A liver full of JNK: signaling in regulation of cell function and disease pathogenesis, and clinical approaches.
c-Jun-N-terminal kinase (JNK) is a mitogen-activated protein kinase family member that is activated by diverse stimuli, including cytokines (such as tumor necrosis factor and interleukin-1), reactive oxygen species (ROS), pathogens, toxins, drugs, endoplasmic reticulum stress, free fatty acids, and metabolic changes. Upon activation, JNK induces multiple biologic events through the transcription factor activator protein-1 and transcription-independent control of effector molecules. JNK isozymes regulate cell death and survival, differentiation, proliferation, ROS accumulation, metabolism, insulin signaling, and carcinogenesis in the liver. The biologic functions of JNK are isoform, cell type, and context dependent. Recent studies using genetically engineered mice showed that loss or hyperactivation of the JNK pathway contributes to the development of inflammation, fibrosis, cancer growth, and metabolic diseases that include obesity, hepatic steatosis, and insulin resistance. We review the functions and pathways of JNK in liver physiology and pathology and discuss findings from preclinical studies with JNK inhibitors.
Department of Medicine, University of California, La Jolla, CA, USA. ekseki@ucsd.edu
Ekihiro
E
Seki
David A
DA
Brenner
Michael
M
Karin
D000082:Acetaminophen / Q000009:adverse effects; D018712:Analgesics, Non-Narcotic / Q000009:adverse effects; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism; D016923:Cell Death; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy / Q000378:metabolism; D005234:Fatty Liver / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D008099:Liver / Q000378:metabolism* / Q000502:physiology / Q000503:physiopathology; D008107:Liver Diseases / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism; D008115:Liver Regeneration; D016031:Liver Transplantation; D020935:MAP Kinase Signaling System; D024821:Metabolic Syndrome / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D055031:Primary Graft Dysfunction / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use
D018712:Analgesics, Non-Narcotic; D015415:Biomarkers; D047428:Protein Kinase Inhibitors; D000082:Acetaminophen; D048031:JNK Mitogen-Activated Protein Kinases