ORBi: Mottet Denis - Regulation of hypoxia-inducible factor-1alpha protein level during hypoxic conditions by the phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase 3beta pathway in HepG2 cells.

Reference : Regulation of hypoxia-inducible factor-1alpha protein level during hypoxic conditions by...


	Document type :	Scientific journals : Article
	Discipline(s) :	Life sciences : Biochemistry, biophysics & molecular biology Human health sciences : Oncology
	To cite this reference:	http://hdl.handle.net/2268/29049

Title :	Regulation of hypoxia-inducible factor-1alpha protein level during hypoxic conditions by the phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase 3beta pathway in HepG2 cells.
Language :	English
Author, co-author :	Mottet, Denis [Université de Liège - ULg > Département des sciences biomédicales et précliniques > GIGA-R : Labo de recherche sur les métastases >]
	Dumont, Valery [> > > >]
	Deccache, Yann [> > > >]
	Demazy, Catherine [> > > >]
	Ninane, Noelle [> > > >]
	Raes, Martine [> > > >]
	Michiels, Carine [> > > >]
Publication date :	2003
Journal title :	Journal of Biological Chemistry
Publisher :	American Society for Biochemistry and Molecular Biology
Volume :	278
Issue/season :	33
Pages :	31277-85
Audience :	International
ISSN :	0021-9258
e-ISSN :	1083-351X
City :	Baltimore
Country :	MD
Keywords :	[en] 1-Phosphatidylinositol 3-Kinase/metabolism ; Adjuvants, Immunologic/pharmacology ; Anoxia/metabolism ; Carcinoma, Hepatocellular ; Chromones/pharmacology ; DNA-Binding Proteins/genetics/metabolism ; Enzyme Inhibitors/pharmacology ; Gene Expression ; Glycogen Synthase Kinase 3/antagonists & inhibitors/metabolism ; Humans ; Hypoxia-Inducible Factor 1 ; Hypoxia-Inducible Factor 1, alpha Subunit ; Lithium Chloride/pharmacology ; Liver Neoplasms ; Morpholines/pharmacology ; Nuclear Proteins/genetics/metabolism ; Phosphorylation ; Protein-Serine-Threonine Kinases ; Proto-Oncogene Proteins/metabolism ; Proto-Oncogene Proteins c-akt ; Transcription Factors ; Tumor Cells, Cultured
Abstract :	[en] Hypoxia initiates an intracellular signaling pathway leading to the activation of the transcription factor hypoxia-inducible factor-1 (HIF-1). HIF-1 activity is regulated through different mechanisms involving stabilization of HIF-1alpha, phosphorylations, modifications of redox conditions, and interactions with coactivators. However, it appears that some of these steps can be cell type-specific. Among them, the involvement of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in the regulation of HIF-1 by hypoxia remains controversial. Here, we investigated the activation state of PI3K/Akt/glycogen synthase kinase 3beta (GSK3beta) in HepG2 cells. Increasing incubation times in hypoxia dramatically decreased both the phosphorylation of Akt and the inhibiting phosphorylation of GSK3beta. The PI3K/Akt pathway was necessary for HIF-1alpha stabilization early during hypoxia. Indeed, its inhibition was sufficient to decrease HIF-1alpha protein level after 5-h incubation in hypoxia. However, longer exposure (16 h) in hypoxia resulted in a decreased HIF-1alpha protein level compared with early exposure (5 h). At that time, Akt was no longer present or active, which resulted in a decrease in the inhibiting phosphorylation of GSK3beta on Ser-9 and hence in an increased GSK3beta activity. GSK3 inhibition reverted the effect of prolonged hypoxia on HIF-1alpha protein level; more stabilized HIF-1alpha was observed as well as increased HIF-1 transcriptional activity. Thus, a prolonged hypoxia activates GSK3beta, which results in decreased HIF-1alpha accumulation. In conclusion, hypoxia induced a biphasic effect on HIF-1alpha stabilization with accumulation in early hypoxia, which depends on an active PI3K/Akt pathway and an inactive GSK3beta, whereas prolonged hypoxia results in the inactivation of Akt and activation of GSK3beta, which then down-regulates the HIF-1 activity through down-regulation of HIF-1alpha accumulation.
Funders :	Politique Scientifique Fédérale (Belgique) = Belgian Federal Science Policy (PAI) ; Fonds pour la Recherche dans l'Industrie et l'Agriculture (Belgique) ; Fonds de la Recherche Scientifique (Communauté française de Belgique) - F.R.S.-FNRS
Permalink :	http://hdl.handle.net/2268/29049
DOI :	10.1074/jbc.M300763200

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