| Activation of HIF-1alpha in exponentially growing cells via hypoxic stimulation is independent of the Akt/mTOR pathway. | |
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MedLine Citation:
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PMID: 18781596 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Accumulation of HIF-1alpha during normoxic conditions at high cell density has previously been shown to occur and can be used to stabilize HIF-1alpha protein in the absence of a specific anaerobic chamber. However, the impact and origin of this pool of HIF-1alpha, obtained under normoxia, has been underestimated. In this study, we have systematically compared the related pools of HIF-1alpha stabilized in normoxia by high cell density to those obtained at low density in hypoxia. At first glance, these two stimuli appear to have similar outcomes: HIF-1alpha stabilization and induction of HIF-1-dependent genes. However, upon careful analysis, we observed that molecular mechanisms involved are different. We clearly demonstrate that density-dependant HIF-1alpha accumulation during normoxia is due to the cells high consumption of oxygen, as demonstrated by using a respiration inhibitor (oligomycin) and respiratory-defective mutant cells (GSK3). Finally and most importantly, our data indicate that a decrease in AKT activity followed by a total decrease in p70(S6K) phosphorylation reflecting a decrease in mTOR activity occurs during high oxygen consumption, resulting from high cell density. In contrast, hypoxia, even at severe low O(2) levels, only slightly impacts upon the mTOR pathway under low cell density conditions. Thus, activation of HIF-1alpha in exponentially growing cells via hypoxic stimulation is independent of the Akt/mTOR pathway whereas HIF-1alpha activation obtained in high confluency is totally dependent on mTOR pathway as rapamycin totally impaired (i) HIF-1alpha stabilization and (ii) mRNA levels of CA9 and BNIP3, two HIF-target genes. |
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Authors:
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Frédéric Dayan; Rebecca L Bilton; Julie Laferrière; Eric Trottier; Danièle Roux; Jacques Pouyssegur; Nathalie M Mazure |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Journal of cellular physiology Volume: 218 ISSN: 1097-4652 ISO Abbreviation: J. Cell. Physiol. Publication Date: 2009 Jan |
Date Detail:
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Created Date: 2008-11-03 Completed Date: 2008-12-09 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 0050222 Medline TA: J Cell Physiol Country: United States |
Other Details:
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Languages: eng Pagination: 167-74 Citation Subset: IM |
Copyright Information:
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(c) 2008 Wiley-Liss, Inc. |
Affiliation:
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Institute of Developmental Biology and Cancer, CNRS-UMR 6543, Centre Antoine Lacassagne, Nice, France. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cell Count Cell Hypoxia / physiology Cell Line Cell Proliferation Cricetinae Cricetulus Hela Cells Humans Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors, genetics, metabolism* Oxygen Consumption Protein Kinases / metabolism* Proto-Oncogene Proteins c-akt / metabolism* RNA Interference RNA, Small Interfering / genetics Sirolimus / pharmacology |
| Chemical | |
Reg. No./Substance:
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0/Hypoxia-Inducible Factor 1, alpha Subunit; 0/RNA, Small Interfering; 53123-88-9/Sirolimus; EC 2.7.-/Protein Kinases; EC 2.7.1.-/mTOR protein; EC 2.7.11.1/Proto-Oncogene Proteins c-akt |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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