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Hypoxia-inducible factor-1α mRNA: a new target for destabilization by tristetraprolin in endothelial cells
Endothelial cells (ECs) are the primary sensors of variations in blood oxygen concentrations. They use the hypoxia-sensitive stabilization of the hypoxia-inducible factor-1α (HIF-1α) transcription factor to engage specific transcriptional programs in response to oxygen changes. The regulation of HIF...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The American Society for Cell Biology
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3172262/ https://www.ncbi.nlm.nih.gov/pubmed/21775632 http://dx.doi.org/10.1091/mbc.E10-07-0617 |
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author | Chamboredon, Sandrine Ciais, Delphine Desroches-Castan, Agnès Savi, Pierre Bono, Françoise Feige, Jean-Jacques Cherradi, Nadia |
author_facet | Chamboredon, Sandrine Ciais, Delphine Desroches-Castan, Agnès Savi, Pierre Bono, Françoise Feige, Jean-Jacques Cherradi, Nadia |
author_sort | Chamboredon, Sandrine |
collection | PubMed |
description | Endothelial cells (ECs) are the primary sensors of variations in blood oxygen concentrations. They use the hypoxia-sensitive stabilization of the hypoxia-inducible factor-1α (HIF-1α) transcription factor to engage specific transcriptional programs in response to oxygen changes. The regulation of HIF-1α expression is well documented at the protein level, but much less is known about the control of its mRNA stability. Using small interfering RNA knockdown experiments, reporter gene analyses, ribonucleoprotein immunoprecipitations, and mRNA half-life determinations, we report a new regulatory mechanism of HIF-1α expression in ECs. We demonstrate that 1) sustained hypoxia progressively decreases HIF-1α mRNA while HIF-1α protein levels rapidly peak after 3 h and then slowly decay; 2) silencing the mRNA-destabilizing protein tristetraprolin (TTP) in ECs reverses hypoxia-induced down-regulation of HIF-1α mRNA; 3) the decrease in the half-life of Luciferase-HIF-1α-3′UTR reporter transcript that is observed after prolonged hypoxia is mediated by TTP; 4) TTP binds specifically to HIF-1α 3′UTR; and 5) the most distal AU-rich elements present in HIF-1α 3′UTR (composed of two hexamers) are sufficient for TTP-mediated repression. Finally, we bring evidence that silencing TTP expression enhances hypoxia-induced increase in HIF-1α protein levels with a concomitant increase in the levels of the carbonic anhydrase enzyme CA IX, thus suggesting that TTP physiologically controls the expression of a panel of HIF-1α target genes. Altogether, these data reveal a new role for TTP in the control of gene expression during the response of endothelial cell to hypoxia. |
format | Online Article Text |
id | pubmed-3172262 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | The American Society for Cell Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-31722622011-11-30 Hypoxia-inducible factor-1α mRNA: a new target for destabilization by tristetraprolin in endothelial cells Chamboredon, Sandrine Ciais, Delphine Desroches-Castan, Agnès Savi, Pierre Bono, Françoise Feige, Jean-Jacques Cherradi, Nadia Mol Biol Cell Articles Endothelial cells (ECs) are the primary sensors of variations in blood oxygen concentrations. They use the hypoxia-sensitive stabilization of the hypoxia-inducible factor-1α (HIF-1α) transcription factor to engage specific transcriptional programs in response to oxygen changes. The regulation of HIF-1α expression is well documented at the protein level, but much less is known about the control of its mRNA stability. Using small interfering RNA knockdown experiments, reporter gene analyses, ribonucleoprotein immunoprecipitations, and mRNA half-life determinations, we report a new regulatory mechanism of HIF-1α expression in ECs. We demonstrate that 1) sustained hypoxia progressively decreases HIF-1α mRNA while HIF-1α protein levels rapidly peak after 3 h and then slowly decay; 2) silencing the mRNA-destabilizing protein tristetraprolin (TTP) in ECs reverses hypoxia-induced down-regulation of HIF-1α mRNA; 3) the decrease in the half-life of Luciferase-HIF-1α-3′UTR reporter transcript that is observed after prolonged hypoxia is mediated by TTP; 4) TTP binds specifically to HIF-1α 3′UTR; and 5) the most distal AU-rich elements present in HIF-1α 3′UTR (composed of two hexamers) are sufficient for TTP-mediated repression. Finally, we bring evidence that silencing TTP expression enhances hypoxia-induced increase in HIF-1α protein levels with a concomitant increase in the levels of the carbonic anhydrase enzyme CA IX, thus suggesting that TTP physiologically controls the expression of a panel of HIF-1α target genes. Altogether, these data reveal a new role for TTP in the control of gene expression during the response of endothelial cell to hypoxia. The American Society for Cell Biology 2011-09-15 /pmc/articles/PMC3172262/ /pubmed/21775632 http://dx.doi.org/10.1091/mbc.E10-07-0617 Text en © 2011 Chamboredon 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 Biology. |
spellingShingle | Articles Chamboredon, Sandrine Ciais, Delphine Desroches-Castan, Agnès Savi, Pierre Bono, Françoise Feige, Jean-Jacques Cherradi, Nadia Hypoxia-inducible factor-1α mRNA: a new target for destabilization by tristetraprolin in endothelial cells |
title | Hypoxia-inducible factor-1α mRNA: a new target for destabilization by tristetraprolin in endothelial cells |
title_full | Hypoxia-inducible factor-1α mRNA: a new target for destabilization by tristetraprolin in endothelial cells |
title_fullStr | Hypoxia-inducible factor-1α mRNA: a new target for destabilization by tristetraprolin in endothelial cells |
title_full_unstemmed | Hypoxia-inducible factor-1α mRNA: a new target for destabilization by tristetraprolin in endothelial cells |
title_short | Hypoxia-inducible factor-1α mRNA: a new target for destabilization by tristetraprolin in endothelial cells |
title_sort | hypoxia-inducible factor-1α mrna: a new target for destabilization by tristetraprolin in endothelial cells |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3172262/ https://www.ncbi.nlm.nih.gov/pubmed/21775632 http://dx.doi.org/10.1091/mbc.E10-07-0617 |
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