Scientific Publications

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
AuthorsKelly, TJ, Souza AL, Clish CB, and Puigserver P.
AbstractOxygen-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.
Year of Publication2011
JournalMolecular and cellular biology
Volume31
Issue13
Pages2696-706
Date Published (YYYY/MM/DD)2011/07/01
ISSN Number0270-7306
DOI10.1128/MCB.01242-10
PubMedhttp://www.ncbi.nlm.nih.gov/pubmed/21555452?dopt=Abstract