Abstract
BackgroundHypoxia is associated with many disease conditions in humans, such as cancer, stroke and traumatic injuries. Hypoxia elicits broad molecular and cellular changes in diverse eukaryotes. Our recent studies suggest that one likely mechanism mediating such broad changes is through changes in the cellular localization of important regulatory proteins. Particularly, we have found that over 120 nuclear proteins with important functions ranging from transcriptional regulation to RNA processing exhibit altered cellular locations under hypoxia. In this report, we describe further experiments to identify and evaluate the role of nuclear protein relocalization in mediating hypoxia responses in yeast.ResultsTo identify regulatory proteins that play a causal role in mediating hypoxia responses, we characterized the time courses of relocalization of hypoxia-altered nuclear proteins in response to hypoxia and reoxygenation. We found that 17 nuclear proteins relocalized in a significantly shorter time period in response to both hypoxia and reoxygenation. Particularly, several components of the SWI/SNF complex were fast responders, and analysis of gene expression data show that many targets of the SWI/SNF proteins are oxygen regulated. Furthermore, confocal fluorescent live cell imaging showed that over 95% of hypoxia-altered SWI/SNF proteins accumulated in the cytosol in hypoxic cells, while over 95% of the proteins were nuclear in normoxic cells, as expected.ConclusionsSWI/SNF proteins relocalize in response to hypoxia and reoxygenation in a quick manner, and their relocalization likely accounts for, in part or in whole, oxygen regulation of many SWI/SNF target genes.
Highlights
Hypoxia is associated with many disease conditions in humans, such as cancer, stroke and traumatic injuries
These results suggest that hypoxia can significantly alter the composition and property of the SWI/SNF complex and mediate oxygen regulation of gene expression
Among the hypoxia-redistributed nuclear proteins we previously identified, some are likely involved in mediating oxygen signaling and regulation of gene expression
Summary
Hypoxia is associated with many disease conditions in humans, such as cancer, stroke and traumatic injuries. Living organisms ranging from yeast to mammals use oxygen to generate their cellular energy supply and to synthesize important biomolecules. They need to respond effectively to changes in oxygen levels in the environment, to hypoxia [1,2]. In the human primary astrocytes, more than 5% of the genes alter their transcript levels by at least 2-fold in response to hypoxia [8]. Such broad changes in gene expression likely involve coordinated actions of multiple pathways and regulators
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