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Switch from Mnt-Max to Myc-Max induces p53 and cyclin D1 expression and apoptosis during cholestasis in mouse and
Heping Yang1, Tony W H Li, Kwang Suk Ko
1Division of Gastroenterology and Liver Diseases, USC Research Center for Liver Diseases, USC-UCLA Research Center for Alcoholic Liver and Pancreatic Diseases, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
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.
Insights
A shift from Mnt to Myc proteins drives p53 and cyclin D1 increases, leading to hepatocyte apoptosis in cholestasis. This molecular switch is key to understanding liver injury during bile duct obstruction.
Area of Science:
- Hepatology
- Molecular Biology
- Cell Death Research
Background:
- Toxic bile acids cause hepatocyte apoptosis, with p53 and cyclin D1 implicated as mediators.
- c-Myc, a regulator of p53 and cyclin D1, is upregulated during cholestasis (bile duct obstruction).
- Myc-Max and Mnt-Max complexes bind DNA via Max, with Myc-Max activating and Mnt-Max repressing transcription.
Purpose of the Study:
- To investigate if a switch from Mnt-Max to Myc-Max complex activity underlies p53 and cyclin D1 upregulation and apoptosis in cholestasis.
- To determine the role of c-Myc in mediating the effects of lithocholic acid (LCA) on hepatocytes.
- To assess the therapeutic potential of inhibiting c-Myc in cholestatic liver injury.
Main Methods:
- Common bile duct ligation (CBDL) in mice to induce cholestasis.
- Treatment of primary human hepatocytes and HuH-7 cells with lithocholic acid (LCA).
- Analysis of protein expression (p53, c-Myc, cyclin D1, Mnt), nuclear protein-DNA binding activity, and apoptosis.
- Gene silencing of c-Myc using small interfering RNA (siRNA) in cell culture and in vivo.
Main Results:
- CBDL and LCA treatment increased p53, c-Myc, and cyclin D1 expression while decreasing Mnt expression.
- Nuclear Myc binding to p53 and cyclin D1 promoter E-box elements increased, while Mnt binding decreased.
- LCA-induced apoptosis and p53/cyclin D1 upregulation were blocked by inhibiting c-Myc.
- Reduced Mnt expression potentiated LCA's effects, and c-Myc inhibition protected mice from cholestasis-induced liver injury.
Conclusions:
- The switch from Mnt to Myc activity is responsible for inducing p53 and cyclin D1 expression during cholestasis.
- This molecular switch significantly contributes to hepatocyte apoptosis in bile duct ligation models.
- Targeting the Mnt-Myc switch presents a potential therapeutic strategy for cholestatic liver diseases.
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