn, Reinhard
    Department of Neurobiology, Max-Planck-Institute for Biophysical Chemistry, Göttingen D-37077, Germany.
    Lindau, Manfred
    Nanoscale Cell Biology, Max-Planck-Institute for Biophysical Chemistry, Göttingen D-37077, Germany;Department of Physiology and Biophysics, University of Miami School of Medicine, Miami, FL 33136.
    All SNAP25 molecules in the vesicle–plasma membrane contact zone change conformation during vesicle priming2024In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 121, no 2, article id e2309161121Article in journal (Refereed)
    Abstract [en]

    In neuronal cell types, vesicular exocytosis is governed by the SNARE (soluble NSF attachment receptor) complex consisting of synaptobrevin2, SNAP25, and syntaxin1. These proteins are required for vesicle priming and fusion. We generated an improved SNAP25- based SNARE COmplex Reporter (SCORE2) incorporating mCeruelan3 and Venus and overexpressed it in SNAP25 knockout embryonic mouse chromaffin cells. This construct rescues vesicle fusion with properties indistinguishable from fusion in wild- type cells. Combining electrochemical imaging of individual release events using electrochemical detector arrays with total internal reflection fluorescence resonance energy transfer (TIR- FRET) imaging reveals a rapid FRET increase preceding indi-vidual fusion events by 65 ms. The experiments are performed under conditions of a steady- state cycle of docking, priming, and fusion, and the delay suggests that the FRET change reflects tight docking and priming of the vesicle, followed by fusion after ~65 ms. Given the absence of wt SNAP25, SCORE2 allows determination of the number of molecules at fusion sites and the number that changes conformation. The number of SNAP25 molecules changing conformation in the priming step increases with vesicle size and SNAP25 density in the plasma membrane and equals the number of copies present in the vesicle–plasma membrane contact zone. We estimate that in wt cells, 6 to 7 copies of SNAP25 change conformation during the priming step.

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  • 418.
    Zhou, Yan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Biology Education Centre.
    Regulation of Aurora A activity during checkpoint recovery2012Independent thesis Advanced level (degree of Master (Two Years)), 30 credits / 45 HE creditsStudent thesis
    Abstract [en]

    Cell division requires accurate DNA replication and cells develop checkpoint mechanisms toensure the correct passage of the genetic material. Cells arrest by a checkpoint when DNAdamage is found. After the checkpoint is silenced, the cell cycle can be resumed. Polo-likekinase 1 (Plk1) and Aurora A kinase (AurA) are both important regulators for checkpointrecovery. The question how AurA is activated was studied by many researchers, but the exactmechanism stays unclear.We developed a new setup to study AurA activation during checkpoint recovery. Quantitativeimmunofluorescence of fixed cells as well as a FRET probe that monitors Plk1 activity intime-lapse filming were applied in this study as indirect readouts of Aurora A activation. Theresult suggests that a Plk1-AurA feedback loop exists during checkpoint recovery. It can alsobe concluded that the inhibition of Cdk1 reduces Plk1 and AurA activity during checkpointrecovery. We also investigated the effect of calcium interfering drugs on AurA activation butno conclusive result was obtained.

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    Yan.Zhou.report
  • 419.
    Zieba, Agata
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pardali, Katerina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Söderberg, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lindbom, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nyström, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Moustakas, Aristidis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Landegren, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Intercellular variation in signaling through the TGF-β pathway and its relation to cell densityand cell cycle phase2012In: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 11, no 7, article id M111.013482Article in journal (Refereed)
    Abstract [en]

    Fundamental open questions in signal transduction remain concerning the sequence and distribution of molecular signaling events among individual cells. In this work we have characterized the intercellular variability of transforming growth factor β-induced Smad interactions, providing essential information about TGF-β signaling and its dependence on the density of cell populations and the cell-cycle phase. By employing the recently developed in situ proximity ligation assay, we investigated the dynamics of interactions and modifications of Smad proteins and their partners under native and physiological conditions. We analyzed the kinetics of assembly of Smad complexes and the influence of cellular environment and relation to mitosis. We report rapid kinetics of formation of Smad complexes, including native Smad2-Smad3-Smad4 trimeric complexes, in a manner influenced by the rate of proteasomal degradation of these proteins, and we found a striking cell to cell variation of signaling complexes. The single-cell analysis of TGF-β signaling in genetically unmodified cells revealed previously unknown aspects of regulation of this pathway, and it provided a basis for analysis of these signaling events to diagnose pathological perturbations in patient samples, and to evaluate their susceptibility to drug treatment.

  • 420.
    Zyśk, Marlena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Beretta, Chiara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Naia, Luana
    Karolinska Inst, Div Neurogeriatr, Dept Neurobiol Care Sci & Soc, BioClinicum, S-17164 Stockholm, Sweden..
    Dakhel, Abdulkhalek
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Pavenius, Linnea
    Karolinska Inst, Dept Womens & Childrens Hlth, Sci Life Lab, S-17165 Stockholm, Sweden..
    Brismar, Hjalmar
    Karolinska Inst, Dept Womens & Childrens Hlth, Sci Life Lab, S-17165 Stockholm, Sweden.;Royal Inst Technol, Dept Appl Phys, Sci Life Lab, S-17165 Stockholm, Sweden..
    Lindskog, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Research group Mia Lindskog.
    Ankarcrona, Maria
    Karolinska Inst, Div Neurogeriatr, Dept Neurobiol Care Sci & Soc, BioClinicum, S-17164 Stockholm, Sweden..
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Amyloid-beta accumulation in human astrocytes induces mitochondrial disruption and changed energy metabolism2023In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 20, article id 43Article in journal (Refereed)
    Abstract [en]

    Background: Astrocytes play a central role in maintaining brain energy metabolism, but are also tightly connected to the pathogenesis of Alzheimer's disease (AD). Our previous studies demonstrate that inflammatory astrocytes accumulate large amounts of aggregated amyloid-beta (A beta). However, in which way these A beta deposits influence their energy production remain unclear.

    Methods: The aim of the present study was to investigate how A beta pathology in astrocytes affects their mitochondria functionality and overall energy metabolism. For this purpose, human induced pluripotent cell (hiPSC)-derived astrocytes were exposed to sonicated A beta(42) fibrils for 7 days and analyzed over time using different experimental approaches.

    Results: Our results show that to maintain stable energy production, the astrocytes initially increased their mitochondrial fusion, but eventually the A beta-mediated stress led to abnormal mitochondrial swelling and excessive fission. Moreover, we detected increased levels of phosphorylated DRP-1 in the A beta-exposed astrocytes, which co-localized with lipid droplets. Analysis of ATP levels, when blocking certain stages of the energy pathways, indicated a metabolic shift to peroxisomal-based fatty acid beta-oxidation and glycolysis.

    Conclusions: Taken together, our data conclude that A beta pathology profoundly affects human astrocytes and changes their entire energy metabolism, which could result in disturbed brain homeostasis and aggravated disease progression.

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  • 421.
    Åström, Miranda
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Biology Education Centre.
    Functional studies of structural elements in toti-like virus through the development of new fluorescence-based methods2023Independent thesis Advanced level (degree of Master (Two Years)), 40 credits / 60 HE creditsStudent thesis
    Abstract [en]

    Omono River virus (OmRV), which infects Culex mosquitoes, belongs to the group of dsRNA toti-like viruses. Some members of toti-like viruses have a large negative impact on the fishing industry, which has increased the interest in understanding their propagation cycle. The structural elements of the OmRV such as the obstructed 5-fold pores and the surface crown proteins (CrPs) have been hypothesized to be of importance for viral particle replication as well as the ability of the virus to recognize and enter the host as part of the transmission cycle. In this study, a newly developed method based on fluorescence in situ hybridization (FISH) was used to observe the effect of OmRV pore mutants on viral particle genome transcription. Immobilized-metal affinity chromatography-based pull-down assays and Förster resonance energy transfer (FRET) assays were used to study the interactions between the CrPs and the viral capsid in vitro. The results show that perturbation of the obstructed pore function has a negative impact on viral propagation. One of the mutants, R925A, resulted in a reduction of viral nascent (+)ssRNA synthesis. The findings are to our knowledge the first indication that positively charged arginine residues in the pore structure might be crucial for intraparticle genome synthesis. Specific CrPs-capsid interaction could however not be detected using these in vitro methods, indicating the need for additional optimization to allow for detection of the weak and transient interactions between CrPs and capsid structure. In summary, these studies and a further development of quantitative methods will serve as starting point for and lead to a deeper understanding of the transmission cycle of the dsRNA toti-like virus family, including also the economically and societal important variants.

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    Strukturer som avslöjar virusets hemligheter
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  • 422.
    Çağlayan, Demet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Molecular and Cellular Complexity of Glioma: Highlights on the Double-Edged-Sword of Infiltration Versus Proliferation and the Involvement of T Cells2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Glioblastoma multiforme (GBM), the most common and malignant brain tumor, is characterized by high molecular and cellular heterogeneity within and among tumors. Parameters such as invasive growth, infiltration of immune cells and endothelial proliferation contribute in a systemic manner to maintain the malignancy.

    Studies in this thesis show that the expression of Sox2 is correlated with Sox21 in human gliomas. We demonstrate that an upregulation of Sox21 induces loss of proliferation, apoptosis and differentiation in glioma cells in vitro and in vivo and seems to correlate with decreased Sox2 expression. Induced expression of Sox21 in vivo significantly reduces the tumor size and increase the survival extensively, suggesting that Sox21 can act as a tumor suppressor Our studies indicate that the balance of Sox21-Sox2 in glioma cells is decisive of either a proliferative or a non-proliferative state.

    Several TGFß family members have an important role in glioma development. TGFß promotes proliferation and tumorigenicity whereas BMPs mostly inhibit proliferation. We demonstrate that BMP7 can induce the transcription factor Snail in glioma cells and that this reduces the tumorigenicity with a concomitant increase in invasiveness. Thus, we have identified a mechanism to the double-edged sword of proliferation versus invasiveness in GBM, the latter contributing to relapse in patients.

    Experimental gliomas were induced with the Sleeping Beauty (SB) model in mice with different immunological status of their T cells. The tumors that developed were either GBMs or highly diffuse in their growth, reminiscent of gliomatosis cerebri (GC). GC is a highly uncommon form of glioma characterized by extensive infiltrative growth in large parts of the brain. It is an orphan disease and today there is practically a total lack of relevant experimental models. The SB system would constitute a novel experimental model to study the mechanisms behind the development of diffusely growing tumors like GC. The presence or absence of T cells did not affect tumor development.

    The work in this thesis demonstrates that the proliferative and the invasive capacities of glioma cells can be dissociated and that the SB model constitutes an excellent model to study the highly proliferative cells in GBMs versus the highly invasive cells in diffuse tumors like .GC.

    List of papers
    1. Forced expression of Sox21 inhibits Sox2 and induces apoptosis in human glioma cells
    Open this publication in new window or tab >>Forced expression of Sox21 inhibits Sox2 and induces apoptosis in human glioma cells
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    2011 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 129, no 1, p. 45-60Article in journal (Refereed) Published
    Abstract [en]

    Numerous studies support a role for Sox2 to keep stem cells and progenitor cells in an immature and proliferative state. Coexpression of Sox2 and GFAP has been found in regions of the adult brain where neural stem cells are present and in human glioma cells. In our study, we have investigated the roles of Sox2 and its counteracting partner Sox21 in human glioma cells. We show for the first time that Sox21 is expressed in both primary glioblastoma and in human glioma cell lines. We found that coexpression of Sox2, GFAP and Sox21 was mutually exclusive with expression of fibronectin. Our result suggests that glioma consists of at least two different cell populations: Sox2+/GFAP+/Sox21+/FN- and Sox2-/GFAP-/Sox21-/FN1+. Reduction of Sox2 expression by using siRNA against Sox2 or by overexpressing Sox21 using a tetracyclineregulated expression system (Tet-on) caused decreased GFAP expression and a reduction in cell number due to induction of apoptosis. We suggest that Sox21 can negatively regulate Sox2 in glioma. Our findings imply that Sox2 and Sox21 may be interesting targets for the development of novel glioma therapy.

    Keywords
    Glioma, brain tumor, Sox2, Sox21, GFAP
    National Category
    Cell and Molecular Biology
    Research subject
    Medical Cell Biology
    Identifiers
    urn:nbn:se:uu:diva-151784 (URN)10.1002/ijc.25647 (DOI)000289987300005 ()20824710 (PubMedID)
    Available from: 2011-04-18 Created: 2011-04-18 Last updated: 2022-01-28Bibliographically approved
    2. Sox21 inhibits glioma progression in vivo by reducing Sox2 and stimulating aberrant differentiation
    Open this publication in new window or tab >>Sox21 inhibits glioma progression in vivo by reducing Sox2 and stimulating aberrant differentiation
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    2013 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 133, no 6, p. 1345-1356Article in journal (Refereed) Published
    Abstract [en]

    Sox2 is a transcription factor in neural stem cells and keeps the cells immature and proliferative. Sox2 is expressed in primary human glioma such as glioblastoma multiforme (GBM), primary glioma cells and glioma cell lines and is implicated in signaling pathways in glioma connected to malignancy. Sox21, the counteracting partner of Sox2, has the same expression pattern as Sox2 in glioma but in general induces opposite effects. In this study, Sox21 was overexpressed by using a tetracycline-regulated expression system (tet-on) in glioma cells. The glioma cells were injected subcutaneously into immunodeficient mice. The control tumors were highly proliferative, contained microvascular proliferation and large necrotic areas typical of human GBM. Induction of Sox21 in the tumor cells resulted in a significant smaller tumor size, and the effect correlated with the onset of treatment, where earlier treatment gave smaller tumors. Mice injected with glioma cells orthotopically into the brain survived significantly longer when Sox21 expression was induced. Tumors originating from glioma cells with an induced expression of Sox21 exhibited an increased formation of Sox2:Sox21 complexes and an upregulation of S100β, CNPase and Tuj1. Sox21 appears to decrease the stem-like cell properties of the tumor cells and initiate aberrant differentiation of glioma cells in vivo. Taken together our results indicate that Sox21 can function as a tumor suppressor during gliomagenesis mediated by a shift in the balance between Sox2 and Sox21. The wide distribution of Sox2 and Sox21 in GBM makes the Sox2/Sox21 axis a very interesting target for novel therapy of gliomas.

    Keywords
    brain tumors, glioma, Sox2, Sox21, S100
    National Category
    Medical and Health Sciences Cell and Molecular Biology
    Research subject
    Medical Science
    Identifiers
    urn:nbn:se:uu:diva-182943 (URN)10.1002/ijc.28147 (DOI)
    Available from: 2012-10-19 Created: 2012-10-19 Last updated: 2018-01-12Bibliographically approved
    3.
    The record could not be found. The reason may be that the record is no longer available or you may have typed in a wrong id in the address field.
    4. Induction of Glioblastoma Multiforme and Gliomatosis Cerebri with a Sleeping Beauty gene transfer system, implications for T regulatory cell involvement during glioma formation.
    Open this publication in new window or tab >>Induction of Glioblastoma Multiforme and Gliomatosis Cerebri with a Sleeping Beauty gene transfer system, implications for T regulatory cell involvement during glioma formation.
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Glioblastoma Multiforme (GBM), the most malignant and common  neoplasm of the central nervous system (CNS), has been classified into subgroups with gene-expression profile as the basis for categorization. Among these the mesenchymal subgroup is most greatly associated with inflammatory infiltrates and increased expression of inflammatory associated genes. GBMs exhibit T cell infiltration to a varying degree and today the degree of infiltration is not used in prognostics. The Sleeping Beauty (SB) system was used to introduce AKT, a mutant variant of NRAS and a shp53 coupled to green fluorescent protein (GFP) into mice that are fully immunocomptetent, lack mature T cells or have reduced regulatory T (Treg) cell function respectively. We report, for the first time, the induction of Gliomatosis Cerebri with the SB system. Tumors that originated were either GBM or Gliomatosis Cerebri with a similar incidence. There was no difference in survival, grade or incidence of induced tumors in wild type mice and mice that lack mature T cells.

    Keywords
    : brain tumors, Sleeping Beauty, T cells, AKT, NRAS, shp53
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-183668 (URN)
    Available from: 2012-10-31 Created: 2012-10-31 Last updated: 2013-02-11
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  • 423.
    Čančer, Matko
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hutter, Sonja
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Holmberg Olausson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rosén, Gabriela
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Sundström, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Tailor, Jignesh
    Univ Cambridge, Wellcome Trust MRC Stem Cell Inst, Tennis Court Rd, Cambridge CB2 1QR, England.
    Bergström, Tobias
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Garancher, Alexandra
    NCI, Tumor Initiat & Maintenance Program, Designated Canc Ctr, Sanford Burnham Prebys Med Discovery Inst, La Jolla, CA 92037 USA.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wechsler-Reya, Robert J.
    NCI, Tumor Initiat & Maintenance Program, Designated Canc Ctr, Sanford Burnham Prebys Med Discovery Inst, La Jolla, CA 92037 USA.
    Falk, Anna
    Karolinska Inst, Dept Neurosci, S-17177 Stockholm, Sweden.
    Weishaupt, Holger
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Johansson, Fredrik K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Humanized Stem Cell Models of Pediatric Medulloblastoma Reveal an Oct4/mTOR Axis that Promotes Malignancy2019In: Cell Stem Cell, ISSN 1934-5909, E-ISSN 1875-9777, Vol. 25, no 6, p. 855-870Article in journal (Refereed)
    Abstract [en]

    Medulloblastoma (MB), the most frequent malignant childhood brain tumor, can arise from cellular malfunctions during hindbrain development. Here we generate humanized models for Sonic Hedgehog (SHH)-subgroup MB via MYCN overexpression in primary human hindbrain-derived neuroepithelial stem (hbNES) cells or iPSC-derived NES cells, which display a range of aggressive phenotypes upon xenografting. iPSC-derived NES tumors develop quickly with leptomeningeal dissemination, whereas hbNES-derived cells exhibit delayed tumor formation with less dissemination. Methylation and expression profiling show that tumors from both origins recapitulate hallmarks of infant SHH MB and reveal that mTOR activation, as a result of increased Oct4, promotes aggressiveness of human SHH tumors. Targeting mTOR decreases cell viability and prolongs survival, showing the utility of these varied models for dissecting mechanisms mediating tumor aggression and demonstrating the value of humanized models for a better understanding of pediatric cancers.

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    FULLTEXT01
  • 424.
    Šupraha, Luka
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, Palaeobiology.
    Gerecht, Andrea Cornelia
    Probert, Ian
    Henderiks, Jorijntje
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, Palaeobiology.
    Eco-physiological adaptation shapes the response of calcifying algae to nutrient limitation2015In: Scientific Reports, E-ISSN 2045-2322, Vol. 5, article id 16499Article in journal (Refereed)
    Abstract [en]

    The steady increase in global ocean temperature will most likely lead to nutrient limitation in the photic zone. This will impact the physiology of marine algae, including the globally important calcifying coccolithophores. Understanding their adaptive patterns is essential for modelling carbon production in a low-nutrient ocean. We investigated the physiology of Helicosphaera carteri, a representative of the abundant but under-investigated flagellated functional group of coccolithophores. Two strains isolated from contrasting nutrient regimes (South Atlantic and Mediterranean Sea) were grown in phosphorus-replete and phosphorus-limited batch cultures. While growing exponentially in a phosphorus-replete medium, the Mediterranean strain exhibited on average 24% lower growth rate, 36% larger coccosphere volume and 21% lower particulate inorganic carbon (PIC) production than the Atlantic strain. Under phosphorus limitation, the same strain was capable of reaching a 2.6 times higher cell density than the Atlantic strain due to lower phosphorus requirements. These results suggest that local physiological adaptation can define the performance of this species under nutrient limitation.

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