2024-03-29T01:02:42Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/306432021-12-28T16:09:10Zcom_10261_105com_10261_1col_10261_358
Extended ischemia prevents HIF1α degradation at reoxygenation by impairing prolyl-hydroxylation. Role of Krebs cycle metabolites
Serra-Pérez, Anna
Planas, Anna M.
Santalucía, Tomàs
Gene expression
Glucose
Ischemia
Neuroblastoma
Transcription factors
Transcriptional regulation
HIF
Hypoxia
El pdf del artículo es la versión post-print.-- et al.
Hypoxia-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.
S-P. is recipient of a predoctoral fellowship from the Generalitat de Catalunya, Spain. A.N.O’M. is supported by a FPI fellowship from the Ministerio de Educación y Ciencia. T.S. held a Ramón y Cajal scientist contract from the Spanish Ministry of Science and Innovation (MICINN) and is currently a participant of the Program for Stabilisation of Investigators from the “Direcció d’Estratègia i Coordinació del Departament de Salut” from the Generalitat de Catalunya. This work was funded by projects from MICINN (projects SAF2005-05793-C02-02 and SAF2008-04515-C02-02). E.B. is funded by the Grant SAF2007-64597, the ETORTEK Research Program and the Bizkaia Xede Program from Bizkaia Country.
Peer reviewed
2010-12-21T11:18:47Z
2010-12-21T11:18:47Z
2010-06-11
artículo
http://purl.org/coar/resource_type/c_6501
Journal of Biological Chemistry 285(24): 18217-18224 (2010)
0021-9258
http://hdl.handle.net/10261/30643
10.1074/jbc.M110.101048
20368331
en
Postprint
http://dx.doi.org/10.1074/jbc.M110.101048
open
American Society for Biochemistry and Molecular Biology