| First Author | Philippe C | Year | 2016 |
| Journal | Sci Signal | Volume | 9 |
| Issue | 426 | Pages | ra44 |
| PubMed ID | 27141928 | Mgi Jnum | J:259530 |
| Mgi Id | MGI:6141917 | Doi | 10.1126/scisignal.aaf2753 |
| Citation | Philippe C, et al. (2016) PERK mediates the IRES-dependent translational activation of mRNAs encoding angiogenic growth factors after ischemic stress. Sci Signal 9(426):ra44 |
| abstractText | Angiogenesis is induced by various conditions, including hypoxia. Although cap-dependent translation is globally inhibited during ischemia, the mRNAs encoding two important proangiogenic growth factors, vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF-2), are translated at early time points in ischemic muscle. The translation of these mRNAs can occur through internal ribosome entry sites (IRESs), rather than through cap-dependent translation. Hypoxic conditions also induce the unfolded protein response (UPR) and endoplasmic reticulum (ER) stress, leading us to assess the interplay between hypoxia, ER stress, and IRES-mediated translation of FGF-2 and VEGF We found that unlike cap-dependent translation, translation through FGF-2 and VEGF IRESs was efficient in cells and transgenic mice subjected to ER stress-inducing stimuli. We identified PERK, a kinase that is activated by ER stress, as the driver of VEGF and FGF-2 IRES-mediated translation in cells and in mice expressing IRES-driven reporter genes and exposed to hypoxic stress. These results demonstrate the role of IRES-dependent translation in the induction of the proangiogenic factors VEGF and FGF-2 in response to acute hypoxic stress. Furthermore, the PERK pathway could be a viable pharmacological target to improve physiological responses to ischemic situations. |
