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• W2595536676 abstract "Abstract Upregulation of Smad7, an inhibitor of transforming growth factor- β 1 (TGF- β 1), occurs in sporadic colorectal cancer (CRC) and knockdown of Smad7 inhibits CRC cell growth, a phenomenon that associates with decreased expression of cell division cycle 25 homolog A and arrest of cells in the S phase of the cell cycle. These findings occur in CRC cells unresponsive to TGF-β1, thus suggesting the existence of a Smad7-mediated TGF-β1-independent mechanism that controls CRC cell behavior. Here we show that Smad7 inhibition with a specific Smad7 antisense oligonucleotide upregulates eukaryotic translation initiation factor 2 α (eIF2 α ) phosphorylation, a transcription factor involved in the regulation of cell cycle arrest and induction of cell death, and induces activating transcription factor 4 (ATF4) and CCAAT/enhancer binding protein homology protein (CHOP), two downstream targets of eIF2 α . Among the upstream kinases that control eIF2 α phosphorylation, the serine–threonine protein kinase RNA (PKR), but not general control non-derepressible 2 (GCN2) and protein kinase RNA-like endoplasmic reticulum kinase (PERK), is activated by Smad7 knockdown. PKR silencing abolishes Smad7 antisense-induced eIF2 α phosphorylation and ATF4/CHOP induction, thereby preventing Smad7 antisense-driven cell death. Smad7 inhibition diminishes interaction of PKR with protein kinase inhibitor p58 (p58 IPK ), a cellular inhibitor of PKR, but does not change the expression and/or activity of other factors involved in the control of PKR activation. These findings delineate a novel mechanism by which Smad7 knockdown promotes CRC cell death." @default.
• W2595536676 created "2017-03-23" @default.
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• W2595536676 date "2017-03-16" @default.
• W2595536676 modified "2023-10-17" @default.
• W2595536676 title "Smad7 knockdown activates protein kinase RNA-associated eIF2α pathway leading to colon cancer cell death" @default.
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• W2595536676 doi "https://doi.org/10.1038/cddis.2017.103" @default.
• W2595536676 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/5386514" @default.
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