Switch from Mnt-Max to Myc-Max Induces p53 and cyclin D1 Expression and Apoptosis During Cholestasis in Mice and Human Hepatocytes

摘要

Background and rationaleToxic 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 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.