PMID- 12764143
OWN - NLM
STAT- MEDLINE
DCOM- 20031110
LR  - 20211203
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 278
IP  - 33
DP  - 2003 Aug 15
TI  - 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.
PG  - 31277-85
AB  - 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.
FAU - Mottet, Denis
AU  - Mottet D
AD  - Laboratory of Biochemistry and Cellular Biology, University of Namur, 61 Rue de 
      Bruxelles, 5000 Namur, Belgium.
FAU - Dumont, Valery
AU  - Dumont V
FAU - Deccache, Yann
AU  - Deccache Y
FAU - Demazy, Catherine
AU  - Demazy C
FAU - Ninane, Noelle
AU  - Ninane N
FAU - Raes, Martine
AU  - Raes M
FAU - Michiels, Carine
AU  - Michiels C
LA  - eng
PT  - Journal Article
DEP - 20030522
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Adjuvants, Immunologic)
RN  - 0 (Chromones)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Morpholines)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Transcription Factors)
RN  - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one)
RN  - EC 2.7.11.1 (AKT1 protein, human)
RN  - EC 2.7.11.1 (GSK3B protein, human)
RN  - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.26 (Glycogen Synthase Kinase 3)
RN  - G4962QA067 (Lithium Chloride)
SB  - IM
MH  - Adjuvants, Immunologic/pharmacology
MH  - Carcinoma, Hepatocellular
MH  - Chromones/pharmacology
MH  - DNA-Binding Proteins/genetics/*metabolism
MH  - Enzyme Inhibitors/pharmacology
MH  - Gene Expression
MH  - Glycogen Synthase Kinase 3/antagonists & inhibitors/*metabolism
MH  - Glycogen Synthase Kinase 3 beta
MH  - Humans
MH  - Hypoxia/*metabolism
MH  - Hypoxia-Inducible Factor 1
MH  - Hypoxia-Inducible Factor 1, alpha Subunit
MH  - Lithium Chloride/pharmacology
MH  - Liver Neoplasms
MH  - Morpholines/pharmacology
MH  - Nuclear Proteins/genetics/*metabolism
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Phosphorylation
MH  - *Protein Serine-Threonine Kinases
MH  - Proto-Oncogene Proteins/*metabolism
MH  - Proto-Oncogene Proteins c-akt
MH  - *Transcription Factors
MH  - Tumor Cells, Cultured
EDAT- 2003/05/24 05:00
MHDA- 2003/11/11 05:00
CRDT- 2003/05/24 05:00
PHST- 2003/05/24 05:00 [pubmed]
PHST- 2003/11/11 05:00 [medline]
PHST- 2003/05/24 05:00 [entrez]
AID - S0021-9258(20)84171-4 [pii]
AID - 10.1074/jbc.M300763200 [doi]
PST - ppublish
SO  - J Biol Chem. 2003 Aug 15;278(33):31277-85. doi: 10.1074/jbc.M300763200. Epub 2003 
      May 22.