| First Author | Papadakis AI | Year | 2010 |
| Journal | Cancer Res | Volume | 70 |
| Issue | 20 | Pages | 7820-9 |
| PubMed ID | 20924113 | Mgi Jnum | J:165561 |
| Mgi Id | MGI:4837762 | Doi | 10.1158/0008-5472.CAN-10-0215 |
| Citation | Papadakis AI, et al. (2010) eIF2{alpha} Kinase PKR modulates the hypoxic response by Stat3-dependent transcriptional suppression of HIF-1{alpha}. Cancer Res 70(20):7820-9 |
| abstractText | Hypoxia within the tumor microenvironment promotes angiogenesis, metabolic reprogramming, and tumor progression. In addition to activating hypoxia-inducible factor-1alpha (HIF-1alpha), cells also respond to hypoxia by globally inhibiting protein synthesis via serine 51 phosphorylation of translation eukaryotic initiation factor 2alpha (eIF2alpha). In this study, we investigated potential roles for stress-activated eIF2alpha kinases in regulation of HIF-1alpha. Our investigations revealed that the double-stranded RNA-dependent protein kinase R (PKR) plays a significant role in suppressing HIF-1alpha expression, acting specifically at the level of transcription. HIF-1alpha transcriptional repression by PKR was sufficient to impair the hypoxia-induced accumulation of HIF-1alpha and transcriptional induction of HIF-1alpha-dependent target genes. Inhibition of HIF-1A transcription by PKR was independent of eIF2alpha 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-1alpha expression through Stat3 but is independent of eIF2alpha phosphorylation. |
