Document Detail

Activation mechanisms of the urokinase-type plasminogen activator promoter by hepatocyte growth factor/scatter factor.
MedLine Citation:
PMID:  10347197     Owner:  NLM     Status:  MEDLINE    
Hepatocyte growth factor/scatter factor (HGF/SF) is a pleiotropic effector inducing invasion and metastasis of tumor cells that express the Met tyrosine kinase receptor. One of the effectors of HGF/SF is the urokinase-type plasminogen activator, a serine protease that facilitates tumor progression and metastasis by controlling the synthesis of the extracellular matrix degrading plasmin. Stimulation of NIH 3T3 cells that were stably transfected with the human Met receptor (NIH 3T3-Methum) with HGF/SF induced a trans-activation of the urokinase promoter and urokinase secretion. Induction of the urokinase promoter by HGF/SF via the Met receptor was blocked by co-expression of a dominant-negative Grb2 and Sos1 expression construct. Further, the expression of the catalytically inactive mutants of Ha-Ras, RhoA, c-Raf, and Erk2 or addition of the Mek1-specific inhibitor PD 098059 abrogated the stimulation of the urokinase promoter by HGF/SF. A sequence residing between -2109 and -1870 base pairs (bp) was critical for stimulation of the urokinase gene by HGF/SF. Mobility shift assays with oligonucleotides spanning an AP-1 site at -1880 bp or a combined PEA3/AP-1 site at -1967 bp showed binding of nuclear factors from NIH 3T3-Methum cells. Expression of an expression plasmid that inhibits DNA binding of AP-1 proteins (A-Fos) abrogated inducible and basal activation of the urokinase promoter. Nuclear extract from unstimulated NIH 3T3-Methum cells contained more JunD and showed a stronger JunD supershift with the AP-1 oligonucleotides, compared with HGF/SF-stimulated cells. Consistent with the levels of JunD expression being functionally important for basal expression of the urokinase promoter, we found that overexpression of wild type JunD inhibited the induction of the urokinase promoter by HGF/SF. These data suggest that the induction of urokinase by HGF/SF is regulated by a Grb2/Sos1/Ha-Ras/c-Raf/RhoA/Mek1/Erk2/c-++ +Jun-dependent mitogen-activated protein kinase pathway.
S Ried; C Jäger; M Jeffers; G F Vande Woude; H Graeff; M Schmitt; E Lengyel
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  274     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  1999 Jun 
Date Detail:
Created Date:  1999-07-01     Completed Date:  1999-07-01     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  16377-86     Citation Subset:  IM    
Department of Obstetrics and Gynecology, Technische Universität München, D-81675 München, Germany.
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MeSH Terms
3T3 Cells
DNA / metabolism
Enzyme Activation
Gene Expression Regulation, Enzymologic*
Hepatocyte Growth Factor / metabolism*
Promoter Regions, Genetic*
Protein Precursors / metabolism*
Proto-Oncogene Proteins c-met / metabolism
Signal Transduction
Transcription Factor AP-1 / metabolism
Urokinase-Type Plasminogen Activator / genetics*,  metabolism
Reg. No./Substance:
0/Protein Precursors; 0/Transcription Factor AP-1; 0/pro-hepatocyte growth factor; 67256-21-7/Hepatocyte Growth Factor; 9007-49-2/DNA; EC Proteins c-met; EC Plasminogen Activator

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