English   español  
Please use this identifier to cite or link to this item: http://hdl.handle.net/10261/30643
Share/Impact:
Statistics
logo share SHARE logo core CORE   Add this article to your Mendeley library MendeleyBASE

Visualizar otros formatos: MARC | Dublin Core | RDF | ORE | MODS | METS | DIDL
Exportar a otros formatos:

Title

Extended ischemia prevents HIF1α degradation at reoxygenation by impairing prolyl-hydroxylation. Role of Krebs cycle metabolites

AuthorsSerra-Pérez, Anna ; Planas, Anna M. ; Santalucía, Tomàs
KeywordsGene expression
Glucose
Ischemia
Neuroblastoma
Transcription factors
Transcriptional regulation
HIF
Hypoxia
Issue Date11-Jun-2010
PublisherAmerican Society for Biochemistry and Molecular Biology
CitationJournal of Biological Chemistry 285(24): 18217-18224 (2010)
AbstractHypoxia-inducible factor (HIF) is a heterodimeric transcription factor that activates the cellular response to hypoxia. The HIF1α subunit is constantly synthesized and degraded under normoxia, but degradation is rapidly inhibited when oxygen levels drop. Oxygen-dependent hydroxylation by prolyl-4-hydroxylases (PHD) mediates HIF1α proteasome degradation. Brain ischemia limits the availability not only of oxygen but also of glucose. We hypothesized that this circumstance could have a modulating effect on HIF. We assessed the separate involvement of oxygen and glucose in HIF1α regulation in differentiated neuroblastoma cells subjected to ischemia. We report higher transcriptional activity and HIF1α expression under oxygen deprivation in the presence of glucose (OD), than in its absence (oxygen and glucose deprivation, OGD). Unexpectedly, HIF1α was not degraded at reoxygenation after an episode of OGD. This was not due to impairment of proteasome function, but was associated with lower HIF1α hydroxylation. Krebs cycle metabolites fumarate and succinate are known inhibitors of PHD, while α-ketoglutarate is a co-substrate of the reaction. Lack of HIF1α degradation in the presence of oxygen was accompanied by a very low α-ketoglutarate/fumarate ratio. Furthermore, treatment with a fumarate analogue prevented HIF1α degradation under normoxia. In all, our data suggest that postischemic metabolic alterations in Krebs cycle metabolites impair HIF1α degradation in the presence of oxygen by decreasing its hydroxylation, and highlight the involvement of metabolic pathways in HIF1α regulation besides the well known effects of oxygen.
DescriptionEl pdf del artículo es la versión post-print.-- et al.
Publisher version (URL)http://dx.doi.org/10.1074/jbc.M110.101048
URIhttp://hdl.handle.net/10261/30643
DOI10.1074/jbc.M110.101048
ISSN0021-9258
Appears in Collections:(IIBB) Artículos
Files in This Item:
File Description SizeFormat 
Extended ischemia prevents.pdf683,75 kBAdobe PDFThumbnail
View/Open
Show full item record
Review this work
 

Related articles:


WARNING: Items in Digital.CSIC are protected by copyright, with all rights reserved, unless otherwise indicated.