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Regulation of SREBP during hypoxia requires Ofd1-mediated control of both DNA bindingand degradation
Cells adapt to changes in ambient oxygen by changing their gene expression patterns. In fission yeast, the sterol regulatory element–binding protein Sre1 is proteolytically cleaved under low oxygen, and its N-terminal segment (Sre1N) serves as a hypoxic transcription factor. When oxygen is present,...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The American Society for Cell Biology
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3442422/ https://www.ncbi.nlm.nih.gov/pubmed/22833559 http://dx.doi.org/10.1091/mbc.E12-06-0451 |
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author | Porter, Joshua R. Lee, Chih-Yung S. Espenshade, Peter J. Iglesias, Pablo A. |
author_facet | Porter, Joshua R. Lee, Chih-Yung S. Espenshade, Peter J. Iglesias, Pablo A. |
author_sort | Porter, Joshua R. |
collection | PubMed |
description | Cells adapt to changes in ambient oxygen by changing their gene expression patterns. In fission yeast, the sterol regulatory element–binding protein Sre1 is proteolytically cleaved under low oxygen, and its N-terminal segment (Sre1N) serves as a hypoxic transcription factor. When oxygen is present, the prolyl hydroxylase Ofd1 down-regulates Sre1N activity in two ways: first, by inhibiting its binding to DNA, and second, by accelerating its degradation. Here we use a mathematical model to assess what each of these two regulatory functions contributes to the hypoxic response of the cell. By disabling individual regulatory functions in the model, which would be difficult in vivo, we found that the Ofd1 function of inhibiting Sre1N binding to DNA is essential for oxygen-dependent Sre1N regulation. The other Ofd1 function of accelerating Sre1N degradation is necessary for the yeast to quickly turn off its hypoxic response when oxygen is restored. In addition, the model predicts that increased Ofd1 production at low oxygen plays an important role in the hypoxic response, and the model indicates that the Ofd1 binding partner Nro1 tunes the response to oxygen. This model quantifies our understanding of a novel oxygen-sensing mechanism that is widely conserved. |
format | Online Article Text |
id | pubmed-3442422 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | The American Society for Cell Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-34424222012-11-30 Regulation of SREBP during hypoxia requires Ofd1-mediated control of both DNA bindingand degradation Porter, Joshua R. Lee, Chih-Yung S. Espenshade, Peter J. Iglesias, Pablo A. Mol Biol Cell Articles Cells adapt to changes in ambient oxygen by changing their gene expression patterns. In fission yeast, the sterol regulatory element–binding protein Sre1 is proteolytically cleaved under low oxygen, and its N-terminal segment (Sre1N) serves as a hypoxic transcription factor. When oxygen is present, the prolyl hydroxylase Ofd1 down-regulates Sre1N activity in two ways: first, by inhibiting its binding to DNA, and second, by accelerating its degradation. Here we use a mathematical model to assess what each of these two regulatory functions contributes to the hypoxic response of the cell. By disabling individual regulatory functions in the model, which would be difficult in vivo, we found that the Ofd1 function of inhibiting Sre1N binding to DNA is essential for oxygen-dependent Sre1N regulation. The other Ofd1 function of accelerating Sre1N degradation is necessary for the yeast to quickly turn off its hypoxic response when oxygen is restored. In addition, the model predicts that increased Ofd1 production at low oxygen plays an important role in the hypoxic response, and the model indicates that the Ofd1 binding partner Nro1 tunes the response to oxygen. This model quantifies our understanding of a novel oxygen-sensing mechanism that is widely conserved. The American Society for Cell Biology 2012-09-15 /pmc/articles/PMC3442422/ /pubmed/22833559 http://dx.doi.org/10.1091/mbc.E12-06-0451 Text en © 2012 Porter et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society of Cell BD; are registered trademarks of The American Society of Cell Biology. |
spellingShingle | Articles Porter, Joshua R. Lee, Chih-Yung S. Espenshade, Peter J. Iglesias, Pablo A. Regulation of SREBP during hypoxia requires Ofd1-mediated control of both DNA bindingand degradation |
title | Regulation of SREBP during hypoxia requires Ofd1-mediated control of both DNA bindingand degradation |
title_full | Regulation of SREBP during hypoxia requires Ofd1-mediated control of both DNA bindingand degradation |
title_fullStr | Regulation of SREBP during hypoxia requires Ofd1-mediated control of both DNA bindingand degradation |
title_full_unstemmed | Regulation of SREBP during hypoxia requires Ofd1-mediated control of both DNA bindingand degradation |
title_short | Regulation of SREBP during hypoxia requires Ofd1-mediated control of both DNA bindingand degradation |
title_sort | regulation of srebp during hypoxia requires ofd1-mediated control of both dna bindingand degradation |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3442422/ https://www.ncbi.nlm.nih.gov/pubmed/22833559 http://dx.doi.org/10.1091/mbc.E12-06-0451 |
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