Figure 1.

Hypoxia activates the UPR pathway and causes ATF4 expression to increase. Hypoxia causes inhibition of the canonical translation pathway, resulting in misfolded or unfolded proteins. These peptides activate PERK that consequently induces ATF4 mRNA translation, resulting in an increase in ATF4 protein expression. ATF4 then translocates to the nucleus to initiate gene expression changes. Hypoxia also causes increases in HIF1α and HIF2α. Both HIFs also translocate to the nucleus to function as transcription factors. HIF2α also functions as a translation factor that initiates translation when cells are under hypoxic stress (17). UPR, unfolded protein response; ATF4, activating transcription factor 4; eIF4E, eukaryotic initiation factor 4E; ER, endoplasmic reticulum; HIF1α, hypoxia-inducible factor 1α; HIF2α, hypoxia-inducible factor 2α; PERK, protein kinase R (PKR)-like endoplasmic reticulum kinase; P, phosphate.