Document Detail


Hypoxia-inducible factor 1 alpha under rapid enzymatic hypoxia: cells sense decrements of oxygen but not hypoxia per se.
MedLine Citation:
PMID:  19007879     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
HIF1 (hypoxia-inducible factor 1 alpha) is considered a central oxygen-threshold sensor in mammalian cells. In the presence of oxygen, HIF1 is marked by prolyl hydroxylases (PHDs) at the oxygen-dependent degradation (ODD) domain for ubiquitination followed by rapid proteasomal degradation. However, the actual mechanisms of oxygen sensing by HIF1 are still controversial. Thus, HIF1 expression correlates poorly with tissue oxygen levels, and PHDs are themselves target genes of HIF1 considered to readjust to new oxygen thresholds. In contrast to hypoxia chambers, we here establish an enzymatic model that allows both the rapid induction of stable hypoxia and independent control of H(2)O(2). Rapid enzymatic hypoxia only transiently induced HIF1 in various cell types and the HIF1 was completely degraded within 8-12 h despite sustained hypoxia. HIF1 degradation under sustained hypoxia could be blocked by a competitive ODD-GFP construct and PHD siRNA, but also by cobalt chloride and micromolar H(2)O(2) levels. Concomitant induction of PHDs further confirmed their role in degrading HIF1 under enzymatic hypoxia. The rapid and complete degradation of HIF1 under enzymatic hypoxia suggests that, in addition to hypoxia sensing, the HIF1/PHD loop may also compensate for fluctuations of tissue oxygen staying tuned to other, e.g., metabolic, signals. In addition to hypoxia chambers, enzymatic hypoxia provides a valuable tool for independently studying the regulatory functions of hypoxia and oxidative stress in vitro.
Authors:
Gunda Millonig; Stephan Hegedüsch; Laren Becker; Helmut-Karl Seitz; Detlef Schuppan; Sebastian Mueller
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-11-01
Journal Detail:
Title:  Free radical biology & medicine     Volume:  46     ISSN:  1873-4596     ISO Abbreviation:  Free Radic. Biol. Med.     Publication Date:  2009 Jan 
Date Detail:
Created Date:  2009-01-15     Completed Date:  2009-10-06     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  8709159     Medline TA:  Free Radic Biol Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  182-91     Citation Subset:  IM    
Affiliation:
Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Dana 501, 330 Brookline Avenue, Boston, MA 02215, USA.
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MeSH Terms
Descriptor/Qualifier:
Anoxia / enzymology,  genetics
Catalase / metabolism
Cell Line
DNA-Binding Proteins / genetics,  metabolism*
Dioxygenases / genetics,  metabolism*
Feedback, Physiological
Glucose Oxidase / metabolism
Humans
Hydrogen Peroxide / metabolism*
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
Oxygen Compounds / analysis
Procollagen-Proline Dioxygenase / genetics,  metabolism*
Protein Binding
Protein Conformation
RNA, Small Interfering / genetics
Transcription Factors / genetics,  metabolism*
Chemical
Reg. No./Substance:
0/DNA-Binding Proteins; 0/Hypoxia-Inducible Factor 1, alpha Subunit; 0/Oxygen Compounds; 0/PHF1 protein, human; 0/RNA, Small Interfering; 0/Transcription Factors; 7722-84-1/Hydrogen Peroxide; EC 1.1.3.4/Glucose Oxidase; EC 1.11.1.6/Catalase; EC 1.13.11.-/Dioxygenases; EC 1.14.11.2/EGLN1 protein, human; EC 1.14.11.2/EGLN3 protein, human; EC 1.14.11.2/Procollagen-Proline Dioxygenase

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