title: S100A6 Regulates Endothelial Cell Cycle Progression by Attenuating Antiproliferative Signal Transducers and Activators of Transcription 1 Signaling.
abstract: S100A6, a member of the S100 protein family, has been described as relevant for cell cycle entry and progression in endothelial cells. The molecular mechanism conferring S100A6's proliferative actions, however, remained elusive.
  
  
  
  Originating from the clinically relevant observation of enhanced S100A6 protein expression in proliferating endothelial cells in remodeling coronary and carotid arteries, our study unveiled S100A6 as a suppressor of antiproliferative signal transducers and activators of transcription 1 signaling. Discovery of the molecular liaison was enabled by combining gene expression time series analysis with bioinformatic pathway modeling in S100A6-silenced human endothelial cells stimulated with vascular endothelial growth factor A. This unbiased approach led to successful identification and experimental validation of interferon-inducible transmembrane protein 1 and protein inhibitors of activated signal transducers and activators of transcription as key components of the link between S100A6 and signal transducers and activators of transcription 1.
  
  
  
  Given the important role of coordinated endothelial cell cycle activity for integrity and reconstitution of the inner lining of arterial blood vessels in health and disease, signal transducers and activators of transcription 1 suppression by S100A6 may represent a promising therapeutic target to facilitate reendothelialization in damaged vessels.
authors.affiliation: From the Cardiovascular Research Center, Massachusetts General Hospital (C.L., F.D., A.R.), Cardiovascular Institute, Beth Israel Deaconess Medical Center (F.D.), and Boston Children's Hospital (V.J.B.), Harvard Medical School, Boston, MA; Molecular and Translational Cardiology (MTC), Department of Internal Medicine III, University Hospital Heidelberg, Germany (C.L., J.H., I.K., M. Busch, P.M.); Department of Pathology and Immunology, University of Geneva, Switzerland (M.-L.B.-P.); DZHK (German Center for Cardiovascular Research), Partner site Heidelberg/Mannheim, University of Heidelberg, Germany (K.H., M. Busch, H.A.K., P.M.); Center for Translational Medicine, Jefferson Medical College, Philadelphia, PA (K.P., P.M.); Systems Biology of the Cellular Microenvironment Group, Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University, Freiburg, Germany (H.B., M. Boerries); German Cancer Consortium (DKTK), Freiburg, Germany (H.B., M. Boerries); and German Cancer Research Center (DKFZ), Heidelberg, Germany (H.B., M. Boerries). clerchenmueller@mgh.harvard.edu m.boerries@dkfz.de.
authors.forename: Carolin
authors.initials: C
authors.lastname: Lerchenmüller
authors.affiliation: From the Cardiovascular Research Center, Massachusetts General Hospital (C.L., F.D., A.R.), Cardiovascular Institute, Beth Israel Deaconess Medical Center (F.D.), and Boston Children's Hospital (V.J.B.), Harvard Medical School, Boston, MA; Molecular and Translational Cardiology (MTC), Department of Internal Medicine III, University Hospital Heidelberg, Germany (C.L., J.H., I.K., M. Busch, P.M.); Department of Pathology and Immunology, University of Geneva, Switzerland (M.-L.B.-P.); DZHK (German Center for Cardiovascular Research), Partner site Heidelberg/Mannheim, University of Heidelberg, Germany (K.H., M. Busch, H.A.K., P.M.); Center for Translational Medicine, Jefferson Medical College, Philadelphia, PA (K.P., P.M.); Systems Biology of the Cellular Microenvironment Group, Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University, Freiburg, Germany (H.B., M. Boerries); German Cancer Consortium (DKTK), Freiburg, Germany (H.B., M. Boerries); and German Cancer Research Center (DKFZ), Heidelberg, Germany (H.B., M. Boerries).
authors.forename: Julian
authors.initials: J
authors.lastname: Heißenberg
authors.affiliation: From the Cardiovascular Research Center, Massachusetts General Hospital (C.L., F.D., A.R.), Cardiovascular Institute, Beth Israel Deaconess Medical Center (F.D.), and Boston Children's Hospital (V.J.B.), Harvard Medical School, Boston, MA; Molecular and Translational Cardiology (MTC), Department of Internal Medicine III, University Hospital Heidelberg, Germany (C.L., J.H., I.K., M. Busch, P.M.); Department of Pathology and Immunology, University of Geneva, Switzerland (M.-L.B.-P.); DZHK (German Center for Cardiovascular Research), Partner site Heidelberg/Mannheim, University of Heidelberg, Germany (K.H., M. Busch, H.A.K., P.M.); Center for Translational Medicine, Jefferson Medical College, Philadelphia, PA (K.P., P.M.); Systems Biology of the Cellular Microenvironment Group, Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University, Freiburg, Germany (H.B., M. Boerries); German Cancer Consortium (DKTK), Freiburg, Germany (H.B., M. Boerries); and German Cancer Research Center (DKFZ), Heidelberg, Germany (H.B., M. Boerries).
authors.forename: Federico
authors.initials: F
authors.lastname: Damilano
authors.affiliation: From the Cardiovascular Research Center, Massachusetts General Hospital (C.L., F.D., A.R.), Cardiovascular Institute, Beth Israel Deaconess Medical Center (F.D.), and Boston Children's Hospital (V.J.B.), Harvard Medical School, Boston, MA; Molecular and Translational Cardiology (MTC), Department of Internal Medicine III, University Hospital Heidelberg, Germany (C.L., J.H., I.K., M. Busch, P.M.); Department of Pathology and Immunology, University of Geneva, Switzerland (M.-L.B.-P.); DZHK (German Center for Cardiovascular Research), Partner site Heidelberg/Mannheim, University of Heidelberg, Germany (K.H., M. Busch, H.A.K., P.M.); Center for Translational Medicine, Jefferson Medical College, Philadelphia, PA (K.P., P.M.); Systems Biology of the Cellular Microenvironment Group, Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University, Freiburg, Germany (H.B., M. Boerries); German Cancer Consortium (DKTK), Freiburg, Germany (H.B., M. Boerries); and German Cancer Research Center (DKFZ), Heidelberg, Germany (H.B., M. Boerries).
authors.forename: Vassilios J
authors.initials: VJ
authors.lastname: Bezzeridis
authors.affiliation: From the Cardiovascular Research Center, Massachusetts General Hospital (C.L., F.D., A.R.), Cardiovascular Institute, Beth Israel Deaconess Medical Center (F.D.), and Boston Children's Hospital (V.J.B.), Harvard Medical School, Boston, MA; Molecular and Translational Cardiology (MTC), Department of Internal Medicine III, University Hospital Heidelberg, Germany (C.L., J.H., I.K., M. Busch, P.M.); Department of Pathology and Immunology, University of Geneva, Switzerland (M.-L.B.-P.); DZHK (German Center for Cardiovascular Research), Partner site Heidelberg/Mannheim, University of Heidelberg, Germany (K.H., M. Busch, H.A.K., P.M.); Center for Translational Medicine, Jefferson Medical College, Philadelphia, PA (K.P., P.M.); Systems Biology of the Cellular Microenvironment Group, Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University, Freiburg, Germany (H.B., M. Boerries); German Cancer Consortium (DKTK), Freiburg, Germany (H.B., M. Boerries); and German Cancer Research Center (DKFZ), Heidelberg, Germany (H.B., M. Boerries).
authors.forename: Isabel
authors.initials: I
authors.lastname: Krämer
authors.affiliation: From the Cardiovascular Research Center, Massachusetts General Hospital (C.L., F.D., A.R.), Cardiovascular Institute, Beth Israel Deaconess Medical Center (F.D.), and Boston Children's Hospital (V.J.B.), Harvard Medical School, Boston, MA; Molecular and Translational Cardiology (MTC), Department of Internal Medicine III, University Hospital Heidelberg, Germany (C.L., J.H., I.K., M. Busch, P.M.); Department of Pathology and Immunology, University of Geneva, Switzerland (M.-L.B.-P.); DZHK (German Center for Cardiovascular Research), Partner site Heidelberg/Mannheim, University of Heidelberg, Germany (K.H., M. Busch, H.A.K., P.M.); Center for Translational Medicine, Jefferson Medical College, Philadelphia, PA (K.P., P.M.); Systems Biology of the Cellular Microenvironment Group, Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University, Freiburg, Germany (H.B., M. Boerries); German Cancer Consortium (DKTK), Freiburg, Germany (H.B., M. Boerries); and German Cancer Research Center (DKFZ), Heidelberg, Germany (H.B., M. Boerries).
authors.forename: Marie-Luce
authors.initials: ML
authors.lastname: Bochaton-Piallat
authors.affiliation: From the Cardiovascular Research Center, Massachusetts General Hospital (C.L., F.D., A.R.), Cardiovascular Institute, Beth Israel Deaconess Medical Center (F.D.), and Boston Children's Hospital (V.J.B.), Harvard Medical School, Boston, MA; Molecular and Translational Cardiology (MTC), Department of Internal Medicine III, University Hospital Heidelberg, Germany (C.L., J.H., I.K., M. Busch, P.M.); Department of Pathology and Immunology, University of Geneva, Switzerland (M.-L.B.-P.); DZHK (German Center for Cardiovascular Research), Partner site Heidelberg/Mannheim, University of Heidelberg, Germany (K.H., M. Busch, H.A.K., P.M.); Center for Translational Medicine, Jefferson Medical College, Philadelphia, PA (K.P., P.M.); Systems Biology of the Cellular Microenvironment Group, Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University, Freiburg, Germany (H.B., M. Boerries); German Cancer Consortium (DKTK), Freiburg, Germany (H.B., M. Boerries); and German Cancer Research Center (DKFZ), Heidelberg, Germany (H.B., M. Boerries).
authors.forename: Kristóf
authors.initials: K
authors.lastname: Hirschberg
authors.affiliation: From the Cardiovascular Research Center, Massachusetts General Hospital (C.L., F.D., A.R.), Cardiovascular Institute, Beth Israel Deaconess Medical Center (F.D.), and Boston Children's Hospital (V.J.B.), Harvard Medical School, Boston, MA; Molecular and Translational Cardiology (MTC), Department of Internal Medicine III, University Hospital Heidelberg, Germany (C.L., J.H., I.K., M. Busch, P.M.); Department of Pathology and Immunology, University of Geneva, Switzerland (M.-L.B.-P.); DZHK (German Center for Cardiovascular Research), Partner site Heidelberg/Mannheim, University of Heidelberg, Germany (K.H., M. Busch, H.A.K., P.M.); Center for Translational Medicine, Jefferson Medical College, Philadelphia, PA (K.P., P.M.); Systems Biology of the Cellular Microenvironment Group, Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University, Freiburg, Germany (H.B., M. Boerries); German Cancer Consortium (DKTK), Freiburg, Germany (H.B., M. Boerries); and German Cancer Research Center (DKFZ), Heidelberg, Germany (H.B., M. Boerries).
authors.forename: Martin
authors.initials: M
authors.lastname: Busch
authors.affiliation: From the Cardiovascular Research Center, Massachusetts General Hospital (C.L., F.D., A.R.), Cardiovascular Institute, Beth Israel Deaconess Medical Center (F.D.), and Boston Children's Hospital (V.J.B.), Harvard Medical School, Boston, MA; Molecular and Translational Cardiology (MTC), Department of Internal Medicine III, University Hospital Heidelberg, Germany (C.L., J.H., I.K., M. Busch, P.M.); Department of Pathology and Immunology, University of Geneva, Switzerland (M.-L.B.-P.); DZHK (German Center for Cardiovascular Research), Partner site Heidelberg/Mannheim, University of Heidelberg, Germany (K.H., M. Busch, H.A.K., P.M.); Center for Translational Medicine, Jefferson Medical College, Philadelphia, PA (K.P., P.M.); Systems Biology of the Cellular Microenvironment Group, Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University, Freiburg, Germany (H.B., M. Boerries); German Cancer Consortium (DKTK), Freiburg, Germany (H.B., M. Boerries); and German Cancer Research Center (DKFZ), Heidelberg, Germany (H.B., M. Boerries).
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.affiliation: From the Cardiovascular Research Center, Massachusetts General Hospital (C.L., F.D., A.R.), Cardiovascular Institute, Beth Israel Deaconess Medical Center (F.D.), and Boston Children's Hospital (V.J.B.), Harvard Medical School, Boston, MA; Molecular and Translational Cardiology (MTC), Department of Internal Medicine III, University Hospital Heidelberg, Germany (C.L., J.H., I.K., M. Busch, P.M.); Department of Pathology and Immunology, University of Geneva, Switzerland (M.-L.B.-P.); DZHK (German Center for Cardiovascular Research), Partner site Heidelberg/Mannheim, University of Heidelberg, Germany (K.H., M. Busch, H.A.K., P.M.); Center for Translational Medicine, Jefferson Medical College, Philadelphia, PA (K.P., P.M.); Systems Biology of the Cellular Microenvironment Group, Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University, Freiburg, Germany (H.B., M. Boerries); German Cancer Consortium (DKTK), Freiburg, Germany (H.B., M. Boerries); and German Cancer Research Center (DKFZ), Heidelberg, Germany (H.B., M. Boerries).
authors.forename: Karsten
authors.initials: K
authors.lastname: Peppel
authors.affiliation: From the Cardiovascular Research Center, Massachusetts General Hospital (C.L., F.D., A.R.), Cardiovascular Institute, Beth Israel Deaconess Medical Center (F.D.), and Boston Children's Hospital (V.J.B.), Harvard Medical School, Boston, MA; Molecular and Translational Cardiology (MTC), Department of Internal Medicine III, University Hospital Heidelberg, Germany (C.L., J.H., I.K., M. Busch, P.M.); Department of Pathology and Immunology, University of Geneva, Switzerland (M.-L.B.-P.); DZHK (German Center for Cardiovascular Research), Partner site Heidelberg/Mannheim, University of Heidelberg, Germany (K.H., M. Busch, H.A.K., P.M.); Center for Translational Medicine, Jefferson Medical College, Philadelphia, PA (K.P., P.M.); Systems Biology of the Cellular Microenvironment Group, Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University, Freiburg, Germany (H.B., M. Boerries); German Cancer Consortium (DKTK), Freiburg, Germany (H.B., M. Boerries); and German Cancer Research Center (DKFZ), Heidelberg, Germany (H.B., M. Boerries).
authors.forename: Anthony
authors.initials: A
authors.lastname: Rosenzweig
authors.affiliation: From the Cardiovascular Research Center, Massachusetts General Hospital (C.L., F.D., A.R.), Cardiovascular Institute, Beth Israel Deaconess Medical Center (F.D.), and Boston Children's Hospital (V.J.B.), Harvard Medical School, Boston, MA; Molecular and Translational Cardiology (MTC), Department of Internal Medicine III, University Hospital Heidelberg, Germany (C.L., J.H., I.K., M. Busch, P.M.); Department of Pathology and Immunology, University of Geneva, Switzerland (M.-L.B.-P.); DZHK (German Center for Cardiovascular Research), Partner site Heidelberg/Mannheim, University of Heidelberg, Germany (K.H., M. Busch, H.A.K., P.M.); Center for Translational Medicine, Jefferson Medical College, Philadelphia, PA (K.P., P.M.); Systems Biology of the Cellular Microenvironment Group, Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University, Freiburg, Germany (H.B., M. Boerries); German Cancer Consortium (DKTK), Freiburg, Germany (H.B., M. Boerries); and German Cancer Research Center (DKFZ), Heidelberg, Germany (H.B., M. Boerries).
authors.forename: Hauke
authors.initials: H
authors.lastname: Busch
authors.affiliation: From the Cardiovascular Research Center, Massachusetts General Hospital (C.L., F.D., A.R.), Cardiovascular Institute, Beth Israel Deaconess Medical Center (F.D.), and Boston Children's Hospital (V.J.B.), Harvard Medical School, Boston, MA; Molecular and Translational Cardiology (MTC), Department of Internal Medicine III, University Hospital Heidelberg, Germany (C.L., J.H., I.K., M. Busch, P.M.); Department of Pathology and Immunology, University of Geneva, Switzerland (M.-L.B.-P.); DZHK (German Center for Cardiovascular Research), Partner site Heidelberg/Mannheim, University of Heidelberg, Germany (K.H., M. Busch, H.A.K., P.M.); Center for Translational Medicine, Jefferson Medical College, Philadelphia, PA (K.P., P.M.); Systems Biology of the Cellular Microenvironment Group, Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University, Freiburg, Germany (H.B., M. Boerries); German Cancer Consortium (DKTK), Freiburg, Germany (H.B., M. Boerries); and German Cancer Research Center (DKFZ), Heidelberg, Germany (H.B., M. Boerries). clerchenmueller@mgh.harvard.edu m.boerries@dkfz.de.
authors.forename: Melanie
authors.initials: M
authors.lastname: Boerries
authors.affiliation: From the Cardiovascular Research Center, Massachusetts General Hospital (C.L., F.D., A.R.), Cardiovascular Institute, Beth Israel Deaconess Medical Center (F.D.), and Boston Children's Hospital (V.J.B.), Harvard Medical School, Boston, MA; Molecular and Translational Cardiology (MTC), Department of Internal Medicine III, University Hospital Heidelberg, Germany (C.L., J.H., I.K., M. Busch, P.M.); Department of Pathology and Immunology, University of Geneva, Switzerland (M.-L.B.-P.); DZHK (German Center for Cardiovascular Research), Partner site Heidelberg/Mannheim, University of Heidelberg, Germany (K.H., M. Busch, H.A.K., P.M.); Center for Translational Medicine, Jefferson Medical College, Philadelphia, PA (K.P., P.M.); Systems Biology of the Cellular Microenvironment Group, Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University, Freiburg, Germany (H.B., M. Boerries); German Cancer Consortium (DKTK), Freiburg, Germany (H.B., M. Boerries); and German Cancer Research Center (DKFZ), Heidelberg, Germany (H.B., M. Boerries).
authors.forename: Patrick
authors.initials: P
authors.lastname: Most
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D019295:Computational Biology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D020869:Gene Expression Profiling / Q000379:methods; D053263:Gene Regulatory Networks; D020868:Gene Silencing; D006801:Humans; D008297:Male; D050828:Protein Inhibitors of Activated STAT / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D017207:Rats, Sprague-Dawley; D062326:Re-Epithelialization; D000075383:S100 Calcium Binding Protein A6; D009418:S100 Proteins / Q000235:genetics / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D025841:Small Ubiquitin-Related Modifier Proteins / Q000235:genetics / Q000378:metabolism; D034421:Sus scrofa; D013997:Time Factors; D059467:Transcriptome; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D057772:Vascular System Injuries / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D000943:Antigens, Differentiation; D018797:Cell Cycle Proteins; C106529:PIAS1 protein, human; D050828:Protein Inhibitors of Activated STAT; D000075383:S100 Calcium Binding Protein A6; D009418:S100 Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D025841:Small Ubiquitin-Related Modifier Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C062010:leu-13 antigen; C055351:S100A6 protein, human
keywords: S100A6 protein, human; STAT1 transcription factor; cell cycle; endothelium; protein inhibitors of activated STAT