期刊
PLOS ONE
卷 12, 期 4, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0176096
关键词
-
资金
- National Institute of Health [CA038173, CA054807]
- UNMC Cancer Center Support Grant [CA036727]
- NIH [CA038173, CA054807]
In this study, we have uncovered a novel crosstalk between TGF beta and IGF-1R signaling pathways. We show for the first time that expression and activation of IRS-1, an IGF-1R adaptor protein, is decreased by TGF beta/Smad3 signaling. Loss or attenuation of TGF beta activation leads to elevated expression and phosphorylation of IRS-1 in colon cancer cells, resulting in enhanced cell proliferation, decreased apoptosis and increased tumor growth in vitro and in vivo. Downregulation of IRS-1 expression reversed Smad3 knockdown-mediated oncogenic phenotypes, indicating that TGF beta/Smad3 signaling inhibits cell proliferation and increases apoptosis at least partially through the inhibition of IRS-1 expression and activation. Additionally, the TGF beta/Smad3/IRS-1 signaling axis regulates expression of cyclin D1 and XIAP, which may contribute to TGF beta/Smad3/IRS-1-mediated cell cycle progression and survival. Given that loss of TGF beta signaling occurs frequently in colon cancer, an important implication of our study is that IRS-1 could be a potential therapeutic target for colon cancer treatment.
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