Document Detail


A hypoxia-induced positive feedback loop promotes hypoxia-inducible factor 1alpha stability through miR-210 suppression of glycerol-3-phosphate dehydrogenase 1-like.
MedLine Citation:
PMID:  21555452     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Timothy J Kelly; Amanda L Souza; Clary B Clish; Pere Puigserver
Publication Detail:
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:
Title:  Molecular and cellular biology     Volume:  31     ISSN:  1098-5549     ISO Abbreviation:  Mol. Cell. Biol.     Publication Date:  2011 Jul 
Date Detail:
Created Date:  2011-06-10     Completed Date:  2011-08-23     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  8109087     Medline TA:  Mol Cell Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2696-706     Citation Subset:  IM    
Affiliation:
Department of Cancer Biology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA.
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MeSH Terms
Descriptor/Qualifier:
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:
R01 DK069966/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
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:
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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