Document Detail

Impairment of Na(+),K(+)-ATPase in CD95(APO-1)-induced human T-cell leukemia cell apoptosis mediated by glutathione depletion and generation of hydrogen peroxide.
MedLine Citation:
PMID:  17554377     Owner:  NLM     Status:  MEDLINE    
Human T-cell leukemia is a malignant disease that needs various regimens of cytotoxic chemotherapy to overcome drug resistance. Recently, Na(+),K(+)-ATPase has emerged as a potential target for cancer therapy. However, its exact signaling pathway in human T-cell leukemia cell death has not been well defined. In the current study, we found CD95(APO-1) was able to trigger the internalization of plasma membrane Na(+),K(+)-ATPase in Jurkat cells or primary T cells as a mechanism to suppress its activity. This internalization was closely relevant to intracellular glutathione (GSH) depletion in Jurkat cells downstream of Fas-associated death domain protein (FADD) and caspase 8. GSH depletion in Fas L-treated Jurkat cells induced the generation of hydrogen peroxide (H(2)O(2)), which subsequently increased the serine phosphorylation of Na(+),K(+)-ATPase alpha1 subunit. Exogenous H(2)O(2) even mimicked the effect of Fas L to upregulate the serine phosphorylation of Na(+),K(+)-ATPase alpha1 subunit and suppress Na(+),K(+)-ATPase activity. Overall, our results indicate that CD95(APO-1) induces the FADD- and caspase 8-dependent internalization of Na(+),K(+)-ATPase through intracellular GSH loss, and the subsequent generation of H(2)O(2)-mediated serine phosphorylation of Na(+),K(+)-ATPase alpha1 subunit. Taken together, this study presents a novel regulatory mechanism of Na(+),K(+)-ATPase in CD95(APO-1)-mediated human T-leukemia cell apoptosis.
W Yin; W Cheng; W Shen; L Shu; J Zhao; J Zhang; Z-C Hua
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2007-06-07
Journal Detail:
Title:  Leukemia     Volume:  21     ISSN:  0887-6924     ISO Abbreviation:  Leukemia     Publication Date:  2007 Aug 
Date Detail:
Created Date:  2007-07-19     Completed Date:  2007-09-25     Revised Date:  2013-03-04    
Medline Journal Info:
Nlm Unique ID:  8704895     Medline TA:  Leukemia     Country:  England    
Other Details:
Languages:  eng     Pagination:  1669-78     Citation Subset:  IM    
The State Key Lab of Pharmaceutical Biotechnology, College of Life Science, Nanjing University, Nanjing, People's Republic of China.
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MeSH Terms
Antigens, CD95 / pharmacology*
Caspase 8 / metabolism
Catalase / pharmacology
Cell Membrane / metabolism
Fas Ligand Protein / metabolism
Fas-Associated Death Domain Protein / metabolism
Fluorescent Antibody Technique, Indirect
Glutathione / metabolism*
Hydrogen Peroxide / pharmacology*
Jurkat Cells / drug effects,  metabolism
Leukemia, T-Cell / metabolism,  pathology*
Membrane Potentials / drug effects
Mice, Inbred C57BL
Ouabain / metabolism
Oxidants / pharmacology
Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
Sodium-Potassium-Exchanging ATPase / antagonists & inhibitors*,  metabolism
Superoxide Dismutase / metabolism
Reg. No./Substance:
0/Antigens, CD95; 0/Fas Ligand Protein; 0/Fas-Associated Death Domain Protein; 0/Oxidants; 630-60-4/Ouabain; 70-18-8/Glutathione; 7722-84-1/Hydrogen Peroxide; EC; EC Dismutase; EC protein, human; EC Protein Serine-Threonine Kinases; EC 3.4.22.-/Caspase 8; EC ATPase
Erratum In:
Leukemia. 2007 Nov;21(11):2397

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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