Interferon-γ interferes with transforming growth factor-β signaling through direct interaction of YB-1 with Smad3

被引:135
作者
Higashi, K [1 ]
Inagaki, Y
Fujimori, K
Nakao, A
Kaneko, H
Nakatsuka, I
机构
[1] Sumitomo Chem Co Ltd, Environm Hlth Sci Lab, Konohana Ku, Osaka 5548558, Japan
[2] Tokai Univ, Sch Med, Dept Community Hlth, Kanagawa 2591193, Japan
[3] Juntendo Univ, Sch Med, Allergy Res Ctr, Bunkyo Ku, Tokyo 1138421, Japan
关键词
D O I
10.1074/jbc.M302339200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Transforming growth factor-beta (TGF-beta) and interferon-gamma ( IFN-gamma) exert antagonistic effects on collagen synthesis in human dermal fibroblasts. We have recently shown that Y box-binding protein YB-1 mediates the inhibitory effects of IFN-gamma on alpha2(I) procollagen gene (COL1A2) transcription through the IFN-gamma response element located between - 161 and - 150. Here we report that YB-1 counter-represses TGF-beta-stimulated COL1A2 transcription by interfering with Smad3 bound to the upstream sequence around - 265 and subsequently by interrupting the Smad3-p300 interaction. Western blot and immunofluorescence analyses using inhibitors for Janus kinases or casein kinase II suggested that the casein kinase II-dependent signaling pathway mediates IFN-gamma-induced nuclear translocation of YB-1. Down-regulation of endogenous YB-1 expression by double-stranded YB-1-specific RNA abrogated the transcriptional repression of COL1A2 by IFN-gamma in the absence and presence of TGF-beta. In transient transfection assays, overexpression of YB-1 in human dermal fibroblasts exhibited antagonistic actions against TGF-beta and Smad3. Physical interaction between Smad3 and YB- 1 was demonstrated by immunoprecipitation-Western blot analyses, and electrophoretic mobility shift assays using the recombinant Smad3 and YB- 1 proteins indicated that YB- 1 forms a complex with Smad3 bound to the Smad-binding element. Glutathione S-transferase pull-down assays showed that YB- 1 binds to the MH1 domain of Smad3, whereas the central and carboxyl-terminal regions of YB- 1 were required for its interaction with Smad3. YB- 1 also interferes with the Smad3-p300 interaction by its preferential binding to p300. Altogether, the results provide a novel insight into the mechanism by which IFN-gamma/ YB-1 counteracts TGF-beta/Smad3. They also indicate that IFN-gamma/YB-1 inhibits COL1A2 transcription by dual actions: via the IFN-gamma response element and through a cross-talk with the TGF-beta/Smad signaling pathway.
引用
收藏
页码:43470 / 43479
页数:10
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