Low levels of oxygen (O2), or hypoxia, cause profound adaptive effects on cellular metabolism and gene expression. Most transcriptional responses to O2 deprivation are regulated by the hypoxia inducible factors (HIFs), a family of O2- sensitive transcription factors that transactivate genes with hypoxia response elements (HREs) in their promoters or enhancers. However, the control of hypoxic gene expression also includes a rapid and reversible inhibition of protein synthesis important for energy conservation in O2- deficient environments. Despite this global inhibition of protein synthesis, the translation of genes essential for cellular adaptation to hypoxia must continue. While much is known about HIF transcriptional regulation, relatively little is known about how specific O2- regulated mRNAs are selectively translated in hypoxic cells. The goal of these studies is to delineate the molecular basis of global protein synthesis inhibition and determine how a population of O2- regulated mRNAs are preferentially translated in hypoxic cells. We hypothesize that the mammalian target of rapamycin (mTOR), a critical regulator of translation in response to nutrient quality and quantity, is itself regu/ated by hypoxia. To enhance our understanding of hypoxic translational control, we propose to: (1) determine if mTOR kinase activity is directly or indirectly regulated by O2 availability and define a role for PAS kinase in the regulation of protein synthesis in hypoxic cells, (2) delineate upstream signal(s) that regulate mTOR during hypoxia, such as mitochondrial function, intracellular adenine nucleotide ratios, and AMP activated protein kinase (AMPK), and (3) identify cis- acting elements common to mRNAs selectively translated during hypoxia, focusing on a subclass of internal ribosomal entry sites (IRESs). Cells within solid tumors frequently encounter O2 deprivation, given the poor vascular function of tumor blood vessels. The ultimate goal of this proposal is to better define hypoxic translational control by cancer cells and develop novel therapies designed to combat the unique intracellular metabolism and physiology of these neoplasms.
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