The expanding universe of hypoxia

Zhang, Huafeng; Semenza, Gregg L.

doi:10.1007/s00109-008-0364-9

Cited by 16 publications

(11 citation statements)

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“…Hence, living organisms ranging from yeast to humans need to respond effectively to the changes in oxygen levels in the environment (6,48). In humans, hypoxia is a widely occurring condition associated with an array of disease states, such as cancer and stroke (15,39,48).…”

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“…In humans, hypoxia is a widely occurring condition associated with an array of disease states, such as cancer and stroke (15,39,48). Hypoxia elicits numerous acute and adaptive responses at the molecular and cellular levels, such as changes in gene expression (6,48). To gain a global understanding of hypoxiainduced molecular events, many labs have applied genomewide approaches.…”

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confidence: 99%

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Hypoxia elicits broad and systematic changes in protein subcellular localization

Henke

Dastidar

Shah

et al. 2011

American Journal of Physiology-Cell Physiology

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Oxygen provides a crucial energy source in eukaryotic cells. Hence, eukaryotes ranging from yeast to humans have developed sophisticated mechanisms to respond to changes in oxygen levels. Regulation of protein localization, like protein modifications, can be an effective mechanism to control protein function and activity. However, the contribution of protein localization in oxygen signaling has not been examined on a genomewide scale. Here, we examine how hypoxia affects protein distribution on a genomewide scale in the model eukaryote, the yeast Saccharomyces cerevisiae. We demonstrate, by live cell imaging, that hypoxia alters the cellular distribution of 203 proteins in yeast. These hypoxia-redistributed proteins include an array of proteins with important functions in various organelles. Many of them are nuclear and are components of key regulatory complexes, such as transcriptional regulatory and chromatin remodeling complexes. Under hypoxia, these proteins are synthesized and retained in the cytosol. Upon reoxygenation, they relocalize effectively to their normal cellular compartments, such as the nucleus, mitochondria, endoplasmic reticulum, and cell periphery. The resumption of the normal cellular locations of many proteins can occur even when protein synthesis is inhibited. Furthermore, we show that the changes in protein distribution induced by hypoxia follow a slower trajectory than those induced by reoxygenation. These results show that the regulation of protein localization is a common and potentially dominant mechanism underlying oxygen signaling and regulation. These results may have broad implications in understanding oxygen signaling and hypoxia responses in higher eukaryotes such as humans. oxygen signaling; live cell imaging; nuclear import MOST EUKARYOTIC CELLS rely on aerobic respiration to generate ATP for cellular energy supply. Hence, living organisms ranging from yeast to humans need to respond effectively to the changes in oxygen levels in the environment (6, 48).

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Hypoxia elicits broad and systematic changes in protein subcellular localization

Henke

Dastidar

Shah

et al. 2011

American Journal of Physiology-Cell Physiology

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“…6 The most studied function of VHL protein (pVHL) is the regulation of cellular responses to altered oxygenation through controlling the degradation of the ␣ subunits of the transcription factor hypoxia inducible factor (HIF). 8 In the presence of oxygen, HIF-␣ subunits are hydroxylated by the HIF prolyl hydroxylases, 9 and this generates a binding site for pVHL. Under hypoxia or when pVHL is inactivated, stabilized HIF translocates to the nucleus, binds HIF-␤, and induces many genes.…”

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VHL Inactivation Induces HEF1 and Aurora Kinase A

Wang

et al. 2010

Journal of the American Society of Nephrology

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“…In humans, hypoxia is associated with an array of pathological conditions, such as cancer and stroke. Mechanisms of oxygen sensing and regulation have been implicated in a wide array of physiological and pathological processes (35,99,127). Thus, studying hypoxia responses and resistance/tolerance is of fundamental and broad biological significance (12).…”

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“…Hypoxia can occur in plant roots when a field is flooded, in yeast during fermentation, or in humans at high altitudes or as a result of a heart attack or stroke. Because oxygen is critical for the survival and development of many living organisms, particularly eukaryotes, living organisms ranging from yeast to humans have developed sophisticated mechanisms to respond and adapt to the changes in oxygen levels in the environment (12,127). In the wilderness, several species, including fossorial mammals, diving animals, and birds living at high altitudes, have acquired hypoxia tolerance, which enables them to survive under conditions of limited oxygen supply (9,84,92).…”

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Deletion of a subgroup of ribosome-related genes minimizes hypoxia-induced changes and confers hypoxia tolerance

Shah

Cadinu

Henke

et al. 2011

Physiological Genomics

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Deletion of a subgroup of ribosome-related genes minimizes hypoxia-induced changes and confers hypoxia tolerance. Physiol Genomics 43: 855-872, 2011. First published May 17, 2011 doi:10.1152/physiolgenomics.00232.2010.-Hypoxia is a widely occurring condition experienced by diverse organisms under numerous physiological and disease conditions. To probe the molecular mechanisms underlying hypoxia responses and tolerance, we performed a genome-wide screen to identify mutants with enhanced hypoxia tolerance in the model eukaryote, the yeast Saccharomyces cerevisiae.Yeast provides an excellent model for genomic and proteomic studies of hypoxia. We identified five genes whose deletion significantly enhanced hypoxia tolerance. They are RAI1, NSR1, BUD21, RPL20A, and RSM22, all of which encode functions involved in ribosome biogenesis. Further analysis of the deletion mutants showed that they minimized hypoxia-induced changes in polyribosome profiles and protein synthesis. Strikingly, proteomic analysis by using the iTRAQ profiling technology showed that a substantially fewer number of proteins were changed in response to hypoxia in the deletion mutants, compared with the parent strain. Computational analysis of the iTRAQ data indicated that the activities of a group of regulators were regulated by hypoxia in the wild-type parent cells, but such regulation appeared to be diminished in the deletion strains. These results show that the deletion of one of the genes involved in ribosome biogenesis leads to the reversal of hypoxia-induced changes in gene expression and related regulators. They suggest that modifying ribosomal function is an effective mechanism to minimize hypoxia-induced specific protein changes and to confer hypoxia tolerance. These results may have broad implications in understanding hypoxia responses and tolerance in diverse eukaryotes ranging from yeast to humans.genome-wide screen; proteomic analysis; iTRAQ; regulatory network; stress response LIVING ORGANISMS RANGING FROM aquatic organisms to plants and humans can experience episodes of low oxygen availability, namely, hypoxia. Hypoxia can occur in plant roots when a field is flooded, in yeast during fermentation, or in humans at high altitudes or as a result of a heart attack or stroke. Because oxygen is critical for the survival and development of many living organisms, particularly eukaryotes, living organisms ranging from yeast to humans have developed sophisticated mechanisms to respond and adapt to the changes in oxygen levels in the environment (12, 127). In the wilderness, several species, including fossorial mammals, diving animals, and birds living at high altitudes, have acquired hypoxia tolerance, which enables them to survive under conditions of limited oxygen supply (9, 84, 92). In humans, hypoxia is associated with an array of pathological conditions, such as cancer and stroke. Mechanisms of oxygen sensing and regulation have been implicated in a wide array of physiological and pathological processes (35,99,127). Thus, studying hypoxia ...

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The expanding universe of hypoxia

Cited by 16 publications

References 58 publications

Hypoxia elicits broad and systematic changes in protein subcellular localization

Hypoxia elicits broad and systematic changes in protein subcellular localization

VHL Inactivation Induces HEF1 and Aurora Kinase A

Deletion of a subgroup of ribosome-related genes minimizes hypoxia-induced changes and confers hypoxia tolerance

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