Document Detail

Role of c-Jun and proximal phorbol 12-myristate-13-acetate-(PMA)-responsive elements in the regulation of basal and PMA-stimulated plasminogen-activator inhibitor-1 gene expression in HepG2.
MedLine Citation:
PMID:  8917435     Owner:  NLM     Status:  MEDLINE    
Experiments were designed to clarify the role of c-Jun/c-Fos and of putative phorbol 12-myristate-13-acetate-(PMA)-responsive elements (TREs) in the induction of plasminogen-activator inhibitor 1 (PAI-1) gene transcription in the human hepatoma cell line HepG2 by activators of protein kinase C (PKC). Treatment of HepG2 cells with the phorbol ester PMA or serum rapidly and transiently increased c-Jun and c-Fos mRNA and protein levels prior to PAI-1 induction. This induction of PAI-1 gene transcription was found to be dependent on ongoing protein synthesis. An essential role of c-Jun and c-Fos in basal and PMA-stimulated transcription of the PAI-1 gene is demonstrated by our finding that antisense c-jun and c-fos oligodeoxynucleotides both strongly reduced basal and PMA-stimulated PAI-1 synthesis. Since it has already been shown that two TREs between positions -58 and -50 and between -79 and -72 of the PAI-1 promoter are essential for basal and PMA-induced PAI-1 promoter activity ([16]), we examined binding of nuclear proteins to these elements. The protein-binding activity to the TRE between positions -79 and -72 shows very strong PMA induction of an unknown factor, which is not related to c-Jun or c-Fos. The TRE binding between positions -58 and -50 forms two complexes, both containing c-Jun protein. The faster migrating complex primarily contains c-Jun homodimers. The amount of the faster migrating complex is enhanced more than 30-fold in PMA-treated cells, due to a strongly increased binding of c-Jun homodimers and, to a minor extent, to binding of c-Jun/c-Fos heterodimers. Dissociation experiments suggest that the c-Jun/c-Fos heterodimers bind with much lower affinity compared to binding of c-Jun homodimers. Together with the finding that both antisense c-jun and antisense c-fos oligodeoxynucleotides reduced the amount of c-Jun homodimer, we conclude that binding of c-Jun homodimer to the TRE at positions -58 to -50 is important in the basal activity and PMA activation of the PAI-1 promoter in HepG2 cells.
J Arts; J Grimbergen; P J Bosma; H J Rahmsdorf; T Kooistra
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  European journal of biochemistry / FEBS     Volume:  241     ISSN:  0014-2956     ISO Abbreviation:  Eur. J. Biochem.     Publication Date:  1996 Oct 
Date Detail:
Created Date:  1997-01-09     Completed Date:  1997-01-09     Revised Date:  2007-07-23    
Medline Journal Info:
Nlm Unique ID:  0107600     Medline TA:  Eur J Biochem     Country:  GERMANY    
Other Details:
Languages:  eng     Pagination:  393-402     Citation Subset:  IM    
Gaubius Laboratory, TNO-PG, Leiden, The Netherlands.
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MeSH Terms
Base Sequence
Binding Sites / genetics
Cell Line
Culture Media
Cycloheximide / pharmacology
Gene Expression Regulation / drug effects*
Genes, fos / drug effects
Genes, jun* / drug effects
Oligonucleotides, Antisense / genetics,  pharmacology
Plasminogen Activator Inhibitor 1 / genetics*
Protein Synthesis Inhibitors / pharmacology
Proto-Oncogene Proteins c-fos / biosynthesis,  genetics
Proto-Oncogene Proteins c-jun / biosynthesis,  genetics
RNA, Messenger / genetics,  metabolism
Tetradecanoylphorbol Acetate / pharmacology*
Transcription Factor AP-1 / metabolism
Reg. No./Substance:
0/Culture Media; 0/Oligonucleotides, Antisense; 0/Plasminogen Activator Inhibitor 1; 0/Protein Synthesis Inhibitors; 0/Proto-Oncogene Proteins c-fos; 0/Proto-Oncogene Proteins c-jun; 0/RNA, Messenger; 0/Transcription Factor AP-1; 16561-29-8/Tetradecanoylphorbol Acetate; 66-81-9/Cycloheximide

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