PMID- 23203799
OWN - NLM
STAT- MEDLINE
DCOM- 20130911
LR  - 20220410
IS  - 1477-9137 (Electronic)
IS  - 0021-9533 (Linking)
VI  - 126
IP  - Pt 1
DP  - 2013 Jan 1
TI  - Association of beta-catenin with P-Smad3 but not LEF-1 dissociates in vitro 
      profibrotic from anti-inflammatory effects of TGF-beta1.
PG  - 67-76
LID - 10.1242/jcs.103036 [doi]
AB  - Transforming growth factor beta1 (TGF-beta1) is known to be both anti-inflammatory and 
      profibrotic. Cross-talk between TGF-beta/Smad and Wnt/beta-catenin pathways in 
      epithelial-mesenchymal transition (EMT) suggests a specific role for beta-catenin in 
      profibrotic effects of TGF-beta1. However, no such mechanistic role has been 
      demonstrated for beta-catenin in the anti-inflammatory effects of TGF-beta1. In the 
      present study, we explored the role of beta-catenin in the profibrotic and 
      anti-inflammatory effects of TGF-beta1 by using a cytosolic, but not membrane, 
      beta-catenin knockdown chimera (F-TrCP-Ecad) and the beta-catenin/CBP inhibitor 
      ICG-001. TGF-beta1 induced nuclear Smad3/beta-catenin complex, but not beta-catenin/LEF-1 
      complex or TOP-flash activity, during EMT of C1.1 (renal tubular epithelial) 
      cells. F-TrCP-Ecad selectively degraded TGF-beta1-induced cytoplasmic beta-catenin and 
      blocked EMT of C1.1 cells. Both F-TrCP-Ecad and ICG-001 blocked TGF-beta1-induced 
      Smad3/beta-catenin and Smad reporter activity in C1.1 cells, suggesting that 
      TGF-beta1-induced EMT depends on beta-catenin binding to Smad3, but not LEF-1 
      downstream of Smad3, through canonical Wnt. In contrast, in J774 macrophages, the 
      beta-catenin level was low and was not changed by interferon-gamma (IFN-gamma) or 
      lipopolysaccharide (LPS) with or without TGF-beta1. TGF-beta1 inhibition of LPS-induced 
      TNF-alpha and IFN-gamma-stimulated inducible NO synthase (iNOS) expression was not 
      affected by F-TrCP-Ecad, ICG-001 or by overexpression of wild-type beta-catenin in 
      J774 cells. Inhibition of beta-catenin by either F-TrCP-Ecad or ICG-001 abolished 
      LiCl-induced TOP-flash, but not TGF-beta1-induced Smad reporter, activity in J774 
      cells. These results demonstrate for the first time that beta-catenin is required as 
      a co-factor of Smad in TGF-beta1-induced EMT of C1.1 epithelial cells, but not in 
      TGF-beta1 inhibition of macrophage activation. Targeting beta-catenin may dissociate 
      the TGF-beta1 profibrotic and anti-inflammatory effects.
FAU - Tian, Xinrui
AU  - Tian X
AD  - Centre for Transplantation and Renal Research, the University of Sydney at 
      Westmead Millennium Institute, Sydney, NSW 2145, Australia.
FAU - Zhang, Jianlin
AU  - Zhang J
FAU - Tan, Thian Kui
AU  - Tan TK
FAU - Lyons, J Guy
AU  - Lyons JG
FAU - Zhao, Hong
AU  - Zhao H
FAU - Niu, Bo
AU  - Niu B
FAU - Lee, So Ra
AU  - Lee SR
FAU - Tsatralis, Tania
AU  - Tsatralis T
FAU - Zhao, Ye
AU  - Zhao Y
FAU - Wang, Ya
AU  - Wang Y
FAU - Cao, Qi
AU  - Cao Q
FAU - Wang, Changqi
AU  - Wang C
FAU - Wang, Yiping
AU  - Wang Y
FAU - Lee, Vincent W S
AU  - Lee VW
FAU - Kahn, Michael
AU  - Kahn M
FAU - Zheng, Guoping
AU  - Zheng G
FAU - Harris, David C H
AU  - Harris DC
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20121130
PL  - England
TA  - J Cell Sci
JT  - Journal of cell science
JID - 0052457
RN  - 0 (Anti-Inflammatory Agents)
RN  - 0 (Lymphoid Enhancer-Binding Factor 1)
RN  - 0 (Smad3 Protein)
RN  - 0 (Transforming Growth Factor beta1)
RN  - 0 (beta Catenin)
SB  - IM
MH  - Animals
MH  - Anti-Inflammatory Agents/*pharmacology
MH  - Blotting, Western
MH  - Cell Line
MH  - Epithelial-Mesenchymal Transition/drug effects/genetics
MH  - Immunoprecipitation
MH  - Lymphoid Enhancer-Binding Factor 1/genetics/*metabolism
MH  - Mice
MH  - Microscopy, Fluorescence
MH  - Protein Binding/drug effects
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Smad3 Protein/genetics/*metabolism
MH  - Transforming Growth Factor beta1/*pharmacology
MH  - beta Catenin/genetics/*metabolism
EDAT- 2012/12/04 06:00
MHDA- 2013/09/12 06:00
CRDT- 2012/12/04 06:00
PHST- 2012/12/04 06:00 [entrez]
PHST- 2012/12/04 06:00 [pubmed]
PHST- 2013/09/12 06:00 [medline]
AID - jcs.103036 [pii]
AID - 10.1242/jcs.103036 [doi]
PST - ppublish
SO  - J Cell Sci. 2013 Jan 1;126(Pt 1):67-76. doi: 10.1242/jcs.103036. Epub 2012 Nov 
      30.