Antiapoptotic effect of c-Jun N-terminal Kinase-1 through Mcl-1 stabilization in TNF-induced hepatocyte apoptosis

• Published in: Gastroenterology (New York, N.Y. 1943) Vol. 136; no. 4; p. 1423
• Main Authors: Kodama, Yuzo, Taura, Kojiro, Miura, Kouichi, Schnabl, Bernd, Osawa, Yosuke, Brenner, David A
• Format: Journal Article
• Language: English
• Published: United States 01.04.2009
• Subjects: Animals; Apoptosis - physiology; Cells, Cultured; Disease Models, Animal; Female; Gene Deletion; Hepatocytes - metabolism; Hepatocytes - pathology; Liver Diseases - metabolism; Liver Diseases - pathology; Male; Mice; Mice, Knockout; Mitogen-Activated Protein Kinase 8 - genetics; Mitogen-Activated Protein Kinase 8 - metabolism; Mitogen-Activated Protein Kinase 9 - genetics; Mitogen-Activated Protein Kinase 9 - metabolism; Myeloid Cell Leukemia Sequence 1 Protein; Phosphorylation; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; Signal Transduction - physiology; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 1528-0012
• DOI: 10.1053/j.gastro.2008.12.064

c-Jun N-terminal Kinase (JNK) is a key regulator in tumor necrosis factor (TNF)-mediated liver injury. However, distinct roles for JNK1 and JNK2 in hepatocyte apoptosis are still unresolved. Although myeloid cell leukemia-1 (Mcl-1) has been reported as a substrate of JNK, the role of Mcl-1 and its functional regulation by JNK in TNF-induced hepatocyte apoptosis and liver injury remain to be elucidated. TNF-induced hepatocyte apoptosis was investigated in wild-type, jnk1-/- and jnk2-/- mice in vitro and in the galactosamine/TNF (GalN/TNF) liver injury model. For further analysis, we used adenoviruses expressing wild-type Mcl-1 or its substitution mutant, and the Cre/loxP system (mcl-1f/f) to delete mcl-1. jnk2-/- Hepatocytes showed increased Mcl-1 expression and were more resistant to TNF-induced apoptosis compared with wild-type or jnk1-/- hepatocytes. Increased Mcl-1 expression in jnk2-/- hepatocytes correlated with their JNK activity, which is mediated by residual JNK1 and higher than in wild-type or jnk1-/- hepatocytes. JNK activation led to phosphorylation of Mcl-1 in hepatocytes, and this increased the half-life of the Mcl-1 protein. Overexpression of Mcl-1 confirmed its antiapoptotic effect in TNF-induced hepatocyte apoptosis in vitro and in vivo. Deletion of mcl-1 in jnk2-/- hepatocytes increased TNF-induced hepatocyte apoptosis both in vitro and in GalN/TNF-induced liver injury model. jnk2-/- Hepatocytes are resistant to TNF-induced apoptosis. Activated JNK1 contributes to this antiapoptotic phenotype of jnk2-/- hepatocytes through phosphorylation-mediated stabilization of Mcl-1.