Journal
CELL RESEARCH
Volume 24, Issue 8, Pages 994-1008Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/cr.2014.97
Keywords
ChIP-seq; NKX2-1; Smad3; Smad4; TTF-1; TGF-beta
Categories
Funding
- KAKENHI from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT) [22112002, 20221009, 24890039]
- Ministry of Health, Labor, and Welfare of Japan
- Genome Network Project from MEXT
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Project for Development of Innovative Research on Cancer Therapeutics from MEXT
- Grants-in-Aid for Scientific Research [22112002, 22112001, 24890039] Funding Source: KAKEN
Ask authors/readers for more resources
Thyroid transcription factor-1 (TTF-1, also known as NKX2-1) is a tissue-specific transcription factor in lung epithelial cells. Although TTF-1 inhibits the epithelial-to-mesenchymal transition induced by transforming growth factor-beta (TGF-beta) in lung adenocarcinoma cells, the mechanism through which TTF-1 inhibits the functions of TGF-beta is unknown. Here we show that TTF-1 disrupts the nuclear Smad3-Smad4 complex without affecting the nuclear localization of phospho-Smad3. Genome-wide analysis by chromatin immunoprecipitation followed by sequencing revealed that TTF-1 colocalizes with Smad3 on chromatin and alters Smad3-binding patterns throughout the genome, while TTF-1 generally inhibits Smad4 binding to chromatin. Moreover, Smad3 binds to chromatin together with TTF-1, but not with Smad4, at some Smad3-binding regions when TGF-beta signaling is absent, and knockdown of Smad4 expression does not attenuate Smad3 binding in these regions. Thus, TTF-1 may compete with Smad4 for interaction with Smad3, and in the presence of TTF-1, Smad3 regulates the transcription of certain genes independently of Smad4. These findings provide a new model of regulation of TGF-beta-Smad signaling by TTF-1.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available