Document Detail


Ceramide induces Bcl2 dephosphorylation via a mechanism involving mitochondrial PP2A.
MedLine Citation:
PMID:  10400650     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Phosphorylation of Bcl2 at serine 70 is required for its potent anti-apoptotic function. We have recently shown that Bcl2 phosphorylation is a dynamic process that involves the protein kinase C alpha and protein phosphatase 2A (PP2A) (Ruvolo, P. P., Deng, X., Carr, B. K., and May, W. S. (1998) J. Biol. Chem. 273, 25436-25442; and Deng, X., Ito, T., Carr, B. K., Mumby, M. C., and May, W. S. (1998) J. Biol. Chem. 273, 34157-34163). The potent apoptotic agent ceramide can activate a PP2A, suggesting that one potential component of the ceramide-induced death signal may involve the inactivation of Bcl2. Results indicate that C2-ceramide but not inactive C2-dihydroceramide, was found to specifically activate a mitochondrial PP2A, which rapidly and completely induced Bcl2 dephosphorylation and correlated closely with ceramide-induced cell death. Using a genetic approach, the gain-of-function S70E Bcl2 mutation, which mimics phosphorylation, fails to undergo apoptosis even with the addition of high doses of ceramide (IC50 > 50 microM). In contrast, cells overexpressing exogenous wild-type Bcl2 were sensitive to ceramide at dosages where PP2A is fully active and Bcl2 would be expected to be dephosphorylated (IC50 = 14 microM). These findings indicate that in cells expressing functional Bcl2, the mechanism of death action for ceramide may involve, at least in part, a mitochondrial PP2A that dephosphorylates and inactivates Bcl2.
Authors:
P P Ruvolo; X Deng; T Ito; B K Carr; W S May
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  274     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  1999 Jul 
Date Detail:
Created Date:  1999-08-19     Completed Date:  1999-08-19     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  20296-300     Citation Subset:  IM    
Affiliation:
Sealy Center for Oncology and Hematology and Department of Internal Medicine, The University of Texas Medical Branch, Galveston, Texas 77555-1048, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Ceramides / pharmacology*
Humans
Mice
Mitochondria / enzymology*
Phosphoprotein Phosphatases / metabolism*
Phosphorylation
Protein Phosphatase 2
Proto-Oncogene Proteins c-bcl-2 / metabolism*
Tumor Cells, Cultured
Grant Support
ID/Acronym/Agency:
CA44649/CA/NCI NIH HHS; CA47993/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Ceramides; 0/Proto-Oncogene Proteins c-bcl-2; EC 3.1.3.16/Phosphoprotein Phosphatases; EC 3.1.3.16/Protein Phosphatase 2

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