PMID- 23620592
OWN - NLM
STAT- MEDLINE
DCOM- 20130821
LR  - 20211203
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 288
IP  - 24
DP  - 2013 Jun 14
TI  - Wnt/beta-catenin signaling protects mouse liver against oxidative stress-induced 
      apoptosis through the inhibition of forkhead transcription factor FoxO3.
PG  - 17214-24
LID - 10.1074/jbc.M112.445965 [doi]
AB  - Numerous liver diseases are associated with extensive oxidative tissue damage. It 
      is well established that Wnt/beta-catenin signaling directs multiple hepatocellular 
      processes, including development, proliferation, regeneration, nutrient 
      homeostasis, and carcinogenesis. It remains unexplored whether Wnt/beta-catenin 
      signaling provides hepatocyte protection against hepatotoxin-induced apoptosis. 
      Conditional, liver-specific beta-catenin knockdown (KD) mice and their wild-type 
      littermates were challenged by feeding with a hepatotoxin 
      3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet to induce chronic oxidative 
      liver injury. Following the DDC diet, mice with beta-catenin-deficient hepatocytes 
      demonstrate increased liver injury, indicating an important role of beta-catenin 
      signaling for liver protection against oxidative stress. This finding was further 
      confirmed in AML12 hepatocytes with beta-catenin signaling manipulation in vitro 
      using paraquat, a known oxidative stress inducer. Immunofluorescence staining 
      revealed an intense nuclear FoxO3 staining in beta-catenin-deficient livers, 
      suggesting active FoxO3 signaling in response to DDC-induced liver injury when 
      compared with wild-type controls. Consistently, FoxO3 target genes p27 and Bim 
      were significantly induced in beta-catenin KD livers. Conversely, SGK1, a beta-catenin 
      target gene, was significantly impaired in beta-catenin KD hepatocytes that failed 
      to inactivate FoxO3. Furthermore, shRNA-mediated deletion of FoxO3 increased 
      hepatocyte resistance to oxidative stress-induced apoptosis, confirming a 
      proapoptotic role of FoxO3 in the stressed liver. Our findings suggest that 
      Wnt/beta-catenin signaling is required for hepatocyte protection against oxidative 
      stress-induced apoptosis. The inhibition of FoxO through its phosphorylation by 
      beta-catenin-induced SGK1 expression reduces the apoptotic function of FoxO3, 
      resulting in increased hepatocyte survival. These findings have relevance for 
      future therapies directed at hepatocyte protection, regeneration, and anti-cancer 
      treatment.
FAU - Tao, Guo-Zhong
AU  - Tao GZ
AD  - Department of Surgery, Stanford University School of Medicine, Stanford, 
      California 94305-5148, USA.
FAU - Lehwald, Nadja
AU  - Lehwald N
FAU - Jang, Kyu Yun
AU  - Jang KY
FAU - Baek, Joy
AU  - Baek J
FAU - Xu, Baohui
AU  - Xu B
FAU - Omary, M Bishr
AU  - Omary MB
FAU - Sylvester, Karl G
AU  - Sylvester KG
LA  - eng
GR  - P30 DK056339/DK/NIDDK NIH HHS/United States
GR  - R01 DK047918/DK/NIDDK NIH HHS/United States
GR  - DK56339/DK/NIDDK NIH HHS/United States
GR  - DK47918/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20130425
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (3,5-diethoxycarbonyl-1,4-dihydrocollidine)
RN  - 0 (Apoptosis Regulatory Proteins)
RN  - 0 (Forkhead Box Protein O3)
RN  - 0 (Forkhead Transcription Factors)
RN  - 0 (FoxO3 protein, mouse)
RN  - 0 (Immediate-Early Proteins)
RN  - 0 (Pyridines)
RN  - 0 (RNA, Small Interfering)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (serum-glucocorticoid regulated kinase)
RN  - PLG39H7695 (Paraquat)
SB  - IM
MH  - Animals
MH  - *Apoptosis
MH  - Apoptosis Regulatory Proteins/genetics/metabolism
MH  - Cell Line
MH  - Cell Nucleus/metabolism
MH  - Chemical and Drug Induced Liver Injury/metabolism/pathology
MH  - Forkhead Box Protein O3
MH  - Forkhead Transcription Factors/genetics/*metabolism
MH  - Gene Expression
MH  - Gene Expression Regulation
MH  - Gene Knockdown Techniques
MH  - Hepatocytes/drug effects/*physiology
MH  - Immediate-Early Proteins/genetics/metabolism
MH  - Liver/metabolism/pathology
MH  - Mice
MH  - Mice, Transgenic
MH  - *Oxidative Stress
MH  - Paraquat/pharmacology
MH  - Phosphorylation
MH  - Protein Processing, Post-Translational
MH  - Protein Serine-Threonine Kinases/genetics/metabolism
MH  - Pyridines
MH  - RNA, Small Interfering/genetics
MH  - *Wnt Signaling Pathway
PMC - PMC3682526
OTO - NOTNLM
OT  - Cytoprotection
OT  - Foxo
OT  - Liver Injury
OT  - Oxidative Stress
OT  - Reactive Oxygen Species (ROS)
OT  - Wnt Signaling
EDAT- 2013/04/27 06:00
MHDA- 2013/08/22 06:00
PMCR- 2014/06/14
CRDT- 2013/04/27 06:00
PHST- 2013/04/27 06:00 [entrez]
PHST- 2013/04/27 06:00 [pubmed]
PHST- 2013/08/22 06:00 [medline]
PHST- 2014/06/14 00:00 [pmc-release]
AID - S0021-9258(20)45867-3 [pii]
AID - M112.445965 [pii]
AID - 10.1074/jbc.M112.445965 [doi]
PST - ppublish
SO  - J Biol Chem. 2013 Jun 14;288(24):17214-24. doi: 10.1074/jbc.M112.445965. Epub 
      2013 Apr 25.