Document Detail


Ceramide directly activates protein kinase C zeta to regulate a stress-activated protein kinase signaling complex.
MedLine Citation:
PMID:  10962008     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
We have previously shown that interleukin 1 (IL-1)-receptor-generated ceramide induces growth arrest in smooth muscle pericytes by activating an upstream kinase in the stress-activated protein kinase (SAPK) cascade. We now report the mechanism by which ceramide activates the SAPK signaling pathway in human embryonic kidney cells (HEK-293). We demonstrate that ceramide activation of protein kinase C zeta (PKCzeta) mediates SAPK signal complex formation and subsequent growth suppression. Ceramide directly activates both immunoprecipitated and recombinant human PKCzeta in vitro. Additionally, ceramide activates SAPK activity, which is blocked with a dominant-negative mutant of PKCzeta. Co-immunoprecipitation studies reveal that ceramide induces the association of SAPK with PKCzeta, but not with PKCepsilon. In addition, ceramide treatment induces PKCzeta association with phosphorylated SEK and MEKK1, elements of the SAPK signaling complex. The biological role of ceramide to induce cell cycle arrest is mimicked by overexpression of a constitutively active PKCzeta. Together, these studies demonstrate that ceramide induces cell cycle arrest by enhancing the ability of PKCzeta to form a signaling complex with MEKK1, SEK, and SAPK.
Authors:
N A Bourbon; J Yun; M Kester
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  275     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2000 Nov 
Date Detail:
Created Date:  2000-11-27     Completed Date:  2001-01-04     Revised Date:  2011-11-02    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  35617-23     Citation Subset:  IM    
Affiliation:
Department of Pharmacology, Pennsylvania State University, College of Medicine, Hershey, Pennsylvania 17033, USA.
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MeSH Terms
Descriptor/Qualifier:
Blotting, Western
Cell Division
Cell Line
Ceramides / pharmacology*
Culture Media, Serum-Free
Enzyme Activation
Genes, Dominant
Humans
MAP Kinase Kinase Kinase 1*
Mitogen-Activated Protein Kinase 8
Mitogen-Activated Protein Kinases / metabolism*
Phosphorylation
Precipitin Tests
Protein Binding
Protein Kinase C / genetics,  metabolism*
Protein-Serine-Threonine Kinases / metabolism
Recombinant Proteins / metabolism
Signal Transduction
Transfection
Grant Support
ID/Acronym/Agency:
DK53715/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Ceramides; 0/Culture Media, Serum-Free; 0/Recombinant Proteins; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.1/protein kinase C zeta; EC 2.7.11.13/Protein Kinase C; EC 2.7.11.24/Mitogen-Activated Protein Kinase 8; EC 2.7.11.24/Mitogen-Activated Protein Kinases; EC 2.7.11.25/MAP Kinase Kinase Kinase 1; EC 2.7.11.25/MAP3K1 protein, human

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