Colorado PROFILES, The Colorado Clinical and Translational Sciences Institute (CCTSI)
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Adaptation to changes in oxygen tension in cells, tissues, and organisms depends on changes in the level of expression of a large and diverse group of proteins. Currently, it is not clear how oxygen is sensed in most organisms although it is generally agreed that heme plays a vital role in this process. Also unclear is how an 'oxygen sensor' transmits its signal to a signal transduction pathway for the activation or repression of oxygen-responsive genes. In the yeast Saccharomyces cerevisiae genes that respond to changes in oxygen availability can be placed into two broad categories: aerobic genes, which are optimally expressed under normoxic conditions, and hypoxic genes, which are optimally expressed under low oxygen or anoxic conditions. The current model for oxygen sensing in yeast assumes that heme concentration is affected by oxygen concentration, that heme functions to regulate the activity of transcription factors for oxygen-responsive genes, and that heme is a redox-insensitive cofactor for these transcription factors. Recent findings have cast doubt on this simple model and suggest that multiple pathways/mechanisms are involved in sensing oxygen. The research objectives of this proposal are based on the novel experimental finding that the level of expression of aerobic genes is determined by the concentration of oxygen and not merely its presence or absence. This phenomenon, called oxygen concentration-dependent (OCD) gene expression, implies that cells actually detect and respond to oxygen concentration per se. This type of gene expression, together with the unique fermentor system that permitted its discovery, opens a way to examine upstream events that are involved in oxygen sensing in yeast, by asking the following questions: Aim 1: Can changes in level of expression of aerobic genes be explained by changes in heme levels? Aim 2: Is cytochrome c oxidase, YHb flavohemoglobin, or some other redox-sensitive oxygen binding protein involved in OCD gene expression? Aim 3: Does oxygen affect transcript turnover rate? Aim 4: What cis promoter sites mediate the OCD expression of COX6, COX5a, and CYC1?
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