Document Detail

Dihydroceramide-based response to hypoxia.
MedLine Citation:
PMID:  21914808     Owner:  NLM     Status:  MEDLINE    
To understand the mechanisms of ceramide-based responses to hypoxia, we performed a mass spectrometry-based survey of ceramide species elicited by a wide range of hypoxic conditions (0.2-5% oxygen). We describe a rapid, time-dependent, marked up-regulation of dihydroceramides (DHCs) in mammalian cells and in the lungs of hypoxic rats. The increase affected all DHC species and was proportional with the depth and duration of hypoxia, ranging from 2- (1 h) to 10-fold (24 h), with complete return to normal after 1 h of reoxygenation at the expense of increased ceramides. We demonstrate that a DHC-based response to hypoxia occurs in a hypoxia-inducible factor-independent fashion and is catalyzed by the DHC desaturase (DEGS) in the de novo ceramide pathway. Both the impact of hypoxia on DHC molecular species and its inhibitory effect on cell proliferation were reproduced by knockdown of DEGS1 or DEGS2 by siRNA during normoxia. Conversely, overexpression of DEGS1 or DEGS2 attenuated the DHC accumulation and increased cell proliferation during hypoxia. Based on the amplitude and kinetics of DHC accumulation, the enzymatic desaturation of DHCs fulfills the criteria of an oxygen sensor across physiological hypoxic conditions, regulating the balance between biologically active components of ceramide metabolism.
Cecilia M Devlin; Tim Lahm; Walter C Hubbard; Mary Van Demark; Kevin C Wang; Xue Wu; Alicja Bielawska; Lina M Obeid; Mircea Ivan; Irina Petrache
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2011-09-13
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  286     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2011 Nov 
Date Detail:
Created Date:  2011-10-31     Completed Date:  2012-01-09     Revised Date:  2013-06-27    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  38069-78     Citation Subset:  IM    
Department of Medicine, Indiana University, Indianapolis, Indiana 46202, USA.
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MeSH Terms
Biosensing Techniques
Cell Line, Tumor
Cell Proliferation
Ceramides / chemistry,  pharmacology*
Dose-Response Relationship, Drug
Mass Spectrometry / methods
Oxidoreductases / chemistry*
Oxygen / chemistry
RNA, Small Interfering / metabolism
Rats, Sprague-Dawley
Grant Support
Reg. No./Substance:
0/Ceramides; 0/RNA, Small Interfering; 0/dihydroceramide; 7782-44-7/Oxygen; EC 1.-/Oxidoreductases; EC 1.3.1.-/dihydroceramide desaturase
Erratum In:
J Biol Chem. 2012 May 18;287(21):17425

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