Document Detail

Bcl-2 interrupts the ceramide-mediated pathway of cell death.
MedLine Citation:
PMID:  8643573     Owner:  NLM     Status:  MEDLINE    
Ceramide, a product of sphingomyelin turn-over, has been proposed as a novel lipid second messenger with specific roles in mediating antiproliferative responses including apoptosis and cell cycle arrest. In this study, we examine the relationship between the ceramide-mediated pathway of growth suppression and the bcl-2 protooncogene. In ALL-697 leukemia cells, the addition of the chemotherapeutic agent vincristine resulted in a time-dependent growth suppression characterized by marked apoptosis. The effects of vincristine on cell death were preceded by a prolonged and sustained accumulation of endogenous ceramide levels reaching -10.4 pmol ceramide/nmol phospholipids at 12 hr following the addition of vincristine--an increase of 220% over vehicle-treated cells. Overexpression of bcl-2 resulted in near total protection of cell death in response to vincristine. However, the ceramide response to vincristine was not modulated by overexpression of bcl-2, indicating that bcl-2 does not interfere with ceramide formation. Overexpression of bcl-2 prevented apoptosis in response to ceramide, suggesting that bcl-2 acts at a point downstream of ceramide. On the other hand, bcl-2 did not interfere with the ability of ceramide to activate the retinoblastoma gene product or to induce cell cycle arrest, suggesting that the effects of ceramide on cell cycle arrest can be dissociated from the effects on apoptosis. These studies suggest that ceramide and bcl-2 partake in a common pathway of cell regulation. The results also cast ceramide as a gauge of cell injury rather than an "executor" of cell death with clearly dissociable biological outcomes of its action depending on downstream factors.
J Zhang; N Alter; J C Reed; C Borner; L M Obeid; Y A Hannun
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  93     ISSN:  0027-8424     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  1996 May 
Date Detail:
Created Date:  1996-07-17     Completed Date:  1996-07-17     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  5325-8     Citation Subset:  IM    
Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
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MeSH Terms
Antineoplastic Agents, Phytogenic / pharmacology
Apoptosis* / drug effects
Cell Division / drug effects
Cell Line
Ceramides / pharmacology*,  physiology
Gene Expression
Leukemia, B-Cell
Proto-Oncogene Proteins / biosynthesis*
Proto-Oncogene Proteins c-bcl-2
Recombinant Proteins / biosynthesis
Retinoblastoma Protein / metabolism*
Tumor Cells, Cultured
Vincristine / pharmacology
Reg. No./Substance:
0/Antineoplastic Agents, Phytogenic; 0/Ceramides; 0/Proto-Oncogene Proteins; 0/Proto-Oncogene Proteins c-bcl-2; 0/Recombinant Proteins; 0/Retinoblastoma Protein; 57-22-7/Vincristine

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