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Hydrogen sulfide increases hypoxia-inducible factor-1 activity independently of von Hippel-Lindau tumor suppressor-1 in C. elegans.

Budde MW, Roth MB - Mol. Biol. Cell (2009)

Bottom Line: In nature, low oxygen environments are often found to contain high levels of hydrogen sulfide (H(2)S).Exposure to H(2)S results in HIF-1 nuclear localization and transcription of HIF-1 targets.Because H(2)S is naturally produced by animal cells, our results suggest that endogenous H(2)S may influence HIF-1 activity.

View Article: PubMed Central - PubMed

Affiliation: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA 98109, USA.

ABSTRACT
Rapid alteration of gene expression in response to environmental changes is essential for normal development and behavior. The transcription factor hypoxia-inducible factor (HIF)-1 is well known to respond to alterations in oxygen availability. In nature, low oxygen environments are often found to contain high levels of hydrogen sulfide (H(2)S). Here, we show that Caenorhabditis elegans can have mutually exclusive responses to H(2)S and hypoxia, both involving HIF-1. Specifically, H(2)S results in HIF-1 activity throughout the hypodermis, whereas hypoxia causes HIF-1 activity in the gut as judged by a reporter for HIF-1 activity. C. elegans require hif-1 to survive in room air containing trace amounts of H(2)S. Exposure to H(2)S results in HIF-1 nuclear localization and transcription of HIF-1 targets. The effects of H(2)S on HIF-1 reporter activity are independent of von Hippel-Lindau tumor suppressor (VHL)-1, whereas VHL-1 is required for hypoxic regulation of HIF-1 reporter activity. Because H(2)S is naturally produced by animal cells, our results suggest that endogenous H(2)S may influence HIF-1 activity.

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H2S exposure increases expression of NHR-57::GFP. A midfocal plane of a fluorescent confocal photomicrograph and Nomarski micrograph. Fluorescence is not apparent in untreated L4 nhr-57::gfp(iaIs07) transgenic animals. An nhr-57::gfp(iaIs07) animal exposed to hypoxia exhibits HIF-1 activity in the in the gut but absent in the hypodermis. At 1 h into H2S treatment, fluorescence is apparent in the hypodermis throughout the animal but undetectable in the gut. Fluorescence becomes more intense until 3 h into exposure. nhr-57::gfp(iaIs07); hif-1(ia04) animals fail to show any fluorescence, regardless of H2S treatment. Bar, 40 μm.
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Figure 3: H2S exposure increases expression of NHR-57::GFP. A midfocal plane of a fluorescent confocal photomicrograph and Nomarski micrograph. Fluorescence is not apparent in untreated L4 nhr-57::gfp(iaIs07) transgenic animals. An nhr-57::gfp(iaIs07) animal exposed to hypoxia exhibits HIF-1 activity in the in the gut but absent in the hypodermis. At 1 h into H2S treatment, fluorescence is apparent in the hypodermis throughout the animal but undetectable in the gut. Fluorescence becomes more intense until 3 h into exposure. nhr-57::gfp(iaIs07); hif-1(ia04) animals fail to show any fluorescence, regardless of H2S treatment. Bar, 40 μm.

Mentions: To determine whether nuclear localization of HIF-1 in H2S is associated with transcription of hif-1–responsive genes, we examined expression of nhr-57::gfp(iaIs07), which has HIF-1–dependent expression (Shen et al., 2006). After exposure to hypoxia, NHR-57::GFP was observed in the gut, as has been reported previously (Shen et al., 2006) (Figure 3). In contrast, H2S treatment resulted in expression of NHR-57::GFP in the hypodermis but not in the gut. We tested various H2S exposure lengths (1–3 h) to verify that this expression incongruity was unrelated to the amount of time that worms were exposed to H2S. We found that reporter activity is transient, with maximal fluorescence experienced at 3 h of continuous exposure. We observed bright fluorescence in 100 of 100 worms exposed to H2S, and we observed fluorescence in 0 of 100 untreated worms. We never observed gut fluorescence upon H2S exposure, and we conclude that the pattern of HIF-1 activity in hypoxia and H2S are mutually exclusive. In addition, hif-1(ia04); nhr-57::gfp(iaIs07) worms do not fluoresce when exposed to H2S, showing that hif-1 is required for H2S-induced expression.


Hydrogen sulfide increases hypoxia-inducible factor-1 activity independently of von Hippel-Lindau tumor suppressor-1 in C. elegans.

Budde MW, Roth MB - Mol. Biol. Cell (2009)

H2S exposure increases expression of NHR-57::GFP. A midfocal plane of a fluorescent confocal photomicrograph and Nomarski micrograph. Fluorescence is not apparent in untreated L4 nhr-57::gfp(iaIs07) transgenic animals. An nhr-57::gfp(iaIs07) animal exposed to hypoxia exhibits HIF-1 activity in the in the gut but absent in the hypodermis. At 1 h into H2S treatment, fluorescence is apparent in the hypodermis throughout the animal but undetectable in the gut. Fluorescence becomes more intense until 3 h into exposure. nhr-57::gfp(iaIs07); hif-1(ia04) animals fail to show any fluorescence, regardless of H2S treatment. Bar, 40 μm.
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Related In: Results  -  Collection

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Figure 3: H2S exposure increases expression of NHR-57::GFP. A midfocal plane of a fluorescent confocal photomicrograph and Nomarski micrograph. Fluorescence is not apparent in untreated L4 nhr-57::gfp(iaIs07) transgenic animals. An nhr-57::gfp(iaIs07) animal exposed to hypoxia exhibits HIF-1 activity in the in the gut but absent in the hypodermis. At 1 h into H2S treatment, fluorescence is apparent in the hypodermis throughout the animal but undetectable in the gut. Fluorescence becomes more intense until 3 h into exposure. nhr-57::gfp(iaIs07); hif-1(ia04) animals fail to show any fluorescence, regardless of H2S treatment. Bar, 40 μm.
Mentions: To determine whether nuclear localization of HIF-1 in H2S is associated with transcription of hif-1–responsive genes, we examined expression of nhr-57::gfp(iaIs07), which has HIF-1–dependent expression (Shen et al., 2006). After exposure to hypoxia, NHR-57::GFP was observed in the gut, as has been reported previously (Shen et al., 2006) (Figure 3). In contrast, H2S treatment resulted in expression of NHR-57::GFP in the hypodermis but not in the gut. We tested various H2S exposure lengths (1–3 h) to verify that this expression incongruity was unrelated to the amount of time that worms were exposed to H2S. We found that reporter activity is transient, with maximal fluorescence experienced at 3 h of continuous exposure. We observed bright fluorescence in 100 of 100 worms exposed to H2S, and we observed fluorescence in 0 of 100 untreated worms. We never observed gut fluorescence upon H2S exposure, and we conclude that the pattern of HIF-1 activity in hypoxia and H2S are mutually exclusive. In addition, hif-1(ia04); nhr-57::gfp(iaIs07) worms do not fluoresce when exposed to H2S, showing that hif-1 is required for H2S-induced expression.

Bottom Line: In nature, low oxygen environments are often found to contain high levels of hydrogen sulfide (H(2)S).Exposure to H(2)S results in HIF-1 nuclear localization and transcription of HIF-1 targets.Because H(2)S is naturally produced by animal cells, our results suggest that endogenous H(2)S may influence HIF-1 activity.

View Article: PubMed Central - PubMed

Affiliation: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA 98109, USA.

ABSTRACT
Rapid alteration of gene expression in response to environmental changes is essential for normal development and behavior. The transcription factor hypoxia-inducible factor (HIF)-1 is well known to respond to alterations in oxygen availability. In nature, low oxygen environments are often found to contain high levels of hydrogen sulfide (H(2)S). Here, we show that Caenorhabditis elegans can have mutually exclusive responses to H(2)S and hypoxia, both involving HIF-1. Specifically, H(2)S results in HIF-1 activity throughout the hypodermis, whereas hypoxia causes HIF-1 activity in the gut as judged by a reporter for HIF-1 activity. C. elegans require hif-1 to survive in room air containing trace amounts of H(2)S. Exposure to H(2)S results in HIF-1 nuclear localization and transcription of HIF-1 targets. The effects of H(2)S on HIF-1 reporter activity are independent of von Hippel-Lindau tumor suppressor (VHL)-1, whereas VHL-1 is required for hypoxic regulation of HIF-1 reporter activity. Because H(2)S is naturally produced by animal cells, our results suggest that endogenous H(2)S may influence HIF-1 activity.

Show MeSH
Related in: MedlinePlus