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Repression of hypoxia-inducible factor α signaling by Set7-mediated methylation
Hypoxia-inducible factor (HIF)-1α and HIF-2α are the main regulators of cellular responses to hypoxia. Post-translational modifications of HIF-1α and 2α are necessary to modulate their functions. The methylation of non-histone proteins by Set7, an SET domain-containing lysine methyltransferase, is a...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4446437/ https://www.ncbi.nlm.nih.gov/pubmed/25897119 http://dx.doi.org/10.1093/nar/gkv379 |
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author | Liu, Xing Chen, Zhu Xu, Chenxi Leng, Xiaoqian Cao, Hong Ouyang, Gang Xiao, Wuhan |
author_facet | Liu, Xing Chen, Zhu Xu, Chenxi Leng, Xiaoqian Cao, Hong Ouyang, Gang Xiao, Wuhan |
author_sort | Liu, Xing |
collection | PubMed |
description | Hypoxia-inducible factor (HIF)-1α and HIF-2α are the main regulators of cellular responses to hypoxia. Post-translational modifications of HIF-1α and 2α are necessary to modulate their functions. The methylation of non-histone proteins by Set7, an SET domain-containing lysine methyltransferase, is a novel regulatory mechanism to control cell protein function in response to various cellular stresses. In this study, we show that Set7 methylates HIF-1α at lysine 32 and HIF-2α at lysine K29; this methylation inhibits the expression of HIF-1α/2α targets by impairing the occupancy of HIF-α on hypoxia response element of HIF target gene promoter. Set7-null fibroblasts and the cells with shRNA-knocked down Set7 exhibit upregulated HIF target genes. Set7 inhibitor blocks HIF-1α/2α methylation to enhance HIF target gene expression. Set7-null fibroblasts and the cells with shRNA-knocked down Set7 or inhibition of Set7 by the inhibitor subjected to hypoxia display an increased glucose uptake and intracellular adenosine triphosphate levels. These findings define a novel modification of HIF-1α/2α and demonstrate that Set7-medited lysine methylation negatively regulates HIF-α transcriptional activity and HIF-1α-mediated glucose homeostasis. |
format | Online Article Text |
id | pubmed-4446437 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-44464372015-06-15 Repression of hypoxia-inducible factor α signaling by Set7-mediated methylation Liu, Xing Chen, Zhu Xu, Chenxi Leng, Xiaoqian Cao, Hong Ouyang, Gang Xiao, Wuhan Nucleic Acids Res Molecular Biology Hypoxia-inducible factor (HIF)-1α and HIF-2α are the main regulators of cellular responses to hypoxia. Post-translational modifications of HIF-1α and 2α are necessary to modulate their functions. The methylation of non-histone proteins by Set7, an SET domain-containing lysine methyltransferase, is a novel regulatory mechanism to control cell protein function in response to various cellular stresses. In this study, we show that Set7 methylates HIF-1α at lysine 32 and HIF-2α at lysine K29; this methylation inhibits the expression of HIF-1α/2α targets by impairing the occupancy of HIF-α on hypoxia response element of HIF target gene promoter. Set7-null fibroblasts and the cells with shRNA-knocked down Set7 exhibit upregulated HIF target genes. Set7 inhibitor blocks HIF-1α/2α methylation to enhance HIF target gene expression. Set7-null fibroblasts and the cells with shRNA-knocked down Set7 or inhibition of Set7 by the inhibitor subjected to hypoxia display an increased glucose uptake and intracellular adenosine triphosphate levels. These findings define a novel modification of HIF-1α/2α and demonstrate that Set7-medited lysine methylation negatively regulates HIF-α transcriptional activity and HIF-1α-mediated glucose homeostasis. Oxford University Press 2015-05-26 2015-04-20 /pmc/articles/PMC4446437/ /pubmed/25897119 http://dx.doi.org/10.1093/nar/gkv379 Text en © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Molecular Biology Liu, Xing Chen, Zhu Xu, Chenxi Leng, Xiaoqian Cao, Hong Ouyang, Gang Xiao, Wuhan Repression of hypoxia-inducible factor α signaling by Set7-mediated methylation |
title | Repression of hypoxia-inducible factor α signaling by Set7-mediated methylation |
title_full | Repression of hypoxia-inducible factor α signaling by Set7-mediated methylation |
title_fullStr | Repression of hypoxia-inducible factor α signaling by Set7-mediated methylation |
title_full_unstemmed | Repression of hypoxia-inducible factor α signaling by Set7-mediated methylation |
title_short | Repression of hypoxia-inducible factor α signaling by Set7-mediated methylation |
title_sort | repression of hypoxia-inducible factor α signaling by set7-mediated methylation |
topic | Molecular Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4446437/ https://www.ncbi.nlm.nih.gov/pubmed/25897119 http://dx.doi.org/10.1093/nar/gkv379 |
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