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  • 1.
    Carthy, Jon M.
    et al.
    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. Imperial Coll London, Fac Med, Div Brain Sci, London, England..
    Stoeter, Martin
    Max Planck Inst Mol Cell Biol & Genet, Dresden, Germany..
    Bellomo, Claudia
    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.
    Vanlandewijck, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Heldin, Angelos
    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.
    Moren, Anita
    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.
    Kardassis, Dimitris
    Univ Crete, Sch Med, Dept Biochem, Iraklion 71003, Crete, Greece..
    Gahman, Timothy C.
    Ludwig Inst Canc Res, Small Mol Discovery Program, La Jolla, CA 92093 USA..
    Shiau, Andrew K.
    Ludwig Inst Canc Res, Small Mol Discovery Program, La Jolla, CA 92093 USA..
    Bickle, Marc
    Max Planck Inst Mol Cell Biol & Genet, Dresden, Germany..
    Zerial, Marino
    Max Planck Inst Mol Cell Biol & Genet, Dresden, Germany..
    Heldin, Carl-Henrik
    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, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Chemical regulators of epithelial plasticity reveal a nuclear receptor pathway controlling myofibroblast differentiation2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 29868Article in journal (Refereed)
    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.

  • 2.
    Dahl, Markus
    et al.
    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.
    Maturi, Varun
    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.
    Lönn, Peter
    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.
    Papoutsoglou, Panagiotis
    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.
    Zieba, Agata
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Vanlandewijck, Michael
    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.
    van der Heide, Lars P
    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.
    Watanabe, Yukihide
    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.
    Söderberg, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hottiger, Michael O
    Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich, Zurich, Switzerland.
    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, 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.
    Fine-Tuning of Smad Protein Function by Poly(ADP-Ribose) Polymerases and Poly(ADP-Ribose) Glycohydrolase during Transforming Growth Factor β Signaling2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 8, p. e103651-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Initiation, amplitude, duration and termination of transforming growth factor β (TGFβ) signaling via Smad proteins is regulated by post-translational modifications, including phosphorylation, ubiquitination and acetylation. We previously reported that ADP-ribosylation of Smads by poly(ADP-ribose) polymerase 1 (PARP-1) negatively influences Smad-mediated transcription. PARP-1 is known to functionally interact with PARP-2 in the nucleus and the enzyme poly(ADP-ribose) glycohydrolase (PARG) can remove poly(ADP-ribose) chains from target proteins. Here we aimed at analyzing possible cooperation between PARP-1, PARP-2 and PARG in regulation of TGFβ signaling.

    METHODS:

    A robust cell model of TGFβ signaling, i.e. human HaCaT keratinocytes, was used. Endogenous Smad3 ADP-ribosylation and protein complexes between Smads and PARPs were studied using proximity ligation assays and co-immunoprecipitation assays, which were complemented by in vitro ADP-ribosylation assays using recombinant proteins. Real-time RT-PCR analysis of mRNA levels and promoter-reporter assays provided quantitative analysis of gene expression in response to TGFβ stimulation and after genetic perturbations of PARP-1/-2 and PARG based on RNA interference.

    RESULTS:

    TGFβ signaling rapidly induces nuclear ADP-ribosylation of Smad3 that coincides with a relative enhancement of nuclear complexes of Smads with PARP-1 and PARP-2. Inversely, PARG interacts with Smads and can de-ADP-ribosylate Smad3 in vitro. PARP-1 and PARP-2 also form complexes with each other, and Smads interact and activate auto-ADP-ribosylation of both PARP-1 and PARP-2. PARP-2, similar to PARP-1, negatively regulates specific TGFβ target genes (fibronectin, Smad7) and Smad transcriptional responses, and PARG positively regulates these genes. Accordingly, inhibition of TGFβ-mediated transcription caused by silencing endogenous PARG expression could be relieved after simultaneous depletion of PARP-1.

    CONCLUSION:

    Nuclear Smad function is negatively regulated by PARP-1 that is assisted by PARP-2 and positively regulated by PARG during the course of TGFβ signaling.

  • 3.
    He, Liqun
    et al.
    Tianjin Med Univ Gen Hosp, Key Lab Postneuroinjury Neurorepair & Regenerat C, Minist Educ & Tianjin City, Dept Neurosurg,Tianjin Neurol Inst, Tianjin 300052, Peoples R China.
    Vanlandewijck, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, Dept Med Huddinge, Integrated Cardio Metab Ctr, Blickagangen 6, SE-14157 Huddinge, Sweden.
    Mäe, Maarja Andaloussi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Andrae, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Ando, Koji
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Del Gaudio, Francesca
    Karolinska Inst, Dept Cell & Mol Biol, Von Eulers Vag 3, SE-17177 Stockholm, Sweden.
    Nahar, Khayrun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Lebouvier, Thibaud
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Univ Lille, CHU, Memory Ctr, Inserm,U1171,Distalz, F-59000 Lille, France.
    Lavina, Barbara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Gouveia, Maria Leonor Seguardo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Sun, Ying
    Zhongyuan Union Genet Technol Co Ltd, Dept Bioinformat, 45 9th East Rd, Tianjin 300304, Peoples R China.
    Raschperger, Elisabeth
    Karolinska Inst, Dept Med Huddinge, Integrated Cardio Metab Ctr, Blickagangen 6, SE-14157 Huddinge, Sweden.
    Segerstolpe, Asa
    Karolinska Inst, Dept Med Huddinge, Integrated Cardio Metab Ctr, Blickagangen 6, SE-14157 Huddinge, Sweden.
    Liu, Jianping
    Karolinska Inst, Dept Med Huddinge, Integrated Cardio Metab Ctr, Blickagangen 6, SE-14157 Huddinge, Sweden.
    Gustafsson, Sonja
    Karolinska Inst, Dept Med Huddinge, Integrated Cardio Metab Ctr, Blickagangen 6, SE-14157 Huddinge, Sweden.
    Rasanen, Markus
    Univ Helsinki, Wihuri Res Inst, Haartmaninkatu 8,POB 63, FI-00014 Helsinki, Finland;Univ Helsinki, Translat Canc Biol Program, Biomedicum Helsinki, Haartmaninkatu 8,POB 63, FI-00014 Helsinki, Finland.
    Zarb, Yvette
    Zurich Univ, Univ Zurich Hosp, Div Neurosurg, CH-8091 Zurich, Switzerland.
    Mochizuki, Naoki
    Natl Cerebral & Cardiovasc Ctr, Dept Cell Biol, Res Inst, 5-7-1 Fujishirodai, Suita, Osaka 5658565, Japan;Natl Cerebral & Cardiovasc Ctr, AMED CREST, 5-7-1 Fujishirodai, Suita, Osaka 5658565, Japan.
    Keller, Annika
    Zurich Univ, Univ Zurich Hosp, Div Neurosurg, CH-8091 Zurich, Switzerland.
    Lendahl, Urban
    Karolinska Inst, Dept Med Huddinge, Integrated Cardio Metab Ctr, Blickagangen 6, SE-14157 Huddinge, Sweden;Karolinska Inst, Dept Cell & Mol Biol, Von Eulers Vag 3, SE-17177 Stockholm, Sweden.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, Dept Med Huddinge, Integrated Cardio Metab Ctr, Blickagangen 6, SE-14157 Huddinge, Sweden.
    Single-cell RNA sequencing of mouse brain and lung vascular and vessel-associated cell types2018In: Scientific Data, E-ISSN 2052-4463, Vol. 5, article id 180160Article in journal (Refereed)
    Abstract [en]

    Vascular diseases are major causes of death, yet our understanding of the cellular constituents of blood vessels, including how differences in their gene expression profiles create diversity in vascular structure and function, is limited. In this paper, we describe a single-cell RNA sequencing (scRNA-seq) dataset that defines vascular and vessel-associated cell types and subtypes in mouse brain and lung. The dataset contains 3,436 single cell transcriptomes from mouse brain, which formed 15 distinct clusters corresponding to cell (sub) types, and another 1,504 single cell transcriptomes from mouse lung, which formed 17 cell clusters. In order to allow user-friendly access to our data, we constructed a searchable database (http://betsholtzlab.org/VascularSingleCells/database.html). Our dataset constitutes a comprehensive molecular atlas of vascular and vessel-associated cell types in the mouse brain and lung, and as such provides a strong foundation for future studies of vascular development and diseases.

  • 4.
    Heldin, Carl-Henrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Vanlandewijck, Michael
    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, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Regulation of EMT by TGFβ in cancer2012In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 586, no 14, p. 1959-1970Article, review/survey (Refereed)
    Abstract [en]

    Transforming growth factor-beta (TGF beta) suppresses tumor formation since it inhibits cell growth and promotes apoptosis. However, in advanced cancers TGF beta elicits tumor promoting effects through its ability to induce epithelial-mesenchymal transition (EMT) which enhances invasiveness and metastasis; in addition, TGF beta exerts tumor promoting effects on non-malignant cells of the tumor, including suppression of immune surveillance and stimulation of angiogenesis. TGF beta promotes EMT by transcriptional and posttranscriptional regulation of a group of transcription factors that suppresses epithelial features, such as expression of components of cell junctions and polarity complexes, and enhances mesenchymal features, such as production of matrix molecules and several cytokines and growth factors that stimulate cell migration. The EMT program has certain similarities with the stem cell program. Inducers and effectors of EMT are interesting targets for the development of improved diagnosis, prognosis and therapy of cancer. 

  • 5.
    Loganathan, Krishnapriya
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Salem Said, Ebtisam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Winterrowd, Emily
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Orebrand, Martina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    He, Liqun
    Department of Neurosur gery, Tianjin Medical University General Hospital, Tianjin Neurolo gical Institute, Key Laborat ory of Post-Neur oinjury Neuro-Rep air and Regener ation in Central Nervous System, Ministry of Educatio n and Tianjin City, Tianjin, China,.
    Vanlandewijck, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. ntegrated Cardio Metabolic Centre, Karolinska Institutet, Huddinge , Sweden.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. ntegrated Cardio Metabolic Centre, Karolinska Institutet, Huddinge , Sweden.
    Quaggin, Susan E
    Feinberg Cardiovas cular Research Institute, Northwestern University , Chicago, United States of America.
    Jeansson, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Angiopoietin-1 deficiency increases renal capillary rarefaction and tubulointerstitial fibrosis in mice2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 1, article id e0189433Article in journal (Refereed)
    Abstract [en]

    Presence of tubulointerstitial fibrosis is predictive of progressive decline in kidney function, independent of its underlying cause. Injury to the renal microvasculature is a major factor in the progression of fibrosis and identification of factors that regulate endothelium in fibrosis is desirable as they might be candidate targets for treatment of kidney diseases. The current study investigates how loss of Angipoietin-1 (Angpt1), a ligand for endothelial tyrosine-kinase receptor Tek (also called Tie2), affects tubulointerstitial fibrosis and renal microvasculature. Inducible Angpt1 knockout mice were subjected to unilateral ureteral obstruction (UUO) to induce fibrosis, and kidneys were collected at different time points up to 10 days after obstruction. Staining for aSMA showed that Angpt1 deficient kidneys had significantly more fibrosis compared to wildtype mice 3, 6, and 10 days after UUO. Further investigation 3 days after UUO showed a significant increase of Col1a1 and vimentin in Angpt1 deficient mice, as well as increased gene expression of Tgfb1, Col1a1, Fn1, and CD44. Kidney injury molecule 1 (Kim1/Havcr1) was significantly more increased in Angpt1 deficient mice 1 and 3 days after UUO, suggesting a more severe injury early in the fibrotic process in Angpt1 deficient mice. Staining for endomucin showed that capillary rarefaction was evident 3 days after UUO and Angpt1 deficient mice had significantly less capillaries 6 and 10 days after UUO compared to UUO kidneys in wildtype mice. RNA sequencing revealed downregulation of several markers for endothelial cells 3 days after UUO, and that Angpt1 deficient mice had a further downregulation of Emcn, Plvap, Pecam1, Erg, and Tek. Our results suggest that loss of Angpt1 is central in capillary rarefaction and fibrogenesis and propose that manipulations to maintain Angpt1 levels may slow down fibrosis progression.

  • 6.
    Mäe, Maarja Andaloussi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Li, Tian
    Karolinska Inst, Dept Med, Integrated Cardiometab Ctr, Huddinge, Sweden.
    Bertuzzi, Giacomo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Univ Oxford, Physiol Anat & Genet, Sherrington Bldg,Pk Rd, Oxford, England.
    Raschperger, Elisabeth
    Karolinska Inst, Dept Med, Integrated Cardiometab Ctr, Huddinge, Sweden.
    Vanlandewijck, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, Dept Med, Integrated Cardiometab Ctr, Huddinge, Sweden.
    He, Liqun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Tianjin Med Univ, Gen Hosp, Key Lab Postneuroinjury Neurorepair & Regenerat C, Minist Educ,Tianjin Neurol Inst,Dept Neurosurg, Tianjin, Peoples R China.
    Nahar, Khayrun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Dalheim, Annika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Loyola Univ, Cardinal Bernardin Canc Ctr, Dept Surg, Chicago, IL 60611 USA.
    Hofmann, Jennifer J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Concordia Univ, Austin, TX USA.
    Lavina, Barbara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Keller, Annika
    Zurich Univ, Dept Neurosurg, Clin Neuroctr, Univ Zurich Hosp, Zurich, Switzerland.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, Dept Med, Integrated Cardiometab Ctr, Huddinge, Sweden.
    Genove, Guillem
    Karolinska Inst, Dept Med, Integrated Cardiometab Ctr, Huddinge, Sweden.
    Prolonged systemic hyperglycemia does not cause pericyte loss and permeability at the mouse blood-brain barrier2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 17462Article in journal (Refereed)
    Abstract [en]

    Diabetes mellitus is associated with cognitive impairment and various central nervous system pathologies such as stroke, vascular dementia, or Alzheimer's disease. The exact pathophysiology of these conditions is poorly understood. Recent reports suggest that hyperglycemia causes cerebral microcirculation pathology and blood-brain barrier (BBB) dysfunction and leakage. The majority of these reports, however, are based on methods including in vitro BBB modeling or streptozotocininduced diabetes in rodents, opening questions regarding the translation of the in vitro findings to the in vivo situation, and possible direct effects of streptozotocin on the brain vasculature. Here we used a genetic mouse model of hyperglycemia (Ins2(AKITA)) to address whether prolonged systemic hyperglycemia induces BBB dysfunction and leakage. We applied a variety of methodologies to carefully evaluate BBB function and cellular integrity in vivo, including the quantification and visualization of specific tracers and evaluation of transcriptional and morphological changes in the BBB and its supporting cellular components. These experiments did neither reveal altered BBB permeability nor morphological changes of the brain vasculature in hyperglycemic mice. We conclude that prolonged hyperglycemia does not lead to BBB dysfunction, and thus the cognitive impairment observed in diabetes may have other causes.

  • 7.
    Niaudet, Colin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Hofmann, Jennifer J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, Stockholm, Sweden..
    Mae, Maarja A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Jung, Bongnam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Gängel, Konstantin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Vanlandewijck, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Ekvarn, Elisabet
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, Stockholm, Sweden..
    Salvado, M. Dolores
    Karolinska Inst, Dept Med Biochem & Biophys, Physiol Chem 2, Stockholm, Sweden..
    Mehlem, Annika
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, Stockholm, Sweden..
    Al Sayegh, Sahar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    He, Liqun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Lebouvier, Thibaud
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Castro Freire, Marco
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Katayama, Kan
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, Stockholm, Sweden..
    Hultenby, Kjell
    Div Clin Res Ctr, Dept Lab Med, Stockholm, Sweden.;Karolinska Inst, Stockholm, Sweden..
    Moessinger, Christine
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, Stockholm, Sweden..
    Tannenberg, Philip
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, Stockholm, Sweden.;Karolinska Inst, Dept Mol Med & Surg, Div Vasc Surg, Stockholm, Sweden..
    Cunha, Sara
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, Stockholm, Sweden..
    Pietras, Kristian
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, Stockholm, Sweden.;Lund Univ, Dept Lab Med, Lund, Sweden..
    Lavina Siemsen, Barbara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Hong, JongWook
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, Stockholm, Sweden..
    Berg, Tove
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, Stockholm, Sweden..
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Gpr116 Receptor Regulates Distinctive Functions in Pneumocytes and Vascular Endothelium2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 9, article id e0137949Article in journal (Refereed)
    Abstract [en]

    Despite its known expression in both the vascular endothelium and the lung epithelium, until recently the physiological role of the adhesion receptor Gpr116/ADGRF5 has remained elusive. We generated a new mouse model of constitutive Gpr116 inactivation, with a large genetic deletion encompassing exon 4 to exon 21 of the Gpr116 gene. This model allowed us to confirm recent results defining Gpr116 as necessary regulator of surfactant homeostasis. The loss of Gpr116 provokes an early accumulation of surfactant in the lungs, followed by a massive infiltration of macrophages, and eventually progresses into an emphysemalike pathology. Further analysis of this knockout model revealed cerebral vascular leakage, beginning at around 1.5 months of age. Additionally, endothelial-specific deletion of Gpr116 resulted in a significant increase of the brain vascular leakage. Mice devoid of Gpr116 developed an anatomically normal and largely functional vascular network, surprisingly exhibited an attenuated pathological retinal vascular response in a model of oxygen-induced retinopathy. These data suggest that Gpr116 modulates endothelial properties, a previously unappreciated function despite the pan-vascular expression of this receptor. Our results support the key pulmonary function of Gpr116 and describe a new role in the central nervous system vasculature.

  • 8.
    Niimi, Hideki
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Pardali, Katerina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Vanlandewijck, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Moustakas, Aristidis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Notch signaling is necessary for epithelial growth arrest by TGF-beta2007In: Journal of Cell Biology, ISSN 0021-9525, E-ISSN 1540-8140, Vol. 176, no 5, p. 695-707Article in journal (Refereed)
    Abstract [en]

    Transforming growth factor beta (TGF-beta) and Notch act as tumor suppressors by inhibiting epithelial cell proliferation. TGF-beta additionally promotes tumor invasiveness and metastasis, whereas Notch supports oncogenic growth. We demonstrate that TGF-beta and ectopic Notch1 receptor cooperatively arrest epithelial growth, whereas endogenous Notch signaling was found to be required for TGF-beta to elicit cytostasis. Transcriptomic analysis after blocking endogenous Notch signaling uncovered several genes, including Notch pathway components and cell cycle and apoptosis factors, whose regulation by TGF-beta requires an active Notch pathway. A prominent gene coregulated by the two pathways is the cell cycle inhibitor p21. Both transcriptional induction of the Notch ligand Jagged1 by TGF-beta and endogenous levels of the Notch effector CSL contribute to p21 induction and epithelial cytostasis. Cooperative inhibition of cell proliferation by TGF-beta and Notch is lost in human mammary cells in which the p21 gene has been knocked out. We establish an intimate involvement of Notch signaling in the epithelial cytostatic response to TGF-beta.

  • 9.
    van Kuijk, Kim
    et al.
    MUMC Maastricht, CARIM Sch Cardiovasc Dis, Pathol Dept, P Debyelaan 25, NL-6229HX Maastricht, Netherlands.
    Kuppe, Christoph
    Rhein Westfal TH Aachen, Biochem Dept, Aachen, Germany.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst Stockholm, Integrated Cardio Metab Ctr, Stockholm, Sweden.
    Vanlandewijck, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst Stockholm, Integrated Cardio Metab Ctr, Stockholm, Sweden.
    Kramann, Rafael
    Rhein Westfal TH Aachen, Biochem Dept, Aachen, Germany.
    Sluimer, Judith C.
    MUMC Maastricht, CARIM Sch Cardiovasc Dis, Pathol Dept, P Debyelaan 25, NL-6229HX Maastricht, Netherlands;Univ Edinburgh, British Heart Fdn, Ctr Cardiovasc Sci CVS, Edinburgh, Midlothian, Scotland.
    Heterogeneity and plasticity in healthy and atherosclerotic vasculature explored by single-cell sequencing2019In: Cardiovascular Research, ISSN 0008-6363, E-ISSN 1755-3245, Vol. 115, no 12, p. 1705-1715Article, review/survey (Refereed)
    Abstract [en]

    Cellular characteristics and their adjustment to a state of disease have become more evident due to recent advances in imaging, fluorescent reporter mice, and whole genome RNA sequencing. The uncovered cellular heterogeneity and/or plasticity potentially complicates experimental studies and clinical applications, as markers derived from whole tissue 'bulk' sequencing is unable to yield a subtype transcriptome and specific markers. Here, we propose definitions on heterogeneity and plasticity, discuss current knowledge thereof in the vasculature and how this may be improved by single-cell sequencing (SCS). SCS is emerging as an emerging technique, enabling researchers to investigate different cell populations in more depth than ever before. Cell selection methods, e.g. flow assisted cell sorting, and the quantity of cells can influence the choice of SCS method. Smart-Seq2 offers sequencing of the complete mRNA molecule on a low quantity of cells, while Drop-seq is possible on large numbers of cells on a more superficial level. SCS has given more insight in heterogeneity in healthy vasculature, where it revealed that zonation is crucial in gene expression profiles among the anatomical axis. In diseased vasculature, this heterogeneity seems even more prominent with discovery of new immune subsets in atherosclerosis as proof. Vascular smooth muscle cells and mesenchymal cells also share these plastic characteristics with the ability to up-regulate markers linked to stem cells, such as Sca-1 or CD34. Current SCS studies show some limitations to the number of replicates, quantity of cells used, or the loss of spatial information. Bioinformatical tools could give some more insight in current datasets, making use of pseudo-time analysis or RNA velocity to investigate cell differentiation or polarization. In this review, we discuss the use of SCS in unravelling heterogeneity in the vasculature, its current limitations and promising future applications.

  • 10.
    Vanlandewijck, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Diversification of TGF-β Signaling in Homeostasis and Disease2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    With the dawn of metazoans, the ability of cells to communicate with each other became of paramount importance in maintaining tissue homeostasis. The transforming growth factor β (TGF-β) signaling pathway, which plays important roles during embryogenesis and in the adult organism, signals via a heterodimeric receptor complex consisting of two type II and two type I receptors. After receptor activation through ligand binding, Smads mediate the signal from the receptor complex to the nucleus, where they orchestrate transcription. Depending on the context of activation, TGF-β can mediate a plethora of cellular responses, including proliferation, growth arrest, apoptosis and differentiation. In cancer, TGF-β can act as both as a tumor suppressor and promoter. During early stages of tumorigenesis, TGF-β prevents proliferation. However, TGF-β is also known to promote tumor progression during later stages of the disease, where it can induce differentiation of cancer cells towards a migratory phenotype.

    The aim of this thesis was to investigate how cells can differentiate their response upon TGF-β pathway activation. The first paper describes the role of Notch signaling in TGF-β induced growth arrest, demonstrating that TGF-β promotes Notch activity and that Notch signaling is required for prolonged TGF-β induced cell cycle arrest. In the second and third paper, we investigate the role of SIK, a member of the AMPK family of kinases, mediating signaling strength of TGF-β through degradation of the TGF-β type I receptor ALK5. While the second paper focuses on the effect of SIK on ALK5 stability and subsequent alterations in TGF-β signaling, the third paper emphasizes cooperation between SIK, Smad7 and the E3 ligase Smurf in degradation of ALK5. Finally, the fourth paper explores a novel role of SIK during TGF-β induced epithelial to mesenchymal transition (EMT). SIK binds to and degrades the polarity protein Par3, leading to enhanced EMT.

    List of papers
    1. Notch signaling is necessary for epithelial growth arrest by TGF-beta
    Open this publication in new window or tab >>Notch signaling is necessary for epithelial growth arrest by TGF-beta
    Show others...
    2007 (English)In: Journal of Cell Biology, ISSN 0021-9525, E-ISSN 1540-8140, Vol. 176, no 5, p. 695-707Article in journal (Refereed) Published
    Abstract [en]

    Transforming growth factor beta (TGF-beta) and Notch act as tumor suppressors by inhibiting epithelial cell proliferation. TGF-beta additionally promotes tumor invasiveness and metastasis, whereas Notch supports oncogenic growth. We demonstrate that TGF-beta and ectopic Notch1 receptor cooperatively arrest epithelial growth, whereas endogenous Notch signaling was found to be required for TGF-beta to elicit cytostasis. Transcriptomic analysis after blocking endogenous Notch signaling uncovered several genes, including Notch pathway components and cell cycle and apoptosis factors, whose regulation by TGF-beta requires an active Notch pathway. A prominent gene coregulated by the two pathways is the cell cycle inhibitor p21. Both transcriptional induction of the Notch ligand Jagged1 by TGF-beta and endogenous levels of the Notch effector CSL contribute to p21 induction and epithelial cytostasis. Cooperative inhibition of cell proliferation by TGF-beta and Notch is lost in human mammary cells in which the p21 gene has been knocked out. We establish an intimate involvement of Notch signaling in the epithelial cytostatic response to TGF-beta.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-10286 (URN)10.1083/jcb.200612129 (DOI)000244487100026 ()17325209 (PubMedID)
    Available from: 2007-03-12 Created: 2007-03-12 Last updated: 2017-12-11Bibliographically approved
    2. TGFβ induces SIK to negatively regulate type I receptor kinase signaling
    Open this publication in new window or tab >>TGFβ induces SIK to negatively regulate type I receptor kinase signaling
    Show others...
    2008 (English)In: Journal of Cell Biology, ISSN 0021-9525, E-ISSN 1540-8140, Vol. 182, no 4, p. 655-662Article in journal (Refereed) Published
    Abstract [en]

    Signal transduction by transforming growth factor beta (TGFbeta) coordinates physiological responses in diverse cell types. TGFbeta signals via type I and type II receptor serine/threonine kinases and intracellular Smad proteins that regulate transcription. Strength and duration of TGFbeta signaling is largely dependent on a negative-feedback program initiated during signal progression. We have identified an inducible gene target of TGFbeta/Smad signaling, the salt-inducible kinase (SIK), which negatively regulates signaling together with Smad7. SIK and Smad7 form a complex and cooperate to down-regulate the activated type I receptor ALK5. We further show that both the kinase and ubiquitin-associated domain of SIK are required for proper ALK5 degradation, with ubiquitin functioning to enhance SIK-mediated receptor degradation. Loss of endogenous SIK results in enhanced gene responses of the fibrotic and cytostatic programs of TGFbeta. We thus identify in SIK a negative regulator that controls TGFbeta receptor turnover and physiological signaling.

    Place, publisher, year, edition, pages
    The Rockefeller University Press, 2008
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-103239 (URN)10.1083/jcb.200804107 (DOI)000259050000007 ()18725536 (PubMedID)
    Available from: 2009-05-15 Created: 2009-05-15 Last updated: 2017-12-13Bibliographically approved
    3. SIK and Smurf2 cooperate to downregulate the TGF-β type I receptor
    Open this publication in new window or tab >>SIK and Smurf2 cooperate to downregulate the TGF-β type I receptor
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-128850 (URN)
    Available from: 2010-07-27 Created: 2010-07-27 Last updated: 2012-03-14
    4. SIK phosphorylates and degrades Par3 to mediate tight junction disassembly during epithelial-mesenchymal transition
    Open this publication in new window or tab >>SIK phosphorylates and degrades Par3 to mediate tight junction disassembly during epithelial-mesenchymal transition
    Show others...
    2011 (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Transforming growth factor β (TGFβ) is a multifunctional cytokine involved in homeostasis and disease during embryonic and adult life. TGFβ alters epithelial cell differentiation by inducing epithelial-mesenchymal transition (EMT), which involves disassembly of the epithelial adherens and tight junctions and downregulation of several junctional constituents.The mechanism by which TGFβ controls tight junction disassembly is poorly understood. We found that one of the newly identified gene targets of TGFβ, encodes for the serine/threonine kinase SIK (salt-inducible kinase), and controls tight junction assembly by this cytokine. We then identified a new phosphorylation substrate for SIK, the polarity complex protein Par3, which is an important regulator of tight junction assembly. SIK associates with Par3, phosphorylates serine 885 within the atypical protein kinase C-binding domain of Par3, and causes degradation of Par3. Mutation of serine 885 to alanine renders Par3 resistant to degradation induced by SIK. This mechanism is functionally important because both SIK and Par3 participate in the downregulation of tight junctions during EMT initiated by TGFβ signaling. Furthermore, we verified high level SIK expression in several different advanced and invasive human cancers. Notably, high SIK expression correlated with high level TGFβ/Smad signaling activity and with low or undetectable expression of Par3 in human breast cancers. Our model suggests that as the TGFβ signal progresses, SIK gets engaged in a concerted action that lowers signaling by its own receptor and initiates disassembly of the tight junction by acting directly on the polarity complex protein Par3.

    Publisher
    p. 230
    Keywords
    EMT, Par3, Signal transduction, SIK, TGFβ
    Identifiers
    urn:nbn:se:uu:diva-152266 (URN)
    Available from: 2011-04-27 Created: 2011-04-27 Last updated: 2018-06-26
  • 11.
    Vanlandewijck, Michael
    et al.
    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. Integrated Cardio Metabolic Center, Novum, Karolinska Institute, Huddinge, Sweden.
    Dadras, Mahsa Shahidi
    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.
    Lomnytska, Marta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Reproductive Health. Department of Oncology and Pathology, Karolinska Biomics Center, Karolinska Institute, Stockholm, Sweden.
    Mahzabin, Tanzila
    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. School of Anatomy, Physiology and Human Biology, The University of Western Australia, Crawley, WA, Australia.
    Lee Miller, Martin
    Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark; Cancer Research UK, Cambridge Institute, University of Cambridge, Li Ka Shing Center, Cambridge, UK.
    Busch, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Brunak, Søren
    Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark.
    Heldin, Carl-Henrik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. 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, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    The protein kinase SIK downregulates the polarity protein Par32018In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 9, p. 5716-5735Article in journal (Refereed)
    Abstract [en]

    The multifunctional cytokine transforming growth factor β (TGFβ) controls homeostasis and disease during embryonic and adult life. TGFβ alters epithelial cell differentiation by inducing epithelial-mesenchymal transition (EMT), which involves downregulation of several cell-cell junctional constituents. Little is understood about the mechanism of tight junction disassembly by TGFβ. We found that one of the newly identified gene targets of TGFβ, encoding the serine/threonine kinase salt-inducible kinase 1 (SIK), controls tight junction dynamics. We provide bioinformatic and biochemical evidence that SIK can potentially phosphorylate the polarity complex protein Par3, an established regulator of tight junction assembly. SIK associates with Par3, and induces degradation of Par3 that can be prevented by proteasomal and lysosomal inhibition or by mutation of Ser885, a putative phosphorylation site on Par3. Functionally, this mechanism impacts on tight junction downregulation. Furthermore, SIK contributes to the loss of epithelial polarity and examination of advanced and invasive human cancers of diverse origin displayed high levels of SIK expression and a corresponding low expression of Par3 protein. High SIK mRNA expression also correlates with lower chance for survival in various carcinomas. In specific human breast cancer samples, aneuploidy of tumor cells best correlated with cytoplasmic SIK distribution, and SIK expression correlated with TGFβ/Smad signaling activity and low or undetectable expression of Par3. Our model suggests that SIK can act directly on the polarity protein Par3 to regulate tight junction assembly.

  • 12.
    Vanlandewijck, Michael
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, AstraZeneca Integrated Cardio Metab Ctr KI AZ ICM, Blickagangen 6, SE-14157 Huddinge, Sweden..
    He, Liqun
    Tianjin Med Univ, Key Lab Postneuroinjury Neurorepair & Regenerat C, Dept Neurosurg,Gen Hosp, Tianjin Neurol Inst,Minist Educ & Tianjin City, Tianjin 300052, Peoples R China..
    Mäe, Maarja Andaloussi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Andrae, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Ando, Koji
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Del Gaudio, Francesca
    Karolinska Inst, Dept Cell & Mol Biol, Von Eulers Vag 3, SE-17177 Stockholm, Sweden..
    Nahar, Khayrun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Lebouvier, Thibaud
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Univ Lille, CHU,Memory Ctr, Distalz, Inserm,U1171, F-59000 Lille, France..
    Laviña, Bàrbara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Gouveia, Maria Leonor Seguardo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Sun, Ying
    Zhongyuan Union Genet Technol Co Ltd, Dept Bioinformat, Tianjin Airport Econ Area, 45 9th East Rd, Tianjin 300304, Peoples R China..
    Raschpergert, Elisabeth
    Karolinska Inst, AstraZeneca Integrated Cardio Metab Ctr KI AZ ICM, Blickagangen 6, SE-14157 Huddinge, Sweden..
    Räsänen, Markus
    Univ Helsinki, Wihuri Res Inst, Haartmaninkatu 8,POB 63, FI-00014 Helsinki, Finland.;Univ Helsinki, Translat Canc Biol Program, Biomedicum Helsinki, Haartmaninkatu 8,POB 63, FI-00014 Helsinki, Finland..
    Zarb, Yvette
    Zurich Univ, Univ Zurich Hosp, Div Neurosurg, CH-8091 Zurich, Switzerland..
    Mochizuki, Naoki
    Natl Cerebral & Cardiovasc Ctr, Dept Cell Biol, Res Inst, Suita, Osaka, Japan.;Natl Cerebral & Cardiovasc Ctr, AMED CREST, Suita, Osaka, Japan..
    Keller, Annika
    Zurich Univ, Univ Zurich Hosp, Div Neurosurg, CH-8091 Zurich, Switzerland..
    Lendahl, Urban
    Karolinska Inst, Dept Cell & Mol Biol, Von Eulers Vag 3, SE-17177 Stockholm, Sweden..
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, AstraZeneca Integrated Cardio Metab Ctr KI AZ ICM, Blickagangen 6, SE-14157 Huddinge, Sweden.
    A molecular atlas of cell types and zonation in the brain vasculature2018In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 554, no 7693, p. 475-480Article in journal (Refereed)
    Abstract [en]

    Cerebrovascular disease is the third most common cause of death in developed countries, but our understanding of the cells that compose the cerebral vasculature is limited. Here, using vascular single-cell transcriptomics, we provide molecular definitions for the principal types of blood vascular and vessel-associated cells in the adult mouse brain. We uncover the transcriptional basis of the gradual phenotypic change (zonation) along the arteriovenous axis and reveal unexpected cell type differences: a seamless continuum for endothelial cells versus a punctuated continuum for mural cells. We also provide insight into pericyte organotypicity and define a population of perivascular fibroblast-like cells that are present on all vessel types except capillaries. Our work illustrates the power of single-cell transcriptomics to decode the higher organizational principles of a tissue and may provide the initial chapter in a molecular encyclopaedia of the mammalian vasculature.

  • 13.
    Vanlandewijck, Michael
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, Novum, ICMC, SE-14157 Stockholm, Sweden..
    Lebouvier, Thibaud
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Mae, Maarja Andaloussi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Nahar, Khayrun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Hornemann, Simone
    Univ Zurich, Univ Zurich Hosp, Inst Neuropathol, CH-8091 Zurich, Switzerland..
    Kenkel, David
    Univ Zurich, Univ Zurich Hosp, Inst Diagnost & Intervent Radiol, CH-8091 Zurich, Switzerland..
    Cunha, Sara I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. 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.
    Lennartsson, Johan
    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.
    Boss, Andreas
    Univ Zurich, Univ Zurich Hosp, Inst Diagnost & Intervent Radiol, CH-8091 Zurich, Switzerland..
    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.
    Keller, Annika
    Univ Zurich, Univ Zurich Hosp, Div Neurosurg, CH-8091 Zurich, Switzerland..
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Functional Characterization of Germline Mutations in PDGFB and PDGFRB in Primary Familial Brain Calcification2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 11, article id e0143407Article in journal (Refereed)
    Abstract [en]

    Primary Familial Brain Calcification (PFBC), a neurodegenerative disease characterized by progressive pericapillary calcifications, has recently been linked to heterozygous mutations in PDGFB and PDGFRB genes. Here, we functionally analyzed several of these mutations in vitro. All six analyzed PDGFB mutations led to complete loss of PDGF-B function either through abolished protein synthesis or through defective binding and/or stimulation of PDGF-R beta. The three analyzed PDGFRB mutations had more diverse consequences. Whereas PDGF-R beta autophosphorylation was almost totally abolished in the PDGFRB L658P mutation, the two sporadic PDGFRB mutations R987W and E1071V caused reductions in protein levels and specific changes in the intensity and kinetics of PLC. activation, respectively. Since at least some of the PDGFB mutations were predicted to act through haploinsufficiency, we explored the consequences of reduced Pdgfb or Pdgfrb transcript and protein levels in mice. Heterozygous Pdgfb or Pdgfrb knockouts, as well as double Pdgfb(+/-); Pdgfrb(+/-) mice did not develop brain calcification, nor did Pdgfrb(redeye/redeye) mice, which show a 90% reduction of PDGFR beta protein levels. In contrast, Pdgfb(ret/ret) mice, which have altered tissue distribution of PDGF-B protein due to loss of a proteoglycan binding motif, developed brain calcifications. We also determined pericyte coverage in calcification-prone and non-calcification-prone brain regions in Pdgfb(ret/ret) mice. Surprisingly and contrary to our hypothesis, we found that the calcification-prone brain regions in Pdgfb(ret/ret) mice model had a higher pericyte coverage and a more intact blood-brain barrier (BBB) compared to non-calcification-prone brain regions. While our findings provide clear evidence that loss-of-function mutations in PDGFB or PDGFRB cause PFBC, they also demonstrate species differences in the threshold levels of PDGF-B/PDGF-R beta signaling that protect against small-vessel calcification in the brain. They further implicate region-specific susceptibility factor(s) in PFBC pathogenesis that are distinct from pericyte and BBB deficiency.

  • 14.
    Vanlandewijck, Michael
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Lomnytska, Marta
    Department of Oncology and Pathology, Karolinska Biomics Center, Karolinska Institute, Stockholm, Sweden.
    Busch, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Heldin, Carl-Henrik
    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.
    SIK phosphorylates and degrades Par3 to mediate tight junction disassembly during epithelial-mesenchymal transition2011Manuscript (preprint) (Other academic)
    Abstract [en]

    Transforming growth factor β (TGFβ) is a multifunctional cytokine involved in homeostasis and disease during embryonic and adult life. TGFβ alters epithelial cell differentiation by inducing epithelial-mesenchymal transition (EMT), which involves disassembly of the epithelial adherens and tight junctions and downregulation of several junctional constituents.The mechanism by which TGFβ controls tight junction disassembly is poorly understood. We found that one of the newly identified gene targets of TGFβ, encodes for the serine/threonine kinase SIK (salt-inducible kinase), and controls tight junction assembly by this cytokine. We then identified a new phosphorylation substrate for SIK, the polarity complex protein Par3, which is an important regulator of tight junction assembly. SIK associates with Par3, phosphorylates serine 885 within the atypical protein kinase C-binding domain of Par3, and causes degradation of Par3. Mutation of serine 885 to alanine renders Par3 resistant to degradation induced by SIK. This mechanism is functionally important because both SIK and Par3 participate in the downregulation of tight junctions during EMT initiated by TGFβ signaling. Furthermore, we verified high level SIK expression in several different advanced and invasive human cancers. Notably, high SIK expression correlated with high level TGFβ/Smad signaling activity and with low or undetectable expression of Par3 in human breast cancers. Our model suggests that as the TGFβ signal progresses, SIK gets engaged in a concerted action that lowers signaling by its own receptor and initiates disassembly of the tight junction by acting directly on the polarity complex protein Par3.

1 - 14 of 14
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