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Mol Cell Biol DOI:10.1128/MCB.01242-10

A hypoxia-induced positive feedback loop promotes hypoxia-inducible factor 1alpha stability through miR-210 suppression of glycerol-3-phosphate dehydrogenase 1-like.

Publication TypeJournal Article
Year of Publication2011
AuthorsKelly, TJ, Souza, AL, Clish, CB, Puigserver, P
JournalMol Cell Biol
Volume31
Issue13
Pages2696-706
Date Published2011 Jul
ISSN1098-5549
KeywordsCell Hypoxia, Feedback, Physiological, Glycerolphosphate Dehydrogenase, HEK293 Cells, HeLa Cells, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, MicroRNAs, Neoplasms, Protein Stability, Transcription, Genetic
Abstract

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.

URLhttp://mcb.asm.org/cgi/pmidlookup?view=long&pmid=21555452
DOI10.1128/MCB.01242-10
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/21555452?dopt=Abstract

Alternate JournalMol. Cell. Biol.
PubMed ID21555452
PubMed Central IDPMC3133367
Grant ListR01 DK069966 / DK / NIDDK NIH HHS / United States