title: c-Jun N-terminal kinase activation by oxidative stress suppresses retinoid signaling through proteasomal degradation of retinoic acid receptor α protein in hepatic cells.
abstract: We previously reported that impaired retinoid signaling causes hepatocellular carcinoma (HCC) through oxidative stress. However, the interaction between oxidative stress and retinoid signaling has not been fully understood. To address this issue, the effects of hydrogen peroxide on the transcriptional activity of RAR/RXR heterodimers, RARα and RXRα proteins and intracellular signaling pathways were examined. The transcriptional activity of RAR/RXR examined by the DR5-tk-Luc reporter assay was significantly suppressed. The RARα protein level began to decrease at 6 h after treatment and declined thereafter. However, RARα mRNA were not changed. Activation of extracellular regulated kinases (ERK), p38, c-Jun N-terminal kinase (JNK) and Akt was observed after treatment of hydrogen peroxide. SP600125, an inhibitor of JNK, reversed the RARα protein level reduced by hydrogen peroxide. Anisomycin, an activator of JNK, reduced RARα protein. Transfection of wild-type JNK-constitutive actively expressing plasmid, but not kinase-negative JNK-expressing plasmid caused reduction of RARα protein. Proteasomal degradation of RARα was observed after anisomycin treatment; however, the mutant RARα, of which phosphorylation sites are replaced with alanines, was not degradated. In hepatitis C virus (HCV)-related human liver tissues, phospho-JNK and RARα reciprocally expressed with the progression of liver disease. Finally, the staining of 8-OHdG and thioredoxin was increased with the disease progression. These data indicate that JNK activation by oxidative stress suppresses retinoid signaling through proteasomal degradation of RARα, suggesting that a vicious cycle between aberrant retinoid signaling and oxidative stress accelerates hepatocarcinogenesis.
authors.affiliation: Division of Molecular and Genetic Medicine, Department of Genetic Medicine and Regenerative Therapeutics, Graduate School of Medicine, Tottori University, Yonago, Japan.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Hoshikawa
authors.forename: Keita
authors.initials: K
authors.lastname: Kanki
authors.forename: An Afida
authors.initials: AA
authors.lastname: Ashla
authors.forename: Yuta
authors.initials: Y
authors.lastname: Arakaki
authors.forename: Junya
authors.initials: J
authors.lastname: Azumi
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Yasui
authors.forename: Yuta
authors.initials: Y
authors.lastname: Tezuka
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Matsumi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tsuchiya
authors.forename: Akihiro
authors.initials: A
authors.lastname: Kurimasa
authors.forename: Ichiro
authors.initials: I
authors.lastname: Hisatome
authors.forename: Tadamichi
authors.initials: T
authors.lastname: Hirano
authors.forename: Jiro
authors.initials: J
authors.lastname: Fujimoto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kagechika
authors.forename: Kohei
authors.initials: K
authors.lastname: Shomori
authors.forename: Hisao
authors.initials: H
authors.lastname: Ito
authors.forename: Goshi
authors.initials: G
authors.lastname: Shiota
mesh_terms: D015153:Blotting, Western; D004789:Enzyme Activation / Q000502:physiology*; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007150:Immunohistochemistry; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors / Q000378:metabolism; D012176:Retinoids / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D016877:Oxidants; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D012176:Retinoids; D006861:Hydrogen Peroxide; D048031:JNK Mitogen-Activated Protein Kinases; D046988:Proteasome Endopeptidase Complex