PMID- 21272161
OWN - NLM
STAT- MEDLINE
DCOM- 20110615
LR  - 20220321
IS  - 1349-7006 (Electronic)
IS  - 1347-9032 (Linking)
VI  - 102
IP  - 5
DP  - 2011 May
TI  - c-Jun N-terminal kinase activation by oxidative stress suppresses retinoid 
      signaling through proteasomal degradation of retinoic acid receptor alpha protein in 
      hepatic cells.
PG  - 934-41
LID - 10.1111/j.1349-7006.2011.01889.x [doi]
AB  - 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, RARalpha and RXRalpha 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 RARalpha protein level began to 
      decrease at 6 h after treatment and declined thereafter. However, RARalpha 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 RARalpha protein level reduced 
      by hydrogen peroxide. Anisomycin, an activator of JNK, reduced RARalpha protein. 
      Transfection of wild-type JNK-constitutive actively expressing plasmid, but not 
      kinase-negative JNK-expressing plasmid caused reduction of RARalpha protein. 
      Proteasomal degradation of RARalpha was observed after anisomycin treatment; however, 
      the mutant RARalpha, of which phosphorylation sites are replaced with alanines, was 
      not degradated. In hepatitis C virus (HCV)-related human liver tissues, 
      phospho-JNK and RARalpha 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 RARalpha, suggesting 
      that a vicious cycle between aberrant retinoid signaling and oxidative stress 
      accelerates hepatocarcinogenesis.
CI  - (c) 2011 Japanese Cancer Association.
FAU - Hoshikawa, Yoshiko
AU  - Hoshikawa Y
AD  - Division of Molecular and Genetic Medicine, Department of Genetic Medicine and 
      Regenerative Therapeutics, Graduate School of Medicine, Tottori University, 
      Yonago, Japan.
FAU - Kanki, Keita
AU  - Kanki K
FAU - Ashla, An Afida
AU  - Ashla AA
FAU - Arakaki, Yuta
AU  - Arakaki Y
FAU - Azumi, Junya
AU  - Azumi J
FAU - Yasui, Toshihiro
AU  - Yasui T
FAU - Tezuka, Yuta
AU  - Tezuka Y
FAU - Matsumi, Yoshiaki
AU  - Matsumi Y
FAU - Tsuchiya, Hiroyuki
AU  - Tsuchiya H
FAU - Kurimasa, Akihiro
AU  - Kurimasa A
FAU - Hisatome, Ichiro
AU  - Hisatome I
FAU - Hirano, Tadamichi
AU  - Hirano T
FAU - Fujimoto, Jiro
AU  - Fujimoto J
FAU - Kagechika, Hiroyuki
AU  - Kagechika H
FAU - Shomori, Kohei
AU  - Shomori K
FAU - Ito, Hisao
AU  - Ito H
FAU - Shiota, Goshi
AU  - Shiota G
LA  - eng
PT  - Journal Article
DEP - 20110224
PL  - England
TA  - Cancer Sci
JT  - Cancer science
JID - 101168776
RN  - 0 (Oxidants)
RN  - 0 (RARA protein, human)
RN  - 0 (Receptors, Retinoic Acid)
RN  - 0 (Retinoic Acid Receptor alpha)
RN  - 0 (Retinoid X Receptors)
RN  - 0 (Retinoids)
RN  - BBX060AN9V (Hydrogen Peroxide)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
RN  - EC 3.4.25.1 (Proteasome Endopeptidase Complex)
SB  - IM
MH  - Blotting, Western
MH  - Enzyme Activation/*physiology
MH  - Hepatocytes/*metabolism
MH  - Humans
MH  - Hydrogen Peroxide/pharmacology
MH  - Immunohistochemistry
MH  - JNK Mitogen-Activated Protein Kinases/*metabolism
MH  - Oxidants/pharmacology
MH  - Oxidative Stress/*physiology
MH  - Proteasome Endopeptidase Complex/*metabolism
MH  - Receptors, Retinoic Acid/*metabolism
MH  - Retinoic Acid Receptor alpha
MH  - Retinoid X Receptors/metabolism
MH  - Retinoids/metabolism
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - *Signal Transduction
MH  - Transcription, Genetic
EDAT- 2011/01/29 06:00
MHDA- 2011/06/16 06:00
CRDT- 2011/01/29 06:00
PHST- 2011/01/29 06:00 [entrez]
PHST- 2011/01/29 06:00 [pubmed]
PHST- 2011/06/16 06:00 [medline]
AID - 10.1111/j.1349-7006.2011.01889.x [doi]
PST - ppublish
SO  - Cancer Sci. 2011 May;102(5):934-41. doi: 10.1111/j.1349-7006.2011.01889.x. Epub 
      2011 Feb 24.