ArticleThe Journal of biological chemistry2012
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.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 31 citations in OpenAlex.
- Bilirubin and the Yellow Players in Ferroptosis: A Delicate Balance in Human Health and Disease, with a Focus on the Liver, Cardiovascular System, and Brain.Biomolecules · 2026Review
- FGF4 initiates X-chromosome inactivation via activating YY1 and prompting loss of pluripotency factors.The EMBO journal · 2026Article
- Bilirubin metabolism in relation to cancer.Frontiers in oncology · 2025Review
- Toward nanotechnology-enabled application of bilirubin in the treatment and diagnosis of various civilization diseases.Materials today. Bio · 2023Review
- Molecular Mechanisms of the Melatonin Receptor Pathway Linking Circadian Rhythm to Type 2 Diabetes Mellitus.Nutrients · 2023Review
- Calpain inhibition decreases myocardial fibrosis in chronically ischemic hypercholesterolemic swine.The Journal of thoracic and cardiovascular surgery · 2022Article
- Direct Bilirubin Levels Predict Long-Term Outcomes in Patients With Acute Coronary Syndrome Under Different Glucose Metabolism Status: A 6.5-Year Cohort Study of Three-Vessel Disease.Frontiers in cardiovascular medicine · 2021Article
- Targeting Heme Oxygenase-1 in the Arterial Response to Injury and Disease.Antioxidants (Basel, Switzerland) · 2020Review
- Activated MEK/ERK Pathway Drives Widespread and Coordinated Overexpression of UHRF1 and DNMT1 in Cancer cells.Scientific reports · 2019Article
- Serum bilirubin is negatively associated with white blood cell count.Clinics (Sao Paulo, Brazil) · 2019Article
- Beyond a Measure of Liver Function-Bilirubin Acts as a Potential Cardiovascular Protector in Chronic Kidney Disease Patients.International journal of molecular sciences · 2018Review
- Small Molecules Enhance Scaffold-Based Bone Grafts via Purinergic Receptor Signaling in Stem Cells.International journal of molecular sciences · 2018Review
- Regulatory role of heme oxygenase-1 in silica-induced lung injury.Respiratory research · 2018Article
- Inflammatory signature of cerebellar neurodegeneration during neonatal hyperbilirubinemia in Ugt1Journal of neuroinflammation · 2017Article
- Heme Oxygenases in Cardiovascular Health and Disease.Physiological reviews · 2016Review
- Oncogenic EGFR Represses the TET1 DNA Demethylase to Induce Silencing of Tumor Suppressors in Cancer Cells.Cell reports · 2016Article
- Nrf2/Keap1 system regulates vascular smooth muscle cell apoptosis for vascular homeostasis: role in neointimal formation after vascular injury.Scientific reports · 2016Article
- Conjugated bilirubin triggers anemia by inducing erythrocyte death.Hepatology (Baltimore, Md.) · 2015Article
- Transcriptional profiling reveals functional links between RasGrf1 and Pttg1 in pancreatic beta cells.BMC genomics · 2014Article
- Stem Cells on Biomaterials for Synthetic Grafts to Promote Vascular Healing.Journal of clinical medicine · 2014Review
Corrections and comments
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Authors and funding
11 authors at 6 institutions in 4 countries.
Funding
Abstract
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.