These tools will no longer be maintained as of December 31, 2024. Archived website can be found here. PubMed4Hh GitHub repository can be found here. Contact NLM Customer Service if you have questions.


Pubmed for Handhelds

PUBMED FOR HANDHELDS

Search MEDLINE/PubMed

  • Title: Antiapoptotic effect of c-Jun N-terminal Kinase-1 through Mcl-1 stabilization in TNF-induced hepatocyte apoptosis.
    Author: Kodama Y, Taura K, Miura K, Schnabl B, Osawa Y, Brenner DA.
    Journal: Gastroenterology; 2009 Apr; 136(4):1423-34. PubMed ID: 19249395.
    Abstract:
    BACKGROUND & AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
    [Abstract] [Full Text] [Related] [New Search]