TY  - JOUR
U1  - Zeitschriftenartikel, wissenschaftlich - begutachtet (reviewed)
A1  - Stoeckius, Marlon
A1  - Erat, Anna
A1  - Fujikawa, Tatsuya
A1  - Hiromura, Makoto
A1  - Koulova, Anna
A1  - Otterbein, Leo
A1  - Bianchi, Cesario
A1  - Tobiasch, Edda
A1  - Dagon, Yossi
A1  - Sellke, Frank W.
A1  - Usheva, Anny
T1  - 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
JF  - The Journal of Biological Chemistry
N2  - 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.
KW  - Calcium
KW  - Calcium Intracellular Release
KW  - Cardiovascular Disease
KW  - Cell Cycle
KW  - Cell Differentiation
KW  - Cell Signaling
KW  - DNA Transcription
KW  - Transcription Regulation
KW  - Vascular Smooth Muscle Cells
UN  - https://nbn-resolving.org/urn:nbn:de:hbz:1044-opus-9586
SN  - 0021-9258
SS  - 0021-9258
U6  - https://doi.org/10.1074/jbc.M111.266510
DO  - https://doi.org/10.1074/jbc.M111.266510
PM  - 22262839
VL  - 287
IS  - 19
SP  - 15418
EP  - 15426
PB  - American Society for Biochemistry and Molecular Biology
CY  - Rockville, MD
ER  -