Title |
Smad7 knockdown activates protein kinase RNA-associated eIF2α pathway leading to colon cancer cell death
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Published in |
Cell Death & Disease, March 2017
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DOI | 10.1038/cddis.2017.103 |
Pubmed ID | |
Authors |
Veronica De Simone, Gerolamo Bevivino, Silvia Sedda, Roberta Izzo, Federica Laudisi, Vincenzo Dinallo, Eleonora Franzè, Alfredo Colantoni, Angela Ortenzi, Silvia Salvatori, Piero Rossi, Giuseppe S Sica, Massimo C Fantini, Carmine Stolfi, Giovanni Monteleone |
Abstract |
Upregulation of Smad7, an inhibitor of transforming growth factor-β1 (TGF-β1), 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 2α (eIF2α) 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 eIF2α. Among the upstream kinases that control eIF2α 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 eIF2α 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. |
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Unknown | 2 | 100% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 2 | 100% |
Mendeley readers
Geographical breakdown
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Unknown | 15 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
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Researcher | 3 | 20% |
Student > Master | 3 | 20% |
Student > Doctoral Student | 1 | 7% |
Other | 1 | 7% |
Lecturer | 1 | 7% |
Other | 1 | 7% |
Unknown | 5 | 33% |
Readers by discipline | Count | As % |
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Medicine and Dentistry | 4 | 27% |
Agricultural and Biological Sciences | 2 | 13% |
Nursing and Health Professions | 1 | 7% |
Immunology and Microbiology | 1 | 7% |
Neuroscience | 1 | 7% |
Other | 0 | 0% |
Unknown | 6 | 40% |