uu.seUppsala University Publications
Change search
Refine search result
2345678 201 - 250 of 3545
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rows per page
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sort
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
Select
The maximal number of hits you can export is 250. When you want to export more records please use the Create feeds function.
  • 201.
    Barkefors, Irmeli
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Thorslund, Sara
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Microsystems Technology.
    Nikolajeff, Fredrik
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Microsystems Technology.
    Kreuger, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    A fluidic device to study directional angiogenesis in complex tissue and organ culture models2009In: Lab on a Chip, ISSN 1473-0197, E-ISSN 1473-0189, Vol. 9, no 4, p. 529-535Article in journal (Refereed)
    Abstract [en]

    Many signals that induce angiogenesis have been identified; however, it is still not clear how these signals interact to shape the vascular system. We have developed a fluidic device for generation of molecular gradients in 3-dimensional cultures of complex tissues and organs in order to create an assay for precise induction and guidance of growing blood vessels. The device features a centrally placed culture chamber, flanked by channels attached to a perfusion system used to generate gradients. A separate network of vacuum channels permits reversible attachment of the device to a flat surface. We show that the fluidic device can be used to create growth factor gradients that induce directional angiogenesis in embryonic mouse kidneys and in clusters of differentiating stem cells. These results demonstrate that the device can be used to accurately manipulate complex morphogenetic processes with a high degree of experimental control.

  • 202.
    Barman, Jharna
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry. Chemistry, Department of Biochemistry and Organic Chemistry, Biochemistry.
    Acharya, Sandipta
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry. Chemistry, Department of Biochemistry and Organic Chemistry, Biochemistry.
    Zhou, Chuanzheng
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry. Chemistry, Department of Biochemistry and Organic Chemistry, Biochemistry.
    Chatterjee, Subhrangsu
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry. Chemistry, Department of Biochemistry and Organic Chemistry, Biochemistry.
    Engström, Åke
    Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Chemistry, Department of Biochemistry and Organic Chemistry, Biochemistry.
    Chattopadhyaya, Jyoti
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry. Chemistry, Department of Biochemistry and Organic Chemistry, Biochemistry.
    Non-identical electronic characters of the internucleotidic phosphates in RNA modulate the chemical reactivity of the phosphodiester bonds.2006In: Org Biomol Chem, ISSN 1477-0520, Vol. 4, no 5, p. 928-41Article in journal (Refereed)
  • 203.
    Barman, Jharna
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Acharya, Sandipta
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Zhou, Chuanzheng
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Chatterjee, Subhrangsu
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Engström, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Chattopadhyaya, Jyoti
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Non-identical electronic characters of the internucleotidic phosphates in RNA modulate the chemical reactivity of the phosphodiester bonds2006In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 4, no 5, p. 928-941Article in journal (Refereed)
    Abstract [en]

    We here show that the electronic properties and the chemical reactivities of the internucleotidic phosphates in the heptameric ssRNAs are dissimilar in a sequence-specific manner because of their non-identical microenvironments, in contrast with the corresponding isosequential ssDNAs. This has been evidenced by monitoring the delta H8(G) shifts upon pH-dependent ionization (pK(a1)) of the central 9-guaninyl (G) to the 9-guanylate ion (G(-)), and its electrostatic effect on each of the internucleotidic phosphate anions, as measured from the resultant delta P-31 shifts (pKa(2)) in the isosequential heptameric ssRNAs vis-`a-vis ssDNAs: [d/r( 5'-Cp(1)Ap(2)Q(1)p(3)Gp(4)Q(2)p(5)Ap(6)C-3'): Q(1) = Q(2) = A (5a/5b) or C (8a/8b), Q(1) = A, Q(2) = C (6a/6b), Q(1) = C, Q(2) = A (7a/7b)]. These oligos with single ionizable G in the centre are chosen because of the fact that the pseudoaromatic character of G can be easily modulated in a pH-dependent manner by its transformation to G(-) (the 2'-OH to 2-O- ionization effect is not detectable below pH 11.6 as evident from the N1-Me-G analog), thereby modulating/titrating the nature of the electrostatic interactions of G to G- with the phosphates, which therefore constitute simple models to interrogate how the variable pseudoaromatic characters of nucleobases under different sequence context (J. Am. Chem. Soc., 2004, 126, 8674-8681) can actually influence the reactivity of the internucleotide phosphates as a result of modulation of sequence context-specific electrostatic interactions. In order to better understand the impact of the electrostatic effect of the G to G- on the tunability of the electronic character of internucleotidic phosphates in the heptameric ssRNAs 5b, 6b, 7b and 8b, we have also performed their alkaline hydrolysis at pH 12.5 at 20 degrees C, and have identified the preferences of the cleavage sites at various phosphates, which are p(2), p(3) and p(4) (Fig. 3). The results of these alkaline hydrolysis studies have been compared with the hydrolysis of analogous N1-Me-G heptameric ssRNA sequences 5c, 7c and 8c under identical conditions in order to establish the role of the electrostatic effect of the 9-guanylate ion (and the 2'-OH to 2-O- ionization) on the internucleotidic phosphate. It turned out that the relative alkaline hydrolysis rate at those particular phosphates ( p2, p3 and p(4)) in the N1-Me-G heptamers was reduced from 16-78% compared to those in the native counterparts [Fig. 4, and ESI 2 (Fig. S11)]. Thus, these physico-chemical studies have shown that those p2, p3 and p4 phosphates in the native heptameric RNAs, which show pK(a2) as well as more deshielding ( owing to weaker P-31 screening) in the alkaline pH compared to those at the neutral pH, are more prone to the alkaline hydrolysis because of their relatively enhanced electrophilic character resulting from weaker P-31 screening. This screening effect originates as a result of the systematic charge repulsion effect between the electron cloud in the outermost orbitals of phosphorus and the central guanylate ion, leading to delocalization of the phosphorus pp charge into its d pi orbitals. It is thus likely that, just as in the non-enzymatic hydrolysis, the enzymatic hydrolysis of a specific phosphate in RNA by general base-catalyss in RNA-cleaving proteins (RNase A, RNA phosphodiesterase or nuclease) can potentially be electrostatically influenced by tuning the transient charge on the nucleobase in the steric proximity or as a result of specific sequence context owing to nearest-neighbor interactions.

  • 204. Barnes, Brian R
    et al.
    Glund, Stephan
    Long, Yun Chau
    Hjälm, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Zierath, Juleen R
    5'-AMP-activated protein kinase regulates skeletal muscle glycogen content and ergogenics2005In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 19, no 7, p. 773-779Article in journal (Refereed)
    Abstract [en]

    5'-AMP-activated protein kinase (AMPK) activity is increased during exercise in an intensity- and glycogen-dependent manner. We previously reported that a mutation in the AMPK3 subunit (Prkag3225Q) increases AMPK activity and skeletal muscle glycogen content. Transfection experiments revealed the R225Q mutation is associated with high basal AMPK activity and diminished AMP dependence. Thus, the R225Q mutation can be considered a loss-of-function mutation that abolished allosteric regulation by AMP/ATP, causing increased basal AMPK activity. We used AMPK3 transgenic (Tg-Prkag3225Q) and knockout (Prkag3-/-) mice to determine the relationship between AMPK activity, glycogen content, and ergogenics (ability to perform work) in isolated extensor digitorum longus skeletal muscle after contractions induced by electrical stimulation. Contraction-induced AMPK activity was inversely coupled to glycogen content in wild-type and Tg-Prkag3225Q mice, but not in Prkag3-/- mice, highlighting a partial feedback control of glycogen on contraction-induced AMPK activity in the presence of a functional AMPK3 isoform. Skeletal muscle glycogen content was positively correlated to work performance, regardless of genotype. Thus, chronic activation of AMPK by the Prkag3225Q mutation directly influences skeletal muscle ergogenics by enhancing glycogen content. In conclusion, functional studies of the AMPK3 isoform further support the close connection between glycogen content and exercise performance in skeletal muscle.

  • 205. Barnes, Brian R
    et al.
    Long, Yun Chau
    Steiler, Tatiana L
    Leng, Ying
    Galuska, Dana
    Wojtaszewski, Jörgen F P
    Andersson, Leif
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Zierath, Juleen R
    Changes in Exercise-Induced Gene Expression in 5'-AMP-Activated Protein Kinase {gamma}3-Null and {gamma}3 R225Q Transgenic Mice.2005In: Diabetes, ISSN 0012-1797, Vol. 54, no 12, p. 3484-9Article in journal (Refereed)
  • 206. Barnes, Brian R
    et al.
    Marklund, Stefan
    Steiler, Tatiana L
    Walter, Mark
    Hjälm, Göran
    Amarger, Valerie
    Mahlapuu, Margit
    Leng, Ying
    Johansson, Carina
    Galuska, Dana
    Lindgren, Kerstin
    Åbrink, Magnus
    Stapleton, David
    Zierath, Juleen R
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    The 5'-AMP-activated protein kinase gamma3 isoform has a key role in carbohydrate and lipid metabolism in glycolytic skeletal muscle2004In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 279, no 37, p. 38441-38447Article in journal (Refereed)
    Abstract [en]

    5'-AMP-activated protein kinase (AMPK) is a metabolic stress sensor present in all eukaryotes. A dominant missense mutation (R225Q) in pig PRKAG3, encoding the muscle-specific gamma3 isoform, causes a marked increase in glycogen content. To determine the functional role of the AMPK gamma3 isoform, we generated transgenic mice with skeletal muscle-specific expression of wild type or mutant (225Q) mouse gamma3 as well as Prkag3 knockout mice. Glycogen resynthesis after exercise was impaired in AMPK gamma3 knock-out mice and markedly enhanced in transgenic mutant mice. An AMPK activator failed to increase skeletal muscle glucose uptake in AMPK gamma3 knock-out mice, whereas contraction effects were preserved. When placed on a high fat diet, transgenic mutant mice but not knock-out mice were protected against excessive triglyceride accumulation and insulin resistance in skeletal muscle. Transfection experiments reveal the R225Q mutation is associated with higher basal AMPK activity and diminished AMP dependence. Our results validate the muscle-specific AMPK gamma3 isoform as a therapeutic target for prevention and treatment of insulin resistance.

  • 207. Barqasho, Babilonia
    et al.
    Nowak, Piotr
    Abdurahman, Samir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Walther-Jallow, Lillian
    Sönnerborg, Anders
    Implications of the release of high-mobility group box 1 protein from dying cells during human immunodeficiency virus type 1 infection in vitro2010In: Journal of General Virology, ISSN 0022-1317, E-ISSN 1465-2099, Vol. 91, p. 1800-1809Article in journal (Refereed)
    Abstract [en]

    Plasma levels of high-mobility group box 1 protein (HMGB1) are elevated during the course of human immunodeficiency virus type 1 (HIV-1) infection and the molecule has an impact on virus replication. This study investigated the mode of cell death and release of HMGB1 during HIV-1 infection in vitro. MT4 cells and primary CD4(+) T cells were infected with HIV-1 isolates, and HMGB1 release was monitored in relation to cytopathic effects (CPE) and apoptosis. HMGB1 release from cells was analysed by Western blotting. For MT4 cells, an enzyme-linked immunosorbent spot (ELISPOT) assay was adapted to measure the release during necrosis. Lactate dehydrogenase (LDH) activity was quantified using a commercial assay. Flow cytometry was used to determine the level of infection and apoptosis. MT4 cells were >= 90 % infected at 48 h post-infection (p.i.). CPE was first observed at 60 h and correlated with release of HMGB1, LDH activity and caspase-3 (C3) activation. HMGB1 spots were clearly detected by ELISPOT assay at 72 h p.i. Annexin V and C3 staining showed that apoptosis was substantially involved in HIV-1-related cell death. Addition of Z-VAD (a caspase inhibitor) in a single dose at 24 or 40 h p.i. decreased both the number of caspase-positive cells and the release of HMGB1. Infection of primary CD4(+) T cells showed a 22% (median) infection rate at 96 h. Related CPE corresponded to LDH and HMGB1 release. Both necrosis and apoptosis contributed to HMGB1 liberation during HIV-1-induced cell death and the protein could induce tumour necrosis factor-alpha release from peripheral mononuclear blood cells. These data imply that passive HMGB1 release contributes to the excessive immune activation characteristic of HIV-1 pathogenesis.

  • 208. Barragan, A
    et al.
    Fernandez, V
    Chen, Q
    von Euler, A
    Wahlgren, M
    Spillmann, D
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    The duffy-binding-like domain 1 of Plasmodium falciparum erythrocytemembrane protein 1 (PfEMP1) is a heparan sulfate ligand that requires 12mers for binding.2000In: Blood, Vol. 95, p. 3594-Article in journal (Refereed)
  • 209. Barragan, A
    et al.
    Fernandez, V
    Chen, Q
    von Euler, A
    Wahlgren, M
    Spillmann, Dorothe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    The duffy-binding-like domain 1 of Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is a heparan sulfate ligand that requires 12 mers for binding2000In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 95, no 11, p. 3594-3599Article in journal (Refereed)
    Abstract [en]

    The Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), present on the surfaces of parasitized red blood cells (pRBC), mediates rosetting, a virulent phenotype. Here, we show that pRBC specifically bind heparan sulfate (HS) and heparin onto their surfaces and that the rosetting ligand PfEMP1 specifically adheres to heparin-Sepharose when extracted from the surfaces of radioiodinated infected RBC. An analysis of the binding properties of the different regions of PfEMP1 provides evidence that the Duffy-binding-like domain-1 (DBL-1) is the predominant ligand involved in HS and heparin binding. Soluble DBL-1 requires a minimal heparin fragment size of a 12-mer ( approximately 4 kd) for binding and is critically dependent on N-sulfation. A 12-mer is also the minimal heparin fragment that disrupts naturally formed rosettes. DBL-1 binds specifically to erythrocytes and also to HS from endothelial cells and human aorta but not to chondroitin sulfate A, suggesting that different PfEMP1s mediate adhesion to distinct glycosaminoglycans in individual malaria parasites. Present data suggest that HS on endothelial cells may also be involved in the sequestration of pRBC. Elucidation of these binding mechanisms opens up new possibilities for therapeutic strategies targeting adhesive interactions of pRBC.

  • 210. Barragan, A
    et al.
    Spillmann, D
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Carlson, J
    Wahlgren, M
    Role of glycans in Plasmodium falciparum infection.1999In: Biochem Soc Trans, Vol. 27, p. 487-Article in journal (Refereed)
  • 211. Barragan, A
    et al.
    Spillmann, Dorothe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Carlson, J
    Wahlgren, M
    Role of glycans in Plasmodium falciparum infection1999In: Biochemical Society Transactions, ISSN 0300-5127, E-ISSN 1470-8752, Vol. 27, no 4, p. 487-493Article in journal (Refereed)
  • 212. Barragan, A
    et al.
    Spillmann, Dorothe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Kremsner, PG
    Wahlgren, M
    Carlson, J
    Plasmodium falciparum: molecular background to strain-specific rosettedisruption by glycosaminoglycans and sulfated glycoconjugates1999In: Experimental parasitology, ISSN 0014-4894, E-ISSN 1090-2449, Vol. 91, no 2, p. 133-143Article in journal (Refereed)
    Abstract [en]

    Rosetting, the adhesion of Plasmodium falciparum-infected erythrocytes to uninfected erythrocytes, is a virulent parasite phenotype associated with the occurrence of severe malaria, e.g., cerebral malaria. Compounds with specific anti-rosetting activity are potential therapeutic agents. Glycosaminoglycans and sulfated glycoconjugates were found to disrupt rosettes in a strain- and isolate-specific manner. Rosette disruption was strongly connected to the presence of N-sulfate groups in heparin/heparan sulfate as demonstrated by modified heparin preparations. This finding was corroborated by the disruption of rosettes with mono- and disaccharides derived from heparin/heparan sulfate that contained N-sulfated glucosamine. Furthermore, heparinase III treatment of erythrocyte cultures infected by FCR3S1 (and to some extent TM 284) P. falciparum strains abolished rosetting. Heparinase III treatment of the uninfected erythrocytes prior to mixing with the infected culture impeded formation of rosettes, indicating that the rosetting receptors at least partially are of glycosaminoglycan nature.

  • 213. Barragan, Antonio
    et al.
    Spillmann, Dorothe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Kremsner, Peter G
    Wahlgren, Mats
    Carlson, Johan
    Erythrocyte Glycans as Plasmodium falciparum Rosetting Receptors: Molecular Background of Strain Specific Rosette Disruption by Glycosaminoglycans and Sulfated Glycoconjugates1999In: Experimental parasitology, ISSN 0014-4894, E-ISSN 1090-2449, Vol. 91, no 2, p. 133-143Article in journal (Refereed)
    Abstract [en]

    Rosetting, the adhesion of Plasmodium falciparum-infected erythrocytes to uninfected erythrocytes, is a virulent parasite phenotype associated with the occurrence of severe malaria, e.g., cerebral malaria. Compounds with specific anti-rosetting activity are potential therapeutic agents. Glycosaminoglycans and sulfated glycoconjugates were found to disrupt rosettes in a strain- and isolate-specific manner. Rosette disruption was strongly connected to the presence of N-sulfate groups in heparin/heparan sulfate as demonstrated by modified heparin preparations. This finding was corroborated by the disruption of rosettes with mono- and disaccharides derived from heparin/heparan sulfate that contained N-sulfated glucosamine. Furthermore, heparinase III treatment of erythrocyte cultures infected by FCR3S1 (and to some extent TM 284) P. falciparum strains abolished rosetting. Heparinase III treatment of the uninfected erythrocytes prior to mixing with the infected culture impeded formation of rosettes, indicating that the rosetting receptors at least partially are of glycosaminoglycan nature.

  • 214. Barragan, Antonio
    et al.
    Spillmann, Dorothe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Kremsner, Peter
    Wahlgren, Mats
    Carlson, Johan
    Erythrocyte glycans as Plasmodium Falciparum rosetting receptors: molecular background of strain specific rosette disruption by glycosaminoglycans and sulfated glycoconjugates1998In: Parasitology international, ISSN 1383-5769, E-ISSN 1873-0329, Vol. 47, no Suppl.1, p. 215-Article, book review (Other academic)
  • 215.
    Barrio, Alvaro Martinez
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ekerljung, Marie
    Jern, Patric
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Benachenhou, Farid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Sperber, Göran O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Bongcam-Rudloff, Erik
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Blomberg, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Andersson, Göran
    The First Sequenced Carnivore Genome Shows Complex Host-Endogenous Retrovirus Relationships2011In: PLOS ONE, ISSN 1932-6203, Vol. 6, no 5, p. e19832-Article in journal (Refereed)
    Abstract [en]

    Host-retrovirus interactions influence the genomic landscape and have contributed substantially to mammalian genome evolution. To gain further insights, we analyzed a female boxer (Canis familiaris) genome for complexity and integration pattern of canine endogenous retroviruses (CfERV). Intriguingly, the first such in-depth analysis of a carnivore species identified 407 CfERV proviruses that represent only 0.15% of the dog genome. In comparison, the same detection criteria identified about six times more HERV proviruses in the human genome that has been estimated to contain a total of 8% retroviral DNA including solitary LTRs. These observed differences in man and dog are likely due to different mechanisms to purge, restrict and protect their genomes against retroviruses. A novel group of gammaretrovirus-like CfERV with high similarity to HERV-Fc1 was found to have potential for active retrotransposition and possibly lateral transmissions between dog and human as a result of close interactions during at least 10.000 years. The CfERV integration landscape showed a non-uniform intra-and inter-chromosomal distribution. Like in other species, different densities of ERVs were observed. Some chromosomal regions were essentially devoid of CfERVs whereas other regions had large numbers of integrations in agreement with distinct selective pressures at different loci. Most CfERVs were integrated in antisense orientation within 100 kb from annotated protein-coding genes. This integration pattern provides evidence for selection against CfERVs in sense orientation relative to chromosomal genes. In conclusion, this ERV analysis of the first carnivorous species supports the notion that different mammals interact distinctively with endogenous retroviruses and suggests that retroviral lateral transmissions between dog and human may have occurred.

  • 216. Barsh, Gregory S.
    et al.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Evolutionary genomics: Detecting selection2013In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 495, no 7441, p. 325-326Article in journal (Other academic)
  • 217. Bart, Genevieve
    et al.
    Vico, Nuria Ortega
    Hassinen, Antti
    Pujol, Francois M.
    Deen, Ashik Jawahar
    Ruusala, Aino
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Tammi, Raija H.
    Squire, Anthony
    Heldin, Paraskevi
    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.
    Kellokumpu, Sakari
    Tammi, Markku I.
    Fluorescence Resonance Energy Transfer (FRET) and Proximity Ligation Assays Reveal Functionally Relevant Homo-and Heteromeric Complexes among Hyaluronan Synthases HAS1, HAS2, and HAS32015In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 290, no 18, p. 11479-11490Article in journal (Refereed)
    Abstract [en]

    In vertebrates, hyaluronan is produced in the plasma membrane from cytosolic UDP-sugar substrates by hyaluronan synthase 1-3 (HAS1-3) isoenzymes that transfer N-acetylglucosamine (GlcNAc) and glucuronic acid (GlcUA) in alternative positions in the growing polysaccharide chain during its simultaneous extrusion into the extracellular space. It has been shown that HAS2 immunoprecipitates contain functional HAS2 homomers and also heteromers with HAS3 (Karousou, E., Kamiryo, M., Skandalis, S. S., Ruusala, A., Asteriou, T., Passi, A., Yamashita, H., Hellman, U., Heldin, C. H., and Heldin, P. (2010) The activity of hyaluronan synthase 2 is regulated by dimerization and ubiquitination. J. Biol. Chem. 285, 23647-23654). Here we have systematically screened in live cells, potential interactions among the HAS isoenzymes using fluorescence resonance energy transfer (FRET) and flow cytometric quantification. We show that all HAS isoenzymes form homomeric and also heteromeric complexes with each other. The same complexes were detected both in Golgi apparatus and plasma membrane by using FRET microscopy and the acceptor photobleaching method. Proximity ligation assays with HAS antibodies confirmed the presence of HAS1-HAS2, HAS2-HAS2, and HAS2-HAS3 complexes between endogenously expressed HASs. C-terminal deletions revealed that the enzymes interact mainly via uncharacterized N-terminal 86-amino acid domain(s), but additional binding site(s) probably exist in their C-terminal parts. Of all the homomeric complexes HAS1 had the lowest and HAS3 the highest synthetic activity. Interestingly, HAS1 transfection reduced the synthesis of hyaluronan obtained by HAS2 and HAS3, suggesting functional cooperation between the isoenzymes. These data indicate a general tendency of HAS isoenzymes to form both homomeric and heteromeric complexes with potentially important functional consequences on hyaluronan synthesis.

  • 218.
    Bartke, Katrin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Recombinant mosaic genomes and the evolution of novel antibiotic-resistant bacteria.2017Independent thesis Advanced level (degree of Master (Two Years)), 30 credits / 45 HE creditsStudent thesis
    Abstract [en]

    The frequency of antibiotic resistance and its spread are increasing rapidly. One of the main mechanisms responsible for this is conjugation, a means of horizontal gene transfer (HGT) evolved by many plasmids. Conjugative plasmids can occasionally integrate into a bacterial chromosome and in this way mediate the transfer of small or large regions of chromosomal DNA from one bacterium to another within and across bacterial species. Integration of the foreign chromosomal DNA into the recipient bacterium creates a recombinant mosaic chromosome. The creation of mosaic chromosomes is associated with bacterial speciation and with the success of some globally successful antibiotic resistant strains. However, very little is known about the genetic constraints of these events, in particular how the creation of a mosaic chromosome effects bacterial fitness, and whether compensatory evolution can restore relative fitness. The aims of this study were: (I) to create a number of such recombinants from an hfr E. coli donor and a restriction-negative S. typhimurium recipient with integration of E. coli DNA at different chromosomal locations in S. typhimurium; (II) to analyse recombinant genome architecture by whole genome sequencing (WGS) and relate this to relative growth fitness; and (III) to conduct an evolution experiment with conjugants that had reduced growth fitness compared to the parental strains, to assess their ability to ameliorate these fitness costs by compensatory evolution. Findings from the WGS and growth rate assays suggested a strong correlation between the genetic architecture of a recombinant and its respective relative fitness. It could be seen that specific chromosomal positions are unfavourable for integration and come with a high fitness cost for the recombinant bacterium, while in other positions integrations did not reduce or even improved fitness in comparison to the parental strains. The evolution experiment revealed, that while compensation of high fitness costs is possible, it is a long process that requires the accumulation of multiple changes and mutations. Moreover, no universal way of solving the relative fitness problems associated with the mosaic chromosomes presented itself.

  • 219.
    Baruch, Zdravko
    et al.
    Univ Adelaide, Environm Inst, North Terrace, Adelaide, SA 5005, Australia;Univ Adelaide, Sch Biol Sci, North Terrace, Adelaide, SA 5005, Australia.
    Jones, Alice R.
    Univ Adelaide, Environm Inst, North Terrace, Adelaide, SA 5005, Australia;Univ Adelaide, Sch Biol Sci, North Terrace, Adelaide, SA 5005, Australia.
    Hill, Kathryn E.
    Univ Adelaide, Environm Inst, North Terrace, Adelaide, SA 5005, Australia;Univ Adelaide, Sch Biol Sci, North Terrace, Adelaide, SA 5005, Australia.
    McInerney, Francesca A.
    Univ Adelaide, Sch Phys Sci, Adelaide, SA 5005, Australia;Univ Adelaide, Sprigg Geobiol Ctr, Adelaide, SA 5005, Australia.
    Blyth, Colette
    Univ Adelaide, Environm Inst, North Terrace, Adelaide, SA 5005, Australia;Univ Adelaide, Sch Biol Sci, North Terrace, Adelaide, SA 5005, Australia.
    Caddy-Retalic, Stefan
    Univ Adelaide, Sch Phys Sci, Adelaide, SA 5005, Australia;Univ Adelaide, Environm Inst, North Terrace, Adelaide, SA 5005, Australia;Univ Adelaide, Sprigg Geobiol Ctr, Adelaide, SA 5005, Australia;Univ Adelaide, Sch Biol Sci, North Terrace, Adelaide, SA 5005, Australia.
    Christmas, Matthew J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Univ Adelaide, Environm Inst, North Terrace, Adelaide, SA 5005, Australia;Univ Adelaide, Sch Biol Sci, North Terrace, Adelaide, SA 5005, Australia.
    Gellie, Nicholas J. C.
    Univ Adelaide, Environm Inst, North Terrace, Adelaide, SA 5005, Australia;Univ Adelaide, Sch Biol Sci, North Terrace, Adelaide, SA 5005, Australia.
    Lowe, Andrew J.
    Univ Adelaide, Environm Inst, North Terrace, Adelaide, SA 5005, Australia;Univ Adelaide, Sch Biol Sci, North Terrace, Adelaide, SA 5005, Australia.
    Martin-Fores, Irene
    Spanish Natl Res Council, Natl Museum Nat Sci, Madrid 28006, Spain;Univ Adelaide, Environm Inst, North Terrace, Adelaide, SA 5005, Australia;Univ Adelaide, Sch Biol Sci, North Terrace, Adelaide, SA 5005, Australia.
    Nielson, Kristine E.
    Univ Adelaide, Sch Phys Sci, Adelaide, SA 5005, Australia;Univ Adelaide, Sprigg Geobiol Ctr, Adelaide, SA 5005, Australia.
    Breed, Martin F.
    Univ Adelaide, Environm Inst, North Terrace, Adelaide, SA 5005, Australia;Univ Adelaide, Sch Biol Sci, North Terrace, Adelaide, SA 5005, Australia.
    Functional acclimation across microgeographic scales in Dodonaea viscosa2018In: AoB Plants, ISSN 2041-2851, E-ISSN 2041-2851, Vol. 10, no 3, article id ply029Article in journal (Refereed)
    Abstract [en]

    Intraspecific plant functional trait variation provides mechanistic insight into persistence and can infer population adaptive capacity. However, most studies explore intraspecific trait variation in systems where geographic and environmental distances co-vary. Such a design reduces the certainty of trait-environment associations, and it is imperative for studies that make trait-environment associations be conducted in systems where environmental distance varies independently of geographic distance. Here we explored trait variation in such a system, and aimed to: (i) quantify trait variation of parent and offspring generations, and associate this variation to parental environments; (ii) determine the traits which best explain population differences; (iii) compare parent and offspring trait-trait relationships. We characterized 15 plant functional traits in eight populations of a shrub with a maximum separation ca. 100 km. Populations differed markedly in aridity and elevation, and environmental distance varied independently of geographic distance. We measured traits in parent populations collected in the field, as well as their offspring reared in greenhouse conditions. Parent traits regularly associated with their environment. These associations were largely lost in the offspring generation, indicating considerable phenotypic plasticity. An ordination of parent traits showed clear structure with strong influence of leaf area, specific leaf area, stomatal traits, isotope delta C-13 and delta N-15 ratios, and N-area, whereas the offspring ordination was less structured. Parent trait-trait correlations were in line with expectations from the leaf economic spectrum. We show considerable trait plasticity in the woody shrub over microgeographic scales (<100 km), indicating it has the adaptive potential within a generation to functionally acclimate to a range of abiotic conditions. Since our study shrub is commonly used for restoration in southern Australia and local populations do not show strong genetic differentiation in functional traits, the potential risks of transferring seed across the broad environmental conditions are not likely to be a significant issue.

  • 220.
    Batool, Tahira
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heparan sulfate dependent cell signaling and associated pathophysiology: Implications in tumorigenesis and embryogenesis2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Heparan sulfate proteoglycans (HSPGs) consist of a protein core to which several linear, negatively charged heparan sulfate (HS) chains are covalently attached. HSPGs are expressed on the cell surface and in the extra-cellular matrix (ECM) where they have diverse biological functions, for example co-receptor functions. The diverse functions of HS are linked to structural variability of the polysaccharide. In this thesis, I investigated HS structure-function relationship by using different cell and animal models of one HS-biosynthetic enzyme, glucuronyl C5-epimerase (Hsepi) and one enzyme responsible for post synthetic modification, heparanase.

    Deletion of Hsepi in mice resulted in neonatal lethality, with multiple organ defects, indicating the importance of HS in embryogenesis. Up-regulated expression of heparanase is found in most human tumor tissues, correlating with increased metastatic potential and decreased survival of cancer patients.

    In the first project, I focused on the effects of HS on cancer associated cell signaling and found that heparanase overexpression attenuated TGF-β1 stimulated Smad phosphorylation in tumor cells because of increased sulfation degree and turnover rate of HS.

    Heparanase role in cancer progression has led to clinical trials where inhibition of heparanase activity is currently being evaluated as a potential cancer treatment. Heparin, a HS-related polysaccharide, is being used to inhibit heparanase activity. In my second project, we studied the effect of low molecular weight heparin (LMWH) on cisplatin resistance of ovarian cancer cells (A2780cis). LMWH treatment of A2780cis cells reduced Wnt-activity in these cells and consequently reduce the drug resistance.

    In paper III, we continued exploring the HS/heparanase role in cancer by using heparanase overexpressing mice (Hpa-tg). We found Lewis Lung Carcinoma (LLC2) cells showed faster growth, bigger tumors and more metastasis in the Hpa-tg mice as compared to wild-type (WT) mice, because of suppressed antitumor immunity in the Hpa-tg mice.

    In paper IV and V, we studied the structure-function relationship of HS by using Hsepi-/- mice model. Hsepi-/- results in HS-chains lacking IdoA, which makes the chain rigid and consequently affects its co-receptor function. Skeletal malformation in Hsepi-/- mice, led us in paper IV to investigate bone morphogenic protein (BMP), an important signal molecule during embryogenesis and known to interact with HS. We found upregulation of a number of BMPs and expression of P-smad1/5/8, but reduced expression of inhibitory Smads and Gremlin1 in the Hsepi-/- MEF cells. The study indicated that the developmental defects in Hsepi mice could be contributed by a higher BMP signaling. In paper V we investigated the lung of the Hsepi-/- mice. The distal lung of 17.5 days old embryos remained populated by epithelial tubules, because of impaired differentiation of type I cells of the lungs. Potential mechanisms behind the failure of type I cell formation was identified to be reduced vascularization and a sustained signaling of Smad pathways.

    List of papers
    1. Overexpression of heparanase attenuated TGF-beta-stimulated signaling in tumor cells
    Open this publication in new window or tab >>Overexpression of heparanase attenuated TGF-beta-stimulated signaling in tumor cells
    Show others...
    2017 (English)In: FEBS Open Bio, E-ISSN 2211-5463, Vol. 7, no 3, p. 405-413Article in journal (Refereed) Published
    Abstract [en]

    Heparan sulfate (HS) mediates the activity of various growth factors including TGF-beta. Heparanase is an endo-glucuronidase that specifically cleaves and modifies HS structure. In this study, we examined the effect of heparanase expression on TGF-beta 1-dependent signaling activities. We found that overexpression of heparanase in human tumor cells (i.e., Fadu pharyngeal carcinoma, MCF7 breast carcinoma) attenuated TGF-beta 1-stimulated Smad phosphorylation and led to a slower cell proliferation. TGF-beta 1-stimulated Akt and Erk phosphorylation was also affected in the heparanase overexpression cells. This effect involved the enzymatic activity of heparanase, as overexpression of mutant inactive heparanase did not affect TGF-beta 1 signaling activity. Analysis of HS isolated from Fadu cells revealed an increase in sulfation of the HS that had a rapid turnover in cells overexpressing heparanase. It appears that the structural alterations of HS affect the ability of TGF-beta 1 to signal via its receptors and elicit a growth response. Given that heparanase expression promotes tumor growth in most cancers, this finding highlights a crosstalk between heparanase, HS, and TGF-beta 1 function in tumorigenesis.

    Keywords
    cancer cell, heparan sulfate, heparanase signaling, TGF-beta
    National Category
    Biochemistry and Molecular Biology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-322852 (URN)10.1002/2211-5463.12190 (DOI)000400298500011 ()28286736 (PubMedID)
    Funder
    Swedish Research Council, 2015-02595Swedish Research Council, K2013-66X-14936-10-5Swedish Cancer Society, 150815Swedish Cancer Society, 150834
    Available from: 2017-06-07 Created: 2017-06-07 Last updated: 2018-10-15Bibliographically approved
    2. Heparin antagonizes cisplatin resistance of A2780 ovarian cancer cells by affecting the Wnt signaling pathway
    Open this publication in new window or tab >>Heparin antagonizes cisplatin resistance of A2780 ovarian cancer cells by affecting the Wnt signaling pathway
    Show others...
    2017 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 40, p. 67553-67566Article in journal (Refereed) Published
    Abstract [en]

    Low molecular weight heparin (LMWH), the guideline based drug for prophylaxis and treatment of cancer-associated thrombosis, was recently shown to sensitize cisplatin resistant A2780cis human ovarian cancer cells for cisplatin cytotoxicity upon 24 h pretreatment with 50 mu g x mL(-1) of the LMWH tinzaparin in vitro, equivalent to a therapeutic dosage. Thereby, LMWH induced sensitization by transcriptional reprogramming of A2780cis cells via not yet elucidated mechanisms that depend on cellular proteoglycans. Here we aim to illuminate the underlying molecular mechanisms of LMWH in sensitizing A2780cis cells for cisplatin. Using TCF/LEF luciferase promotor assay (Top/Flash) we show that resistant A2780cis cells possess a threefold higher Wnt signaling activity compared to A2780 cells. Furthermore, Wnt pathway blockade by FH535 leads to higher cisplatin sensitivity of A2780cis cells. Glypican-3 (GPC3) is upregulated in A2780cis cells in response to LMWH treatment, probably as counter-regulation to sustain the high Wnt activity against LMWH. Hence, LMWH reduces the cisplatin-induced rise in Wnt activity and TCF-4 expression in A2780cis cells, but keeps sensitive A2780 cells unaffected. Consequently, Wnt signaling pathway appears as primary target of LMWH in sensitizing A2780cis cells for cisplatin toxicity. Considering the outstanding role of LMWH in clinical oncology, this finding appears as promising therapeutic option to hamper chemoresistance.

    Place, publisher, year, edition, pages
    IMPACT JOURNALS LLC, 2017
    Keywords
    tinzaparin, cancer, chemoresistance, Wnt, cisplatin
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-336049 (URN)10.18632/oncotarget.18738 (DOI)000410790500061 ()28978053 (PubMedID)
    Available from: 2017-12-12 Created: 2017-12-12 Last updated: 2018-10-15Bibliographically approved
    3. Heparanase expression soils the microenvironment for tumor growth by enhancing Notch signaling and suppressing antitumor immunity.: Heparanase effects on immune response in tumor microenvironment.
    Open this publication in new window or tab >>Heparanase expression soils the microenvironment for tumor growth by enhancing Notch signaling and suppressing antitumor immunity.: Heparanase effects on immune response in tumor microenvironment.
    Show others...
    (English)In: Article in journal (Other academic) Submitted
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-363257 (URN)
    Available from: 2018-10-15 Created: 2018-10-15 Last updated: 2018-10-15
    4. Upregulated BMP-Smad signaling activity in the glucuronyl C5-epimerase knock out MEF cells
    Open this publication in new window or tab >>Upregulated BMP-Smad signaling activity in the glucuronyl C5-epimerase knock out MEF cells
    Show others...
    2019 (English)In: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 54, p. 122-129Article in journal (Refereed) Published
    Abstract [en]

    Glucuronyl C5-epimerase (Hsepi) catalyzes the conversion of glucuronic acid to iduronic acid in the process of heparan sulfate biosynthesis. Targeted interruption of the gene, Glce,in mice resulted in neonatal lethality with varied defects in organ development. To understand the molecular mechanisms of the phenotypes, we used mouse embryonic fibroblasts (MEF) as a model to examine selected signaling pathways. Our earlier studies found reduced activities of FGF-2, GDNF, but increased activity of sonic hedgehog in the mutant cells. In this study, we focused on the bone morphogenetic protein (BMP) signaling pathway. Western blotting detected substantially elevated endogenous Smad1/5/8 phosphorylation in the Hsepi mutant (KO) MEF cells, which is reverted by re-expression of the enzyme in the KO cells. The mutant cells displayed an enhanced proliferation and elevated alkaline phosphatase activity, marking higher differentiation, when cultured in osteogenic medium. The high level of Smad1/5/8 phosphorylation was also found in primary calvarial cells isolated from the KO mice. Analysis of the genes involved in the BMP signaling pathway revealed upregulation of a number of BMP ligands, but reduced expression of several Smads and BMP antagonist (Grem1) in the KO MEF cells. The results suggest that Hsepi expression modulates BMP signaling activity, which, at least partially, is associated with defected molecular structure of heparan sulfate expressed in the cells.   

    Place, publisher, year, edition, pages
    Elsevier, 2019
    Keywords
    BMP signaling, Heparan sulfate, MEF cells, Smad, Glucuronyl C5-epimerase, Bone Morphogenetic Protein
    National Category
    Cell and Molecular Biology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
    Identifiers
    urn:nbn:se:uu:diva-363254 (URN)10.1016/j.cellsig.2018.11.010 (DOI)000456752900013 ()30458230 (PubMedID)
    Funder
    Swedish Cancer Society, CAN2015/496Swedish Research Council, 2015-02595Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
    Available from: 2018-10-15 Created: 2018-10-15 Last updated: 2019-02-12Bibliographically approved
    5. Glucuronyl C5-epimerase is crucial for epithelial cell maturation during embryonic lung development: Glucuronyl C5-epimerase in lung development
    Open this publication in new window or tab >>Glucuronyl C5-epimerase is crucial for epithelial cell maturation during embryonic lung development: Glucuronyl C5-epimerase in lung development
    (English)In: Article in journal (Other academic) Submitted
    National Category
    Cell and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-363255 (URN)
    Available from: 2018-10-15 Created: 2018-10-15 Last updated: 2018-10-15
  • 221.
    Batool, Tahira
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Fang, Jianping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Barash, Uri
    Rappaport Technion, Fac Med, Canc & Vasc Biol Res Ctr, Haifa, Israel..
    Moustakas, Aristidis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Vlodavsky, Israel
    Rappaport Technion, Fac Med, Canc & Vasc Biol Res Ctr, Haifa, Israel..
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Overexpression of heparanase attenuated TGF-beta-stimulated signaling in tumor cells2017In: International journal of experimental pathology (Print), ISSN 0959-9673, E-ISSN 1365-2613, Vol. 98, no 3, p. A10-A11Article in journal (Other academic)
  • 222.
    Batool, Tahira
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Fang, Jianping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. GlycoNovo Technol Co Ltd, Shanghai, Peoples R China..
    Barash, Uri
    Technion, Fac Med, Canc & Vasc Biol Res Ctr Rappaport, Haifa, Israel..
    Moustakas, Aristidis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Vlodavsky, Israel
    Technion, Fac Med, Canc & Vasc Biol Res Ctr Rappaport, Haifa, Israel..
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Overexpression of heparanase attenuated TGF-beta-stimulated signaling in tumor cells2017In: FEBS Open Bio, E-ISSN 2211-5463, Vol. 7, no 3, p. 405-413Article in journal (Refereed)
    Abstract [en]

    Heparan sulfate (HS) mediates the activity of various growth factors including TGF-beta. Heparanase is an endo-glucuronidase that specifically cleaves and modifies HS structure. In this study, we examined the effect of heparanase expression on TGF-beta 1-dependent signaling activities. We found that overexpression of heparanase in human tumor cells (i.e., Fadu pharyngeal carcinoma, MCF7 breast carcinoma) attenuated TGF-beta 1-stimulated Smad phosphorylation and led to a slower cell proliferation. TGF-beta 1-stimulated Akt and Erk phosphorylation was also affected in the heparanase overexpression cells. This effect involved the enzymatic activity of heparanase, as overexpression of mutant inactive heparanase did not affect TGF-beta 1 signaling activity. Analysis of HS isolated from Fadu cells revealed an increase in sulfation of the HS that had a rapid turnover in cells overexpressing heparanase. It appears that the structural alterations of HS affect the ability of TGF-beta 1 to signal via its receptors and elicit a growth response. Given that heparanase expression promotes tumor growth in most cancers, this finding highlights a crosstalk between heparanase, HS, and TGF-beta 1 function in tumorigenesis.

  • 223.
    Batool, Tahira
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Fang, Jianping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Glyconovo Technologies Co., Ltd., TianXiong Road, Shanghai International Medical Zone (SIMZ), Pudong New Area, Shanghai 201318, China.
    Jansson, Viktor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Zhao, Hongxing
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Gallant, Caroline J.
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Moustakas, Aristidis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Upregulated BMP-Smad signaling activity in the glucuronyl C5-epimerase knock out MEF cells2019In: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 54, p. 122-129Article in journal (Refereed)
    Abstract [en]

    Glucuronyl C5-epimerase (Hsepi) catalyzes the conversion of glucuronic acid to iduronic acid in the process of heparan sulfate biosynthesis. Targeted interruption of the gene, Glce,in mice resulted in neonatal lethality with varied defects in organ development. To understand the molecular mechanisms of the phenotypes, we used mouse embryonic fibroblasts (MEF) as a model to examine selected signaling pathways. Our earlier studies found reduced activities of FGF-2, GDNF, but increased activity of sonic hedgehog in the mutant cells. In this study, we focused on the bone morphogenetic protein (BMP) signaling pathway. Western blotting detected substantially elevated endogenous Smad1/5/8 phosphorylation in the Hsepi mutant (KO) MEF cells, which is reverted by re-expression of the enzyme in the KO cells. The mutant cells displayed an enhanced proliferation and elevated alkaline phosphatase activity, marking higher differentiation, when cultured in osteogenic medium. The high level of Smad1/5/8 phosphorylation was also found in primary calvarial cells isolated from the KO mice. Analysis of the genes involved in the BMP signaling pathway revealed upregulation of a number of BMP ligands, but reduced expression of several Smads and BMP antagonist (Grem1) in the KO MEF cells. The results suggest that Hsepi expression modulates BMP signaling activity, which, at least partially, is associated with defected molecular structure of heparan sulfate expressed in the cells.   

  • 224.
    Baumann, Martina
    et al.
    Univ Nat Resources & Appl Life Sci, Dept Biotechnol, Vienna, Austria.
    Höppner, Marc P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Meier, Michael
    Univ Nat Resources & Appl Life Sci, Dept Biotechnol, Vienna, Austria.
    Pontiller, Jens
    Univ Nat Resources & Appl Life Sci, Dept Biotechnol, Vienna, Austria.
    Ernst, Wolfgang
    Univ Nat Resources & Appl Life Sci, Dept Biotechnol, Vienna, Austria.
    Grabherr, Reingard
    Univ Nat Resources & Appl Life Sci, Dept Biotechnol, Vienna, Austria.
    Mauceli, Evan
    Broad Inst, Cambridge, MA USA.
    Grabherr, Manfred G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Broad Inst, Cambridge, MA USA.
    Artificially designed promoters: understanding the role of spatial features and canonical binding sites in transcription2012In: Bioengineered Bugs, ISSN 1949-1018, E-ISSN 1949-1026, Vol. 3, no 2, p. 120-123Article in journal (Refereed)
    Abstract [en]

    The promoter is a key element in gene transcription and regulation. We previously reported that artificial sequences rich in the dinucleotide CpG are sufficient to drive expression in vitro in mammalian cell lines, without requiring canonical binding sites for transcription factor proteins. Here, we report that introducing a promoter organization that alternates in CpGs and regions rich in A and T further increases expression strength, as well as how insertion of specific binding sites makes such sequences respond to induced levels of the transcription factor NFκB. Our findings further contribute to the mechanistic understanding of promoters, as well as how these sequences might be shaped by evolutionary pressure in living organisms.

  • 225. Beahm, Brendan J
    et al.
    Dehnert, Karen W
    Derr, Nicolas L
    Kuhn, Joachim
    Eberhart, Johann K
    Spillmann, Dorothe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Amacher, Sharon L
    Bertozzi, Carolyn R
    A visualizable chain-terminating inhibitor of glycosaminoglycan biosynthesis in developing zebrafish2014In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 53, no 13, p. 3347-3352Article in journal (Refereed)
    Abstract [en]

    Heparan sulfate (HS) and chondroitin sulfate (CS) glycosaminoglycans (GAG) are proteoglycan-associated polysaccharides with essential functions in animals. They have been studied extensively by genetic manipulation of biosynthetic enzymes, but chemical tools for probing GAG function are limited. HS and CS possess a conserved xylose residue that links the polysaccharide chain to a protein backbone. Here we report that, in zebrafish embryos, the peptide-proximal xylose residue can be metabolically replaced with a chain-terminating 4-azido-4-deoxyxylose (4-XylAz) residue by administration of UDP-4-azido-4-deoxyxylose (UDP-4-XylAz). UDP-4-XylAz disrupted both HS and CS biosynthesis and caused developmental abnormalities reminiscent of GAG biosynthesis and laminin mutants. The azide substituent of protein-bound 4-XylAz allowed for rapid visualization of the organismal sites of chain termination in vivo through bioorthogonal reaction with fluorescent cyclooctyne probes. UDP-4-XylAz therefore complements genetic tools for studies of GAG function in zebrafish embryogenesis.

  • 226.
    Beckman Sundh, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Studies on Phosphohistidine Phosphatase 1: What? Where? Why?2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Phosphohistidine phosphatase 1 (PHPT1) is a small protein, consisting of 125 amino acids, that catalyzes the dephosphorylation of histidine but does not have any activity towards other phosphorylated amino acids. PHPT1 was identified in 2002, and is so far the only mammalian histidine phosphatase known, but still little is known about its physiological role. No mammalian histidine kinases have hitherto been identified.

    Phosphorylation is one of the most important ways in which the structure and activity of a protein may be changed after translation. Proteins are phosphorylated on the side chain of amino acid residues. When a hydroxyl is phosphorylated the result is a phosphoester and when a nitrogen is phosphorylated the result is a phosphoamidate. Histidine may be phosphorylated on either of the two nitrogens of the imidazole ring of the side chain. The resulting phosphoamidate bond is labile and rich in energy, which makes histidine phosphorylation highly reversible and flexible. However, histidine phosphorylation is less studied than that of the phosphoesters due to the acid lability of the phosphoamidate bond.

    The work described in this thesis was focused on further elucidating the physiological role of PHPT1. Amino acid residues of importance for the activity of PHPT1 were identified, and mutants with decreased phosphatase activity were produced. These mutants have been used in studies on the function of PHPT1. By using immunohistochemical methodology the localization of PHPT1 in both mouse and human tissues was determined, with mainly similar results. A general finding was that expression of PHPT1 was high in epithelial cells with short turnover time, indicating that PHPT1 may have an important role in proliferating cells. We have also developed a comparatively fast and simple screening method for determination of PHPT1 activity. Since research in this field has been hampered by the lack of efficient and practical methodology, hopefully this new method will be an asset in search of inhibitors for PHPT1, which in turn may be used for detection of the elusive mammalian histidine kinases, the finding of which may give major breakthroughs in the field.

    List of papers
    1. Mutational study of human phosphohistidine phosphatase: effect on enzymatic activity.
    Open this publication in new window or tab >>Mutational study of human phosphohistidine phosphatase: effect on enzymatic activity.
    Show others...
    2005 (English)In: Biochem Biophys Res Commun, ISSN 0006-291X, Vol. 337, no 3, p. 887-91Article in journal (Refereed) Published
    Keywords
    Amino Acid Sequence, Amino Acid Substitution, Binding Sites, Enzyme Activation, Evolution; Molecular, Humans, Molecular Sequence Data, Mutagenesis; Site-Directed, Mutation, Phosphoprotein Phosphatase/analysis/*chemistry/genetics/*metabolism, Protein Binding, Recombinant Proteins/analysis/chemistry/metabolism, Research Support; Non-U.S. Gov't, Sequence Homology; Amino Acid, Structure-Activity Relationship, Substrate Specificity
    Identifiers
    urn:nbn:se:uu:diva-80308 (URN)16219293 (PubMedID)
    Available from: 2006-05-05 Created: 2006-05-05 Last updated: 2012-05-30
    2. Immunohistochemical localization of phosphohistidine phosphatase PHPT1 in mouse and human tissues
    Open this publication in new window or tab >>Immunohistochemical localization of phosphohistidine phosphatase PHPT1 in mouse and human tissues
    Show others...
    2009 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 114, no 2, p. 65-72Article in journal (Refereed) Published
    Abstract [en]

    Protein histidine phosphorylation accounts for about 6% of the total protein phosphorylation in eukaryotic cells; still details concerning histidine phosphorylation and dephosphorylation are limited. A mammalian 14-kDa phosphohistidine phosphatase, also denominated PHPT1, was found 6 years ago that provided a new tool in the study of phosphohistidine phosphorylation. The localization of PHPT1 mRNA by Northern blot analysis revealed high expression in heart and skeletal muscle. The main object of the present study was to determine the PHPT1 expression on protein level in mouse tissues in order to get further information on the physiological role of the enzyme. Tissue samples from adult mice and 14.5-day-old mouse embryos were processed for immunostaining using a PHPT1-specific polyclonal antibody. The same antibody was also provided to the Swedish human protein atlas project (HPR) (http://www.proteinatlas.org/index.php). The results from both studies were essentially consistent with the previously reported expression of mRNA of a few human tissues. In addition, several other tissues, including testis, displayed a high protein expression. A salient result of the present investigation was the ubiquitous expression of the PHPT1 protein and its high expression in continuously dividing epithelial cells.

    Keywords
    Phosphohistidine phosphatase, PHPT1, PHP, phosphohistidine, dephosphorylation, HPR-project
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-119851 (URN)10.1080/03009730802642337 (DOI)000265454800001 ()19396692 (PubMedID)
    Available from: 2010-03-02 Created: 2010-03-02 Last updated: 2017-12-12Bibliographically 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.
  • 227.
    Beckman-Sundh, Ulla
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ek, Bo
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Analytical Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Zetterqvist, Örjan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ek, Pia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    A screening method for phosphohistidine phosphatase 1 activity2011In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 116, no 3, p. 161-168Article in journal (Refereed)
    Abstract [en]

    Introduction. Research in the field of protein-bound phosphohistidine phosphorylation has been hampered by the difficulties in analysis and detection of phosphohistidine. Therefore a screening method was developed primarily for the analysis of phosphohistidine phosphatase 1 (PHPT1) activity. Methods. A highly positively charged substrate, Ac-Val-Arg-Leu-Lys-His-Arg-Lys-Leu-Arg-pNA, containing the peptide surrounding the phosphorylated histidine in ion channel KCa3.1 was chemically phosphorylated using phosphoramidate. Excess phosphoramidate was removed by anion exchange chromatography using a micro spin column. After incubation of the eluate with PHPT1, the removed phosphate was bound on a consecutive anion exchange spin column. The eluate was assayed in a micro plate format for remaining phosphate in the substrate Ac-Val-Arg-Leu-Lys-His(P)-Arg-Lys-Leu-Arg-pNA. Histone H4, also highly positive in charge, was subjected to the same procedure to explore the possibility to use other substrates to PHPT1 in this assay format. Results. It was found that Ac-Val-Arg-Leu-Lys-His(P)-Arg-Lys-Leu-Arg-pNA and phosphohistone H4 were dephosphorylated by PHPT1. The apparent K(m) for Ac-Val-Arg-Leu-Lys-His(P)-Arg-Lys-Leu-Arg-pNA was in the order of 10 mu M. Using this method, phosphohistidine phosphatase activity was detected in mouse liver cell sap with Ac-Val-Arg-Leu-Lys-His(P)-Arg-Lys-Leu-Arg-pNA as substrate. Discussion. The described method for determination of PHPT1 activity is comparably much easier and faster than presently used methods for detection of phosphohistidine phosphatase activity. It is also sensitive, since the lower activity limit was 5 pmol phosphate released per min. It has the potential to be used both for more rapid screening for inhibitors and activators to phosphohistidine phosphatases and for screening of histidine kinases.

  • 228.
    Bellomo, Claudia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    TGFβ and LXR signaling in hepatocellular carcinoma2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Hepatocellular carcinoma (HCC) is one of the most prevalent cancer types in the Western world and in the Asia-pacific regions, with its incidence expected to rise up to 22 million cases till 2020. Hepatocellular carcinoma etiology is mainly due to hepatitis B (HBV) and hepatitis C (HCV) infections, and to a lesser extent it is determined by the development of alcohol-driven cirrhosis and non-alcoholic steatohepatitis (NASH). Furthermore, HCC is characterized by a high mortality rate, with poor prognostic expectance and limited therapeutic options currently available in the clinics.

    Transforming growth factor beta (TGFβ) is a pleiotropic cytokine with a janus-role in HCC and in other malignancies. TGFβ can in fact elicit either tumor-suppressive and tumor- promoting effects depending on tumor stage, microenvironmental and immunological cues. In HCC specifically, TGFβ determines cytostasis and cellular senescence during the first stages of tumor development, while it enhances HCC malignancy and progression in the later stages due to increased invasiveness, acquired resistance to cytostatic actions and tumor immunotolerance.

    Liver X receptors (LXRα/NR1H3 and LXRβ/NR1H2) are transcription factors of the nuclear hormone receptor family, which play an important role in oxysterol metabolism and reverse- cholesterol transport to the liver. Their involvement in malignancies has been studied so far to a limited extend, with evidence of both tumor-suppressive -via cytostatic mechanisms- and tumor- immunotolerance activities. Moreover, the potential crosstalk of LXR and TGFβ pathways has not been yet unraveled in the context of hepatocellular carcinoma.

    We have described (Paper I) a high-content imaging platform for the screening of small molecules able to revert the TGFβ-induced epithelial to mesenchymal transition (EMT) in human keratinocytes. This screening allowed us to identify LXR agonists as epithelial plasticity modulators in established terminally differentiated and mouse embryonic fibroblast, as well as in epithelial and mesenchymal HCC cell lines.

    We have identified (Paper II) the transcription factor SNAI1 (Snail) as the mediator of the crosstalk between TGFβ and LXRα pathways in epithelial and mesenchymal HCC cell models. LXRα activation diminishes the transcriptional induction of SNAI1 by TGFβ, thus antagonizing the induction of mesenchymal features and the production of reactive oxygen species by TGFβ. However, we have unraveled that LXRα and TGFβ signaling still positively interact in increasing cytostasis in HCC, in order to preserve liver epithelial features.

    We have described (Paper III) that LXRα activation counteracts the transcriptional induction of α smooth muscle actin (αSMA), a major hallmark of fibroblast activation, elicited by TGFβ in patient-derived primary liver fibroblasts.

    In conclusion, we herein report that the signaling crosstalk between TGFβ and LXRα pathways results in antagonistic effects either on parenchymal and fibroblast cell lines representative of the HCC disease, suggesting the potential future application of LXR agonists as clinical therapeutic options.

    List of papers
    1. Chemical regulators of epithelial plasticity reveal a nuclear receptor pathway controlling myofibroblast differentiation
    Open this publication in new window or tab >>Chemical regulators of epithelial plasticity reveal a nuclear receptor pathway controlling myofibroblast differentiation
    Show others...
    2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 29868Article in journal (Refereed) Published
    Abstract [en]

    Plasticity in epithelial tissues relates to processes of embryonic development, tissue fibrosis and cancer progression. Pharmacological modulation of epithelial transitions during disease progression may thus be clinically useful. Using human keratinocytes and a robotic high-content imaging platform, we screened for chemical compounds that reverse transforming growth factor beta (TGF-beta)-induced epithelial-mesenchymal transition. In addition to TGF-beta receptor kinase inhibitors, we identified small molecule epithelial plasticity modulators including a naturally occurring hydroxysterol agonist of the liver X receptors (LXRs), members of the nuclear receptor transcription factor family. Endogenous and synthetic LXR agonists tested in diverse cell models blocked alpha-smooth muscle actin expression, myofibroblast differentiation and function. Agonist-dependent LXR activity or LXR overexpression in the absence of ligand counteracted TGF-beta-mediated myofibroblast terminal differentiation and collagen contraction. The protective effect of LXR agonists against TGF-beta-induced pro-fibrotic activity raises the possibility that anti-lipidogenic therapy may be relevant in fibrotic disorders and advanced cancer.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-301020 (URN)10.1038/srep29868 (DOI)000379878300001 ()27430378 (PubMedID)
    Funder
    Swedish Cancer Society, CAN 2006/1078, CAN 2009/900, CAN 2012/438Swedish Research Council, K2007-66X-14936-04-3, K2010-67X-14936-07-3, K2013-66X-14936-10-5EU, FP7, Seventh Framework Programme
    Available from: 2016-08-17 Created: 2016-08-17 Last updated: 2017-12-05Bibliographically approved
    2. Snail mediates crosstalk between TGFβ and LXRα in hepatocellular carcinoma
    Open this publication in new window or tab >>Snail mediates crosstalk between TGFβ and LXRα in hepatocellular carcinoma
    Show others...
    (English)In: Cell Death and Differentiation, ISSN 1350-9047, E-ISSN 1476-5403Article in journal (Refereed) Accepted
    National Category
    Cell Biology Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-334443 (URN)
    Available from: 2017-11-23 Created: 2017-11-23 Last updated: 2017-12-05
    3. LXRα limits the pro-fibrotic action of TGFβ in liver cancer-associated fibroblasts
    Open this publication in new window or tab >>LXRα limits the pro-fibrotic action of TGFβ in liver cancer-associated fibroblasts
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Cell Biology Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-334448 (URN)
    Available from: 2017-11-23 Created: 2017-11-23 Last updated: 2017-12-05
  • 229.
    Bellomo, Claudia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. 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.
    Caja, Laia
    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.
    Fabregat, Isabel
    Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet, and Department of Physiological Sciences, School of Medicine, University of Barcelona, ES-08908, Barcelona, Spain.
    Mikulits, Wolfgang
    Department of Medicine I, Division: Institute of Cancer Research, Comprehensive Cancer Center Vienna, Medical University of Vienna, A-1090, Vienna, Austria.
    Kardassis, Dimitris
    Division of Basic Medical Sciences, University of Crete Medical School and Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology of Hellas, GR-71003, Heraklion, Greece.
    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.
    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.
    Snail mediates crosstalk between TGFβ and LXRα in hepatocellular carcinoma2018In: Cell Death and Differentiation, ISSN 1350-9047, E-ISSN 1476-5403, Vol. 25, no 5, p. 885-903Article in journal (Refereed)
    Abstract [en]

    Understanding the complexity of changes in differentiation and cell survival in hepatocellular carcinoma (HCC) is essential for the design of new diagnostic tools and therapeutic modalities. In this context, we have analyzed the crosstalk between transforming growth factor β (TGFβ) and liver X receptor α (LXRα) pathways. TGFβ is known to promote cytostatic and pro-apoptotic responses in HCC, and to facilitate mesenchymal differentiation. We here demonstrate that stimulation of the nuclear LXRα receptor system by physiological and clinically useful agonists controls the HCC response to TGFβ. Specifically, LXRα activation antagonizes the mesenchymal, reactive oxygen species and pro-apoptotic responses to TGFβ and the mesenchymal transcription factor Snail mediates this crosstalk. In contrast, LXRα activation and TGFβ cooperate in enforcing cytostasis in HCC, which preserves their epithelial features. LXRα influences Snail expression transcriptionally, acting on the Snail promoter. These findings propose that clinically used LXR agonists may find further application to the treatment of aggressive, mesenchymal HCCs, whose progression is chronically dependent on autocrine or paracrine TGFβ.

  • 230.
    Bellomo, Claudia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. 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.
    Caja, Laia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Moustakas, Aristidis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. 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.
    Transforming growth factor beta as regulator of cancer stemness and metastasis2016In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 115, no 7, p. 761-769Article, review/survey (Refereed)