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Essential Roles of Raf/Extracellular Signal-regulated Kinase/Mitogen-activated Protein Kinase Pathway, YY1, and Ca2+ Influx in Growth Arrest of Human Vascular Smooth Muscle Cells by Bilirubin

  • The biological effects of bilirubin, still poorly understood, are concentration-dependent ranging from cell protection to toxicity. Here we present data that at high nontoxic physiological concentrations, bilirubin inhibits growth of proliferating human coronary artery smooth muscle cells by three events. It impairs the activation of Raf/ERK/MAPK pathway and the cellular Raf and cyclin D1 content that results in retinoblastoma protein hypophosphorylation on amino acids S608 and S780. These events impede the release of YY1 to the nuclei and its availability to regulate the expression of genes and to support cellular proliferation. Moreover, altered calcium influx and calpain II protease activation leads to proteolytical degradation of transcription factor YY1. We conclude that in the serum-stimulated human vascular smooth muscle primary cell cultures, bilirubin favors growth arrest, and we propose that this activity is regulated by its interaction with the Raf/ERK/MAPK pathway, effect on cyclin D1 and Raf content, altered retinoblastoma protein profile of hypophosphorylation, calcium influx, and YY1 proteolysis. We propose that these activities together culminate in diminished 5 S and 45 S ribosomal RNA synthesis and cell growth arrest. The observations provide important mechanistic insight into the molecular mechanisms underlying the transition of human vascular smooth muscle cells from proliferative to contractile phenotype and the role of bilirubin in this transition.

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Document Type:Article
Author:Marlon Stoeckius, Anna Erat, Tatsuya Fujikawa, Makoto Hiromura, Anna Koulova, Leo Otterbein, Cesario Bianchi, Edda Tobiasch, Yossi Dagon, Frank W. Sellke, Anny Usheva
Parent Title (English):The Journal of Biological Chemistry
First Page:15418
Last Page:15426
Publisher:American Society for Biochemistry and Molecular Biology
Place of publication:Rockville, MD
Publishing Institution:Hochschule Bonn-Rhein-Sieg
Date of first publication:2012/01/19
Embargo Date:2020/12/22
Copyright:© 2012 by The American Society for Biochemistry and Molecular Biology, Inc.
Funding:This work was supported, in whole or in part, by National Institutes of Health Grants R01HL062458 (to A. U.) and RO1HL46716 and RO1HL69024 (to F. W. S.). This work was also supported by a fellowship from the Swiss Public Health Institute, the Finnish Medical Society, and the Academy of Finland (to A. E.).
Keyword:Calcium; Calcium Intracellular Release; Cardiovascular Disease; Cell Cycle; Cell Differentiation; Cell Signaling; DNA Transcription; Transcription Regulation; Vascular Smooth Muscle Cells
Departments, institutes and facilities:Fachbereich Angewandte Naturwissenschaften
Dewey Decimal Classification (DDC):5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
Entry in this database:2015/04/02
Licence (German):License LogoCreative Commons - CC BY - Namensnennung 4.0 International