dc.creator | Papadakis, A. I. | en |
dc.creator | Paraskeva, E. | en |
dc.creator | Peidis, P. | en |
dc.creator | Muaddi, H. | en |
dc.creator | Li, S. Y. | en |
dc.creator | Raptis, L. | en |
dc.creator | Pantopoulos, K. | en |
dc.creator | Simos, G. | en |
dc.creator | Koromilas, A. E. | en |
dc.date.accessioned | 2015-11-23T10:42:42Z | |
dc.date.available | 2015-11-23T10:42:42Z | |
dc.date.issued | 2010 | |
dc.identifier | 10.1158/0008-5472.can-10-0215 | |
dc.identifier.issn | 0008-5472 | |
dc.identifier.uri | http://hdl.handle.net/11615/31643 | |
dc.description.abstract | Hypoxia within the tumor microenvironment promotes angiogenesis, metabolic reprogramming, and tumor progression. In addition to activating hypoxia-inducible factor-1 alpha (HIF-1 alpha), cells also respond to hypoxia by globally inhibiting protein synthesis via serine 51 phosphorylation of translation eukaryotic initiation factor 2 alpha (eIF2 alpha). In this study, we investigated potential roles for stress-activated eIF2 alpha kinases in regulation of HIF-1 alpha. Our investigations revealed that the double-stranded RNA-dependent protein kinase R (PKR) plays a significant role in suppressing HIF-1 alpha expression, acting specifically at the level of transcription. HIF-1 alpha transcriptional repression by PKR was sufficient to impair the hypoxia-induced accumulation of HIF-1 alpha and transcriptional induction of HIF-1 alpha-dependent target genes. Inhibition of HIF-1A transcription by PKR was independent of eIF2 alpha phosphorylation but dependent on inhibition of the signal transducer and activator of transcription 3 (Stat3). Furthermore, HIF-1A repression required the T-cell protein tyrosine phosphatase, which acts downstream of PKR, to suppress Stat3. Our findings reveal a novel tumor suppressor function for PKR, which inhibits HIF-1 alpha expression through Stat3 but is independent of eIF2 alpha phosphorylation. Cancer Res; 70(20); 7820-9. (C) 2010 AACR. | en |
dc.source | Cancer Research | en |
dc.source.uri | <Go to ISI>://WOS:000282879900010 | |
dc.subject | PROTEIN-TYROSINE-PHOSPHATASE | en |
dc.subject | ENDOTHELIAL GROWTH-FACTOR | en |
dc.subject | INDUCIBLE | en |
dc.subject | FACTOR-I | en |
dc.subject | GENE-EXPRESSION | en |
dc.subject | TRANSLATIONAL CONTROL | en |
dc.subject | MALIGNANT-TRANSFORMATION | en |
dc.subject | SIGNAL TRANSDUCER | en |
dc.subject | CELL-DEATH | en |
dc.subject | KAPPA-B | en |
dc.subject | PHOSPHORYLATION | en |
dc.subject | Oncology | en |
dc.title | eIF2 alpha Kinase PKR Modulates the Hypoxic Response by Stat3-Dependent Transcriptional Suppression of HIF-1 alpha | en |
dc.type | journalArticle | en |