Switch from Mnt‐Max to Myc‐Max induces p53 and cyclin D1 expression and apoptosis during cholestasis in mouse and human hepatocytes†
Open accessAbstract
UNLABELLED: Toxic bile acids induce hepatocyte apoptosis, for which p53 and cyclin D1 have been implicated as underlying mediators. Both p53 and cyclin D1 are targets of c-Myc, which is also up-regulated in cholestasis. Myc and Mnt use Max as a cofactor for DNA binding. Myc-Max typically activates transcription via E-box binding. Mnt-Max also binds the E-box sequence but serves as a repressor and inhibits the enhancer activity of Myc-Max. The current work tested the hypothesis that the switch from Mnt-Max to Myc-Max is responsible for p53 and cyclin D1 up-regulation and apoptosis during cholestasis. Following common bile duct ligation or left hepatic bile duct ligation, the expression of p53, c-Myc, and cyclin D1 increased markedly, whereas Mnt expression decreased. Nuclear binding activity of Myc to the E-box element of p53 and cyclin D1 increased, whereas that of Mnt decreased in a time-dependent fashion. Lithocholic acid (LCA) treatment of primary human hepatocytes and HuH-7 cells induced a similar switch from Mnt to Myc and increased p53 and cyclin D1 promoter activity and endogenous p53 and cyclin D1 expression and apoptosis. Blocking c-Myc induction in HuH-7 cells prevented the LCA-mediated increase in p53 and cyclin D1 expression and reduced apoptosis. Lowering Mnt expression further enhanced LCA's inductive effect on p53 and cyclin D1. Bile duct-ligated mice treated with a lentivirus harboring c-myc small interfering RNA were protected from hepatic induction of p53 and cyclin D1, a switch from Mnt to Myc nuclear binding to E-box, and hepatocyte apoptosis. CONCLUSION: The switch from Mnt to Myc during bile duct ligation and in hepatocytes treated with LCA is responsible for the induction in p53 and cyclin D1 expression and contributes to apoptosis.
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CHR reduces c-Myc mRNA levels in both WT and CarKO mice post-PHx.
“In line with previous findings that elevated BAs can induce c-Myc expression,37,38 CHR reduced c-Myc mRNA levels in both WT and CarKO mice post-PHx (Figure 9A).”
From Constitutive Androstane Receptor Regulates Bile Acid Homeostasis and Metabolism During Liver Regeneration (2026) · cites this paper as [37]
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- Authors
- Yang, H., Li, T. W. H., Ko, K. S., Xia, M., & Lu, S. C.
- Affiliations
- University of Southern California (US)
- Corresponding author
- Yang, Heping
- Lu, Shelly C.
- Venue
- Hepatology
- Published
- 2009-03
- Volume
- 49
- Issue
- 3
- Pages
- 860-870
- ISSN
- 0270-9139 (ISSN-L)
- PMC
- PMC4427513
- OpenAlex
- W2070024353
- Cited by
- 58
- References
- 32
- Citations by year
- 2026: 3 · 2024: 3 · 2023: 1 · 2022: 2 · 2021: 5 · 2020: 3 · 2019: 3 · 2018: 2 · 2017: 6 · 2016: 7 · 2015: 4 · 2014: 3 · 2013: 7 · 2012: 1
- FWCI
- 1.97
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (DK45334, DK51719)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK51719, R01DK045334, DK-45334, P30-DK-48522, P30DK048522, R56DK045334, R01DK051719)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- cholestasis, hepatocyte apoptosis, c-Myc, p53, cyclin D1, bile acids, lithocholic acid, E-box binding, bile duct ligation
- MeSH terms
- Animals, Base Sequence, Cells, Cultured, Cholestasis, Disease Models, Animal, Humans, Ligation, Lithocholic Acid, Male, Mice, Inbred C57BL, Repressor Proteins, Signal Transduction, Tumor Suppressor Protein p53, Proto-Oncogene Proteins c-myc, Apoptosis, Cyclin D1, Hepatocytes, Cell Line, Tumor, Mice, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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