Translational control of gene expression during hypoxia

Poor oxygenation is a unique and prevalent feature of solid tumors associated with poor patient prognosis. In part, this is caused by a series of adaptive cellular responses that together have a large impact on gene expression and cell phenotype. HIF plays a key role in this response by activating a transcriptional program that stimulates genes involved in angiogenesis, cell metabolism, cell survival and cell invasion. Recently, hypoxia has also been shown to suppress protein synthesis through the regulation of the initiation step of mRNA translation. This appears to be a common feature of the cell in response to hypoxia and is mediated by two distinct pathways. The first occurs rapidly, is transient, and is associated with activation of the unfolded protein response (UPR) that occurs in response to endoplasmic reticulum (ER) stress. Translation inhibition during this initial phase is due to phosphorylation of eukaryotic initiation factor 2 alpha (eIF2 alpha) in a PERK dependent manner. Although this effect is transient, overall levels of translation remain low during hypoxia due to inhibition of a second eukaryotic initiation complex, eIF4F. This second mechanism is multi-factorial, but due at least in part to inhibition of the mTOR kinase. Although each of these pathways leads to a general inhibition in translation, the consequence at the individual gene level is highly variable. This is due to sequences in the 5' and 3' untranslated regions (UTRs) of mRNA that confer their ability to maintain, or even increase, translation efficiency in spite of the overall inhibition. Consequently, regulation of mRNA translation appears to be an important mediator of gene expression during hypoxia.