ArticleJournal of molecular medicine (Berlin, Germany)2007
Bilirubin-induced cell toxicity involves PTEN activation through an APE1/Ref-1-dependent pathway.
Article in Journal of molecular medicine (Berlin, Germany), 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
What it found
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Who cites it
24 citing papers in PubMed, 2 citations in OpenAlex.
- The Role of ER Stress in Bilirubin Neurotoxicity: A Complex Molecular Network.Antioxidants (Basel, Switzerland) · 2026Review
- Article
- Role of APE1/Ref-1 in hydrogen peroxide-induced apoptosis in human renal HK-2 cells.Kidney research and clinical practice · 2024Article
- A new parameter for predict the clinical outcome of patients with COVID-19 pneumonia: The direct/total bilirubin ratio.International journal of clinical practice · 2021Article
- The multifunctional APE1 DNA repair-redox signaling protein as a drug target in human disease.Drug discovery today · 2021Review
- Liver-lung interactions in acute respiratory distress syndrome.Intensive care medicine experimental · 2020Article
- Review
- Experimental models assessing bilirubin neurotoxicity.Pediatric research · 2020Review
- Friend or foe, the role of EGR-1 in cancer.Medical oncology (Northwood, London, England) · 2019Review
- Bilirubin-Induced Oxidative Stress Leads to DNA Damage in the Cerebellum of Hyperbilirubinemic Neonatal Mice and Activates DNA Double-Strand Break Repair Pathways in Human Cells.Oxidative medicine and cellular longevity · 2018Article
- Paradoxical induction of growth arrest and apoptosis by EGF via the up-regulation of PTEN by activating Redox factor-1/Egr-1 in human lung cancer cells.Oncotarget · 2017Article
- Glucose-6-Phosphate Dehydrogenase Deficiency and the Need for a Novel Treatment to Prevent Kernicterus.Clinics in perinatology · 2016Review
- Impairment of enzymatic antioxidant defenses is associated with bilirubin-induced neuronal cell death in the cerebellum of Ugt1 KO mice.Cell death & disease · 2015Article
- Biliverdin reductase: a target for cancer therapy?Frontiers in pharmacology · 2015Review
- End-tidal carbon monoxide and hemolysis.Journal of perinatology : official journal of the California Perinatal Association · 2014Review
- Role of the phosphatase PTEN in early vascular remodeling.PloS one · 2013Article
- Modulation of Mrp1 (ABCc1) and Pgp (ABCb1) by bilirubin at the blood-CSF and blood-brain barriers in the Gunn rat.PloS one · 2011Article
- Functional induction of the cystine-glutamate exchanger system Xc(-) activity in SH-SY5Y cells by unconjugated bilirubin.PloS one · 2011Article
- Pathophysiological preconditions promoting mixed "black" pigment plus cholesterol gallstones in a DeltaF508 mouse model of cystic fibrosis.American journal of physiology. Gastrointestinal and liver physiology · 2010Article
- A transcriptome analysis identifies molecular effectors of unconjugated bilirubin in human neuroblastoma SH-SY5Y cells.BMC genomics · 2009Article
Corrections and comments
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Authors and funding
9 authors at 4 institutions in 2 countries.
Funding
Abstract
Unconjugated bilirubin (UCB) is the major degradation product of the heme catabolism. A growing body of evidences suggests that UCB plays major biological effects by inhibiting cell proliferation in cancer cell lines and eliciting cell toxicity particularly in neurons and glial cells. Early molecular events responsible for bilirubin-induced cytotoxicity remain poorly understood. Using HeLa cells and mouse embryonic fibroblasts, we found that UCB at a concentration of free pigment (Bf) of 80 nM induced oxidative stress, promoting a significant increase in intracellular reactive oxygen species (ROS) and a decreased cell survival (by the MTT test). The ROS increase activated the antioxidant cell response through APE1/Ref-1, a master redox regulator in eukaryotic cells. Activation of APE1/Ref-1 was followed by a concomitant activation of Egr-1 transcription factor and by an upregulation of PTEN tumor suppressor, an Egr-1 target gene, leading to inhibition of cell growth. Blocking ROS generation with N-acetylcysteine pretreatment, restored cell survival, limited the upregulation of PTEN in response to UCB, and prevented the inhibition of cell proliferation. HeLa cells transfected with mutants of the PTEN promoter or silenced with APE1/Ref-1 small interference RNA confirmed that UCB modulates a signaling pathway involving APE1/Ref-1, Egr-1, and PTEN. These findings describe a new molecular pathway involved in the cytotoxic effects of UCB.
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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.