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  • 1.
    Asplund, Annika
    et al.
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Takara Bio Europe AB (former Cellartis AB), Gothenburg, Sweden.
    Pradip, Arvind
    Takara Bio Europe AB (former Cellartis AB), Gothenburg, Sweden / Novo Nordisk A/S, Bagsværd, Denmark.
    van Giezen, Mariska
    Takara Bio Europe AB (former Cellartis AB), Gothenburg, Sweden.
    Aspegren, Anders
    Takara Bio Europe AB (former Cellartis AB), Gothenburg, Sweden.
    Choukair, Helena
    Takara Bio Europe AB (former Cellartis AB), Gothenburg, Sweden.
    Rehnström, Marie
    Takara Bio Europe AB (former Cellartis AB), Gothenburg, Sweden.
    Jacobsson, Susanna
    Takara Bio Europe AB (former Cellartis AB), Gothenburg, Sweden.
    Ghosheh, Nidal
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    El Hajjam, Dorra
    Takara Bio Europe AB (former Cellartis AB), Gothenburg, Sweden.
    Holmgren, Sandra
    Takara Bio Europe AB (former Cellartis AB), Gothenburg, Sweden / Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Larsson, Susanna
    Takara Bio Europe AB (former Cellartis AB), Gothenburg, Sweden.
    Benecke, Jörg
    Takara Bio Europe AB (former Cellartis AB), Gothenburg, Sweden.
    Butron, Mariela
    Takara Bio Europe AB (former Cellartis AB), Gothenburg, Sweden.
    Wigander, Annelie
    Takara Bio Europe AB (former Cellartis AB), Gothenburg, Sweden.
    Noaksson, Karin
    Takara Bio Europe AB (former Cellartis AB), Gothenburg, Sweden.
    Sartipy, Peter
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. AstraZeneca R&D, GMD CVMD GMed, Mölndal, Sweden.
    Björquist, Petter
    Takara Bio Europe AB (former Cellartis AB), Gothenburg, Sweden / NovaHep AB, Gothenburg, Sweden.
    Edsbagge, Josefina
    Takara Bio Europe AB (former Cellartis AB), Gothenburg, Sweden.
    Küppers-Munther, Barbara
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Takara Bio Europe AB (former Cellartis AB), Arvid Wallgrens Backe 20, 413 46, Gothenburg, Sweden.
    One Standardized Differentiation Procedure Robustly Generates Homogenous Hepatocyte Cultures Displaying Metabolic Diversity from a Large Panel of Human Pluripotent Stem Cells2016In: Stem Cell Reviews, ISSN 1550-8943, E-ISSN 1558-6804, Vol. 12, no 1, p. 90-104Article in journal (Refereed)
    Abstract [en]

    Human hepatocytes display substantial functional inter-individual variation regarding drug metabolizing functions. In order to investigate if this diversity is mirrored in hepatocytes derived from different human pluripotent stem cell (hPSC) lines, we evaluated 25 hPSC lines originating from 24 different donors for hepatic differentiation and functionality. Homogenous hepatocyte cultures could be derived from all hPSC lines using onestandardized differentiation procedure. To the best of our knowledge this is the first report of a standardized hepatic differentiation procedure that is generally applicable across a large panel of hPSC lines without any adaptations to individual lines. Importantly, with regard to functional aspects, such as Cytochrome P450 activities, we observed that hepatocytes derived from different hPSC lines displayed inter-individual variation characteristic for primary hepatocytes obtained from different donors, while these activities were highly reproducible between repeated experiments using the same line. Taken together, these data demonstrate the emerging possibility to compile panels of hPSC-derived hepatocytes of particular phenotypes/genotypes relevant for drug metabolism and toxicity studies. Moreover, these findings are of significance for applications within the regenerative medicine field, since our stringent differentiation procedure allows the derivation of homogenous hepatocyte cultures from multiple donors which is a prerequisite for the realization of future personalized stem cell based therapies.

  • 2.
    Brackmann, Christian
    et al.
    Chalmers University of Technology, Molecular Microscopy, Department of Chemical and Biological Engineering, Göteborg, Sweden.
    Esguerra, Maricris
    Sahlgrenska Academy at University of Gothenburg, Institute of Clinical Sciences, Department of Surgery, Göteborg, Sweden.
    Olausson, Daniel
    Sahlgrenska Academy at University of Gothenburg, Institute of Clinical Sciences, Department of Surgery, Göteborg, Sweden.
    Delbro, Dick
    Sahlgrenska Academy at University of Gothenburg, Institute of Clinical Sciences, Department of Surgery, Göteborg, Sweden.
    Krettek, Alexandra
    Sahlgrenska Academy at University of Gothenburg, Institute of Medicine, Department of Internal Medicine, Göteborg, Sweden.
    Gatenholm, Paul
    Chalmers University of Technology, Polymer Science, Department of Chemical and Biological Engineering, Göteborg, Sweden.
    Enejder, Annika
    Chalmers University of Technology, Molecular Microscopy, Department of Chemical and Biological Engineering, Göteborg, Sweden.
    Coherent anti-Stokes Raman scattering microscopy of human smooth muscle cells in bioengineered tissue scaffolds2011In: Journal of Biomedical Optics, ISSN 1083-3668, E-ISSN 1560-2281, Vol. 16, no 2, article id 021115Article in journal (Refereed)
    Abstract [en]

    The integration of living, human smooth muscle cells in biosynthesized cellulose scaffolds was monitored by nonlinear microscopy toward contractile artificial blood vessels. Combined coherent anti-Stokes Raman scattering (CARS) and second harmonic generation (SHG) microscopy was applied for studies of the cell interaction with the biopolymer network. CARS microscopy probing CH(2)-groups at 2845 cm(-1) permitted three-dimensional imaging of the cells with high contrast for lipid-rich intracellular structures. SHG microscopy visualized the fibers of the cellulose scaffold, together with a small signal obtained from the cytoplasmic myosin of the muscle cells. From the overlay images we conclude a close interaction between cells and cellulose fibers. We followed the cell migration into the three-dimensional structure, illustrating that while the cells submerge into the scaffold they extrude filopodia on top of the surface. A comparison between compact and porous scaffolds reveals a migration depth of <10 μm for the former, whereas the porous type shows cells further submerged into the cellulose. Thus, the scaffold architecture determines the degree of cell integration. We conclude that the unique ability of nonlinear microscopy to visualize the three-dimensional composition of living, soft matter makes it an ideal instrument within tissue engineering.

  • 3.
    Chaudhari, Aditi
    et al.
    University of Gothenburg.
    Ejeskär, Katarina
    University of Skövde, School of Health and Education. University of Skövde, Health and Education.
    Wettergren, Yvonne
    University of Gothenburg, Sahlgrenska University Hospital/Östra.
    Kahn, Ronald
    Joslin Diabetes Center and Harvard Medical School, United States.
    Rotter Sopasakis, Victoria
    University of Gothenburg / Joslin Diabetes Center and Harvard Medical School, United states.
    Hepatic deletion of p110α and p85α results in insulin resistance despite sustained IRS1-associated phosphatidylinositol kinase activity2017In: F1000 Research, E-ISSN 2046-1402, Vol. 6, article id 1600Article in journal (Refereed)
    Abstract [en]

    Background: Class IA phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) is an integral mediator of insulin signaling. The p110 catalytic and p85 regulatory subunits of PI3K are the products of separate genes, and while they come together to make the active heterodimer, they have opposing roles in insulin signaling and action. Deletion of hepatic p110α results in an impaired insulin signal and severe insulin resistance, whereas deletion of hepatic p85α results in improved insulin sensitivity due to sustained levels of phosphatidylinositol (3,4,5)-trisphosphate. Here, we created mice with combined hepatic deletion of p110α and p85α (L-DKO) to study the impact on insulin signaling and whole body glucose homeostasis.Methods: Six-week old male flox control and L-DKO mice were studied over a period of 18 weeks, during which weight and glucose levels were monitored, and glucose tolerance tests, insulin tolerance test and pyruvate tolerance test were performed. Fasting insulin, insulin signaling mediators, PI3K activity and insulin receptor substrate (IRS)1-associated phosphatidylinositol kinase activity were examined at 10 weeks. Liver, muscle and white adipose tissue weight was recorded at 10 weeks and 25 weeks.Results: The L-DKO mice showed a blunted insulin signal downstream of PI3K, developed markedly impaired glucose tolerance, hyperinsulinemia and had decreased liver and adipose tissue weights. Surprisingly, however, these mice displayed normal hepatic glucose production, normal insulin tolerance, and intact IRS1-associated phosphatidylinositol kinase activity without compensatory upregulated signaling of other classes of PI3K.Conclusions: The data demonstrate an unexpectedly overall mild metabolic phenotype of the L-DKO mice, suggesting that lipid kinases other than PI3Ks might partially compensate for the loss of p110α/p85α by signaling through other nodes than Akt/Protein Kinase B.

  • 4.
    Chaudhari, Aditi
    et al.
    Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden.
    Krumlinde, Daniel
    Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden.
    Lundqvist, Annika
    Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden.
    Akyürek, Levent M.
    Department of Medical Chemistry and Cell biology, University of Gothenburg, Sweden.
    Bandaru, Sashidhar
    Department of Medical Chemistry and Cell biology, University of Gothenburg, Sweden.
    Skålén, Kristina
    Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden.
    Ståhlman, Marcus
    Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden.
    Borén, Jan
    Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden.
    Wettergren, Yvonne
    Department of Surgery, University of Gothenburg, Sweden.
    Ejeskär, Katarina
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Department of Medical and Clinical Genetics, University of Gothenburg, Sweden.
    Rotter Sopasakis, Victoria
    Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    p110α hot spot mutations E545K and H1047R exert metabolic reprogramming independently of p110α kinase activity2015In: Molecular and Cellular Biology, ISSN 0270-7306, E-ISSN 1098-5549, Vol. 35, no 19, p. 3258-3273Article in journal (Refereed)
    Abstract [en]

    The phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) catalytic subunit p110α is the most frequently mutated kinase in human cancer, and the hot spot mutations E542K, E545K, and H1047R are the most common mutations in p110α. Very little is known about the metabolic consequences of the hot spot mutations of p110α in vivo. In this study, we used adenoviral gene transfer in mice to investigate the effects of the E545K and H1047R mutations on hepatic and whole-body glucose metabolism. We show that hepatic expression of these hot spot mutations results in rapid hepatic steatosis, paradoxically accompanied by increased glucose tolerance, and marked glycogen accumulation. In contrast, wild-type p110α expression does not lead to hepatic accumulation of lipids or glycogen despite similar degrees of upregulated glycolysis and expression of lipogenic genes. The reprogrammed metabolism of the E545K and H1047R p110α mutants was surprisingly not dependent on altered p110α lipid kinase activity.

  • 5.
    Ehtesham, Ehtesham
    University of Skövde, School of Life Sciences.
    Embryonic Gene Alterations in rats Caused by Exposure to Diabetes and/or Obesity2012Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    There is ample evidence that both diabetes as well as obesity leads to various metabolic disturbances that leads to oxidative stress. Oxidative stress has been shown  to  be  associated  with  congenital  malformations  of  which  neural  tube defects  and  cardiac  malformations  are  more  common.  The  cellular  and molecular  mechanisms  through  which  oxidative  stress  induces  these  defects during the developmental stage are not well known. Previous work in this field suggests   that   oxidative   stress   results   in   lipid   peroxidation   and   altered expression  of  genes  that  have  key  roles  in  the  developmental  processes.  The present study aimed to investigate gene alterations in embryos from pregnant diabetic  or  obese  rats.  Embryos  and  adipose  tissue  obtained  from  the  locally bred  diabetic  and  obese  Sprague-Dawley  inbred  rat  strain  were  subjected  to Total  RNA  extraction  and  were  quantified  using  Real  time  PCR  for  relative gene expressions analysis. The present study showed that maternal diabetes as well  as  obesity  diminishes  the  antioxidative  defense  mechanisms  by  down regulating the gene expressions of the key reactive oxygen species scavenging enzymes   copper   zinc   superoxide   dismutase   and   manganese   superoxide dismutase  in  day  10  rat  embryos.  There  was  also  altered  embryonic  gene expression  for  several  developmental  genes  due  to  maternal  diabetes  at gestational day 11 and 13 in rat embryos.

  • 6.
    Ejeskär, Katarina
    et al.
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Department of Medical and Clinical Genetics, Gothenburg University, Gothenburg, Sweden.
    Vickes, Oscar
    University of Skövde, The Systems Biology Research Centre.
    Kuchipudi, Arunakar
    University of Skövde, The Systems Biology Research Centre.
    Wettergren, Yvonne
    Department of General Surgery, Gothenburg University, Gothenburg, Sweden.
    Uv, Anne
    Department of Medical and Clinical Genetics, Gothenburg University, Gothenburg, Sweden.
    Rotter Sopasakis, Victoria
    Department of Molecular and Clinical Medicine, Institute of Medicine, Wallenberg Laboratory, Gothenburg University, Gothenburg, Sweden.
    The unique non-catalytic C-terminus of p37delta-PI3K adds proliferative properties in vitro and in vivo2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 5, article id e0127497Article in journal (Refereed)
    Abstract [en]

    The PI3K/Akt pathway is central for numerous cellular functions and is frequently deregulated in human cancers. The catalytic subunits of PI3K, p110, are thought to have a potential oncogenic function, and the regulatory subunit p85 exerts tumor suppressor properties. The fruit fly, Drosophila melanogaster, is a highly suitable system to investigate PI3K signaling, expressing one catalytic, Dp110, and one regulatory subunit, Dp60, and both show strong homology with the human PI3K proteins p110 and p85. We recently showed that p37δ, an alternatively spliced product of human PI3K p110δ, displayed strong proliferation-promoting properties despite lacking the catalytic domain completely. Here we functionally evaluate the different domains of human p37δ in Drosophila. The N-terminal region of Dp110 alone promotes cell proliferation, and we show that the unique C-terminal region of human p37δ further enhances these proliferative properties, both when expressed in Drosophila, and in human HEK-293 cells. Surprisingly, although the N-terminal region of Dp110 and the C-terminal region of p37δ both display proliferative effects, over-expression of full length Dp110 or the N-terminal part of Dp110 decreases survival in Drosophila, whereas the unique C-terminal region of p37δ prevents this effect. Furthermore, we found that the N-terminal region of the catalytic subunit of PI3K p110, including only the Dp60 (p85)-binding domain and a minor part of the Ras binding domain, rescues phenotypes with severely impaired development caused by Dp60 over-expression in Drosophila, possibly by regulating the levels of Dp60, and also by increasing the levels of phosphorylated Akt. Our results indicate a novel kinase-independent function of the PI3K catalytic subunit.

  • 7.
    Fetah, Alija
    University of Skövde, School of Life Sciences.
    Mutations E688K and G569R within the NALP3 gene, associated with development of hereditary auto inflammatory disorders   2009Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Different mutations within the NALP3 gene are thought to be associated with development of several types of hereditary auto inflammatory disorders such as neonatal onset multisystem inflammatory disorder (NOMID) and muckle-wells syndrome (MWS). In this work two separate mutations E688K and G569R were supposed to be constructed by site-directed mutagenesis in the cloned wild type NALP3 genes and further expressed in bacterial and mammalian host cells for functional studies in protein -protein interaction models.

  • 8.
    Harsha Vardhan Reddy, Burri
    University of Skövde, School of Life Sciences.
    Design, Synthesis and Biological testing of Novel ligands for Ghrelin Receptor2008Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Abstract

    G-protein coupled receptors (GPCRs) are having the high medical importance since almost half of the medicinal drugs are designed as modulators of receptor molecules. Crystal structure or NMR structures of GPCRs are very difficult to determine because all GPCRs are typically bound to the cell membrane and thus their molecular activation mechanism is still unclear. The recent publication of the crystal structure of the 2-adrenoreceptor will provide new insights in the field of GPCR research.

    Ghrelin is a peptide growth hormone which binds to the growth hormone secretagogue receptor (GHS-R) and stimulates the release of growth hormone. Based on the known ghrelin receptor binding core sequences wFwLL (upper letter and lower letter representative for L-form and D-form of the amino acids respectively), we prepared two novel peptide analogs with terminal S-(2-aminoethylsulfenyl) cysteine residues. These peptides were tested for their ability to suppress the binding of ghrelin to transfected COS7 cell-line (Kidney fibroblast line from the green African monkey) cells expressing the ghrelin wild-type receptor or certain mutants thereof. As a result we observed a significant reduction of the total number of binding sites accessible for ghrelin, which increased with the time the cells were incubated with our test compounds. This observations support our hypothesis that the peptides we tested form a covalent bond with free thiols located closely to the ligand binding-site of the receptor protein by disulfide thiol exchange which is an interesting target for development of anti-obesity drugs.

  • 9.
    Karlsson, Sandra
    University of Skövde, School of Life Sciences.
    Expression analysis of genes involved in the development of endometrial adenocarcinoma in a rat model of human cancer2006Licentiate thesis, monograph (Other scientific)
  • 10.
    Karlsson, Sandra
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences.
    Gene Expression Patterns in a Rat Model of Human Endometrial Adenocarcinoma2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Endometrial cancer develops from the endometrium of the uterus and is the most common pelvic malignancy diagnosed in women in the western society. Similar to all cancer diseases, endometrial cancer is a disorder that results from complex patterns of genetic and epigenetic alterations involved in the malignant transformation. The BDII/Han rat model is unique for spontaneous hormonal carcinogenesis since more than 90% of the female virgins spontaneously develop endometrial cancer. The possibility to perform global gene expression profiling of tumor cells would likely provide important information of the genes and pathways that are aberrant in endometrial adenocarcinoma (EAC). The works in the present thesis have been focused on investigating the expression patterns in endometrial tumors.  The findings in this thesis involve the identification of a novel candidate tumor suppressor region of rat chromosome 10. This genomic segment contains 18 potential tumor suppressor genes. Preliminary microarray data analysis confirmed that this region might contain relevant candidate genes as the EACs on average had 3.8 times lower expression of Crk in comparison to the normal/premalignant endometrial tissue cultures. Furthermore, an expression analysis using qPCR, revealed a significant down-regulation of Myo1c and Hic.   We were also able to identify a group of genes associated with the TGF-Beta pathway that were differentially expressed between endometrial tumors and normal/pre-malignant endometrium. These results suggest that the TGF-Beta signaling pathway is disrupted in EAC. This has previously been demonstrated in human EAC, although this is the first report on aberrant expression of TGF-Beta downstream target genes.  Evaluation of Gpx3 down-regulation in the rat EAC cell lines revealed an almost complete loss of expression in a majority of the endometrial tumors. From methylation studies, we could conclude that the loss of expression of Gpx3 is correlated with biallelic hypermethylation in the Gpx3 promoter region. This result was confirmed with a demethylation study of EAC cell lines, where the Gpx3 mRNA expression was restored after treatment with a demethylation agent and a deacetylation inhibitor. We also showed that mRNA expression of the well-known oncogene, Met, was slightly higher in endometrial tumors with loss of Gpx3 expression. A likely consequence of loss of Gpx3 function is a higher amount of reactive oxygen species (ROS) in the cancer cell environment. Since it has been proposed that overproduction of ROS is required for the hypoxic activation of HIF-1, we suggest that loss of Gpx3 expression activates transcription of Met through induction of the transcription factor HIF-1. The loss of the protective properties of GPX3 most likely makes the endometrial cells more vulnerable to ROS damage and genome instability.  We extended the results obtained from the rat endometrial tumors to human material, and conducted expression analysis of GPX3 in 30 endometrial human tumors using qPCR. The results showed a uniformly down-regulation of GPX3 in 29 of the tumors, independent of tumor grade. We thus concluded that the down-regulation of GPX3 probably occurs at an early stage of EAC and therefore contributes to the EAC carcinogenesis. These results suggest that there are important clinical implications of GPX3 expression in EAC, both as a biomarker for EAC and as a potential target for therapeutics.

     

  • 11.
    Kashash, Hadeel
    University of Skövde, School of Health and Education.
    Effects of missense mutation of Unc45B on sarcomeric structure of rat cardiomyocytes2018Independent thesis Basic level (degree of Bachelor), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    UNC-45B is a crucial chaperone protein that aids in myosin folding and assembly and is an essential component for sarcomeric organization in muscle cell development and myofibrillogenesis. UNC45B is exclusively expressed in striated muscles and comprises 3 conserved domains: the N-terminal triple tetratricopeptide repeat (TPR) domain, the central domain of armadillo repeats and the C-terminal UNC45/Cro1/She4p (UCS) domain. The C-terminal UCS domain predominantly mediates the chaperone activity of UNC45B and is crucial for myosin binding, and induces a protective response under stressful conditions, stabilizing myosin and preventing aggregation. The central domain binds the myosin motor domain independent of UCS-myosin binding and exhibits inhibitory effects on the myosin motor domain, halting the power stroke and preventing myosin-mediated actin translocations. The TPR domain interacts with another chaperone protein, the heat shock protein 90 (Hsp90), with which UNC-45B forms a stable complex, binding unfolded myosin motor domains and promoting its folding, as well as mediating a protective response to disruptions in myosin homeostasis. A novel missense mutation in an evolutionarily conserved residue of one of the domains of UNC-45B has recently been identified to be associated with hypertrophic cardiomyopathy by whole exome sequencing. To assess the structural effects of this mutation, rat cardiomyocytes were transfected with GFP-labeled wild-type and mutant UNC-45, and immunostaining was performed to produce an illustration of the morphological effects of the mutation in question. Western blot was also performed to validate the presence of UNC-45 proteins in transfected samples. The results generated in this study were deemed inconclusive and no significant conclusions can be made regarding the possible effects of this mutant variant on sarcomeric organization.

  • 12.
    Olsen, Oddrun Elise
    et al.
    Department of Clinical and Molecular Medicine, NTNU–Norwegian University of Science and Technology, Trondheim, Norway / Department of Hematology, St. Olav’s University Hospital, Trondheim, Norway.
    Sankar, Meenu
    University of Skövde, School of Health and Education. University of Skövde, Health and Education.
    Elsaadi, Samah
    Department of Clinical and Molecular Medicine, NTNU–Norwegian University of Science and Technology, Trondheim, Norway.
    Hella, Hanne
    Department of Clinical and Molecular Medicine, NTNU–Norwegian University of Science and Technology, Trondheim, Norway.
    Buene, Glenn
    Department of Clinical and Molecular Medicine, NTNU–Norwegian University of Science and Technology, Trondheim, Norway.
    Darvekar, Sagar Ramesh
    Department of Clinical and Molecular Medicine, NTNU–Norwegian University of Science and Technology, Trondheim, Norway.
    Misund, Kristine
    Department of Clinical and Molecular Medicine, NTNU–Norwegian University of Science and Technology, Trondheim, Norway / Department of Hematology, St. Olav’s University Hospital, Trondheim, Norway.
    Katagiri, Takenobu
    Division of Pathophysiology, Research Center for Genomic Medicine, Saitama Medical University, Hidaka-shi, Saitama, Japan.
    Knaus, Petra
    Institute for Chemistry and Biochemistry, Freie Universitaet Berlin, Berlin, Germany.
    Holien, Toril
    Department of Clinical and Molecular Medicine, NTNU–Norwegian University of Science and Technology, Trondheim, Norway / Department of Hematology, St. Olav’s University Hospital, Trondheim, Norway.
    BMPR2 inhibits activin and BMP signaling via wild-type ALK22018In: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 131, no 11, article id UNSP jcs213512Article in journal (Refereed)
    Abstract [en]

    TGF-beta/BMP superfamily ligands require heteromeric complexes of type 1 and 2 receptors for ligand-dependent downstream signaling. Activin A, a TGF-beta superfamily member, inhibits growth of multiple myeloma cells, but the mechanism for this is unknown. We therefore aimed to clarify how activins affect myeloma cell survival. Activin A activates the transcription factors SMAD2/3 through the ALK4 type 1 receptor, but may also activate SMAD1/5/8 through mutated variants of the type 1 receptor ALK2 ( also known as ACVR1). We demonstrate that activin A and B activate SMAD1/5/8 in myeloma cells through endogenous wild-type ALK2. Knockdown of the type 2 receptor BMPR2 strongly potentiated activin A- and activin B-induced activation of SMAD1/5/8 and subsequent cell death. Furthermore, activity of BMP6, BMP7 or BMP9, which may also signal via ALK2, was potentiated by knockdown of BMPR2. Similar results were seen in HepG2 liver carcinoma cells. We propose that BMPR2 inhibits ALK2-mediated signaling by preventing ALK2 from oligomerizing with the type 2 receptors ACVR2A and ACVR2B, which are necessary for activation of ALK2 by activins and several BMPs. In conclusion, BMPR2 could be explored as a possible target for therapy in patients with multiple myeloma.

  • 13.
    Uvnäs-Moberg, Kerstin
    et al.
    Department of Animal Environment and Health, Swedish University of Agricultural Sciences, Skara, Sweden.
    Handlin, Linda
    University of Skövde, School of Health and Education. University of Skövde, Health and Education.
    Kendall-Tackett, Kathleen
    Texas Tech University School of Medicine, Amarillo, TX, USA.
    Petersson, Maria
    Department of Molecular Medicine and Surgery, Endocrine and Diabetes Unit, Karolinska Institutet, Sweden.
    Oxytocin is a principal hormone that exerts part of its effects by active fragments2019In: Medical Hypotheses, ISSN 0306-9877, E-ISSN 1532-2777, Vol. 133, p. 1-9, article id 109394Article in journal (Refereed)
    Abstract [en]

    Oxytocin is a nonapeptide consisting of a cyclic six amino-acid structure and a tail of three amino acids. It was originally known for its ability to induce milk ejection and to stimulate uterine contractions. More recently, oxytocin has been shown to stimulate social behaviors, and exert pain-relieving, anti-stress/anti-inflammatory and restorative effects. We hypothesize that oxytocin is a principal hormone that, in part, exerts its effects after degradation to active fragments with more specific effect profiles. Experimental findings on rats show that administered oxytocin exerts biphasic effects. For example, after an initial increase in pain threshold, a second more long-lasting increase follows. Blood pressure and cortisol levels initially increase and then reverse into a long-lasting decrease in blood pressure and cortisol. Whereas the initial effects are, the second-phase effects are not blocked by an oxytocin antagonist, but by an opioid mu-antagonist and by an alpha 2-adrenoreceptor antagonist, respectively, suggesting that other receptors are involved. Repeated administration of oxytocin induces multiple anti-stress effects, which are mediated by alpha 2-adrenoreceptors. Repeated administration of linear oxytocin and linear oxytocin fragments with a retained C-terminal reduce spontaneous motor activity, a sedative or anti-stress effect, suggesting that alpha 2-adrenoreceptors have been activated. In contrast, linear mid-fragments stimulate motor activity. Low-intensity stimulation of cutaneous nerves in rats, as well as breastfeeding and skin-to-skin contact between mothers and babies, trigger immediate anti-stress effects. Some of these effects are likely caused by open ring/linear C-terminal fragments activating alpha 2-adrenoreceptors. Oxytocin fragments may be pre-formed and released in the brain or created by metabolic conversion of the principal hormone oxytocin in the central nervous system. Oxytocin and its fragments may also be released from peripheral sites, such as peripheral nerves, the gastrointestinal tract, and blood vessels in response to decreased sympathetic or increased parasympathetic nervous tone. Smaller fragments of oxytocin produced in the periphery may easily pass the blood-brain barrier to induce effects in the brain. In conclusion, oxytocin is linked to many different, sometimes opposite effects. The intact cyclic molecule may act to initiate social interaction and associated psychophysiological effects, whereas linear oxytocin and C-terminal fragments may induce relaxation and anti-stress effects following social interaction. In this way, the principal hormone oxytocin and its fragments may take part in a behavioral sequence, ranging from approach and interaction to calm and relaxation. Linear fragments, with an exposed cysteine-residue, may exert anti-inflammatory and antioxidant effects and thereby contribute to the health-promoting effects of oxytocin. 

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