| A hypoxia-induced positive feedback loop promotes hypoxia-inducible factor 1alpha stability through miR-210 suppression of glycerol-3-phosphate dehydrogenase 1-like. | |
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MedLine Citation:
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PMID: 21555452 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Oxygen-dependent regulation of the transcription factor HIF-1α relies on a family of prolyl hydroxylases (PHDs) that hydroxylate hypoxia-inducible factor 1α (HIF-1α) protein at two prolines during normal oxygen conditions, resulting in degradation by the proteasome. During low-oxygen conditions, these prolines are no longer hydroxylated and HIF-1α degradation is blocked. Hypoxia-induced miRNA-210 (miR-210) is a direct transcriptional target of HIF-1α, but its complete role and targets during hypoxia are not well understood. Here, we identify the enzyme glycerol-3-phosphate dehydrogenase 1-like (GPD1L) as a novel regulator of HIF-1α stability and a direct target of miR-210. Expression of miR-210 results in stabilization of HIF-1α due to decreased levels of GPD1L resulting in an increase in HIF-1α target genes. Altering GPD1L levels by overexpression or knockdown results in a decrease or increase in HIF-1α stability, respectively. GPD1L-mediated decreases in HIF-1α stability can be reversed by pharmacological inhibition of the proteasome or PHD activity. When rescued from degradation by proteasome inhibition, elevated amounts of GPD1L cause hyperhydroxylation of HIF-1α, suggesting increases in PHD activity. Importantly, expression of GPD1L attenuates the hypoxic response, preventing complete HIF-1α induction. We propose a model in which hypoxia-induced miR-210 represses GPD1L, contributing to suppression of PHD activity, and increases of HIF-1α protein levels. |
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Authors:
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Timothy J Kelly; Amanda L Souza; Clary B Clish; Pere Puigserver |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. Date: 2011-05-09 |
Journal Detail:
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Title: Molecular and cellular biology Volume: 31 ISSN: 1098-5549 ISO Abbreviation: Mol. Cell. Biol. Publication Date: 2011 Jul |
Date Detail:
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Created Date: 2011-06-10 Completed Date: 2011-08-23 Revised Date: 2012-03-06 |
Medline Journal Info:
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Nlm Unique ID: 8109087 Medline TA: Mol Cell Biol Country: United States |
Other Details:
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Languages: eng Pagination: 2696-706 Citation Subset: IM |
Affiliation:
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Department of Cancer Biology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Cell Hypoxia Feedback, Physiological* Glycerolphosphate Dehydrogenase / genetics, metabolism* HEK293 Cells HeLa Cells Humans Hypoxia-Inducible Factor 1, alpha Subunit / metabolism* MicroRNAs / genetics, metabolism* Neoplasms / metabolism* Protein Stability Transcription, Genetic |
| Grant Support | |
ID/Acronym/Agency:
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R01 DK069966/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Hypoxia-Inducible Factor 1, alpha Subunit; 0/MIRN210 microRNA, human; 0/MicroRNAs; EC 1.1.-/GPD1-L protein, human; EC 1.1.-/Glycerolphosphate Dehydrogenase |
| Comments/Corrections | |
Erratum In:
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Mol Cell Biol. 2012 Feb;32(4):898 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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