Document Detail


An inhibitor of c-jun aminoterminal kinase (SP600125) represses c-Jun activation, DNA-binding and PMA-inducible 92-kDa type IV collagenase expression.
MedLine Citation:
PMID:  12031798     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The 92-kDa type IV collagenase (MMP-9) contributes to tumor invasion and metastases and strategies to down-regulate its expression could ultimately be of clinical utility. Although the expression of this collagenase is regulated by numerous growth factors, the signaling pathways that transduce these signals are fewer in number and therefore represent pharmacological targets. In this regard, we previously reported that MMP-9 expression was regulated by the c-jun amino terminal kinase (JNK) signaling cascade. Therefore, we undertook a study to determine the efficacy of a novel compound (SP600125), which binds to the ATP binding site of all known JNKs, in repressing MMP-9 expression. In OVCAR-3 cells, SP600125 inhibited the PMA-dependent secretion of MMP-9 in a time-dependent manner and over a dose range that blocked c-Jun phosphorylation and AP-1 binding. SP600125 repressed the activity of a PMA-stimulated MMP-9 promoter-driven luciferase reporter, suggesting that diminished secretion of this collagenase reflected reduced transcription. Further, the activity of a GAL4-driven reporter in PMA-treated cells, co-transfected with an expression construct encoding the trans-activation domain of c-Jun fused to the DNA binding domain of GAL4, was repressed by SP600125. These findings indicate the efficacy of SP600125 in inhibiting c-Jun activation, DNA-binding and the PMA-dependent induction of MMP-9 expression.
Authors:
M Shin; C Yan; D Boyd
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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:  Biochimica et biophysica acta     Volume:  1589     ISSN:  0006-3002     ISO Abbreviation:  Biochim. Biophys. Acta     Publication Date:  2002 May 
Date Detail:
Created Date:  2002-05-28     Completed Date:  2002-08-27     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  0217513     Medline TA:  Biochim Biophys Acta     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  311-6     Citation Subset:  IM    
Affiliation:
MD Anderson Cancer Center, Department of Cancer Biology, Box 179, 1515 Holcombe Blvd., Houston, TX 77030, USA.
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MeSH Terms
Descriptor/Qualifier:
Anthracenes / pharmacology*
DNA / metabolism
Enzyme Induction / drug effects
Genes, jun / drug effects
Humans
JNK Mitogen-Activated Protein Kinases
Matrix Metalloproteinase 9 / biosynthesis*,  genetics
Mitogen-Activated Protein Kinases / antagonists & inhibitors*
Promoter Regions, Genetic
Tetradecanoylphorbol Acetate
Transcription Factors / metabolism
Tumor Cells, Cultured
Grant Support
ID/Acronym/Agency:
P50 DE11906-01/DE/NIDCR NIH HHS; R01 CA58311/CA/NCI NIH HHS; R01 DE10845/DE/NIDCR NIH HHS
Chemical
Reg. No./Substance:
0/Anthracenes; 0/Transcription Factors; 0/anthra(1,9-cd)pyrazol-6(2H)-one; 16561-29-8/Tetradecanoylphorbol Acetate; 9007-49-2/DNA; EC 2.7.11.24/JNK Mitogen-Activated Protein Kinases; EC 2.7.11.24/Mitogen-Activated Protein Kinases; EC 3.4.24.35/Matrix Metalloproteinase 9

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


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