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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,...

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Autores principales: Porter, Joshua R., Lee, Chih-Yung S., Espenshade, Peter J., Iglesias, Pablo A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2012
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.
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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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