Document Detail

MEKK1 regulates the AP-1 dimer repertoire via control of JunB transcription and Fra-2 protein stability.
MedLine Citation:
PMID:  15558021     Owner:  NLM     Status:  MEDLINE    
Activator protein 1 (AP-1) transcription factor dimers are composed of Jun, Fos, and ATF member proteins, but the mechanisms that determine AP-1 composition are not clearly defined and the function of specific dimers is not well understood. MEKK1 is a mitogen-activated protein kinase (MAPK) kinase kinase and an ubiquitin ligase that regulates both the extracellular signal-regulated kinase 1/2 and the c-Jun amino-terminal kinase. Herein, we demonstrate that MEKK1 regulates the AP-1 protein repertoire. Both FGF-2 and phorbol ester-inducible urokinase-type plasminogen activator (uPA) expression requires AP-1 binding to an enhancer element in the uPA promoter, and we have previously shown that FGF-2 or PMA induction of uPA expression is strongly dependent on MEKK1. JunB mRNA is significantly increased in MEKK1-/- cells, demonstrating that MEKK1 suppresses JunB mRNA expression. Upregulation of JunB expression in MEKK1-/- cells forms an inhibitory AP-1 complex that binds to the uPA promoter and inhibits uPA transcription. MEKK1 also regulates Fra-2 protein stability by inducing Fra-2 ubiquitination and degradation. MEKK1 regulates AP-1-dependent gene expression by regulating the expression, activity and degradation of component members of the AP-1 complex. Controlling the repertoire of a transcription factor complex is a newly defined function for an MAPK kinase kinase.
Bruce D Cuevas; Mark T Uhlik; Timothy P Garrington; Gary L Johnson
Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Oncogene     Volume:  24     ISSN:  0950-9232     ISO Abbreviation:  Oncogene     Publication Date:  2005 Jan 
Date Detail:
Created Date:  2005-01-28     Completed Date:  2005-03-07     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  8711562     Medline TA:  Oncogene     Country:  England    
Other Details:
Languages:  eng     Pagination:  801-9     Citation Subset:  IM    
Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7365, USA.
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MeSH Terms
Base Sequence
Cell Nucleus / physiology
Cells, Cultured
DNA-Binding Proteins / metabolism*
Embryo, Mammalian
Fos-Related Antigen-2
MAP Kinase Kinase Kinase 1 / deficiency,  genetics,  physiology*
Molecular Sequence Data
Oligonucleotide Probes
Promoter Regions, Genetic
Proto-Oncogene Proteins c-jun / genetics*
Tetradecanoylphorbol Acetate / pharmacology
Transcription Factor AP-1 / metabolism*
Transcription Factors / metabolism*
Transcription, Genetic
Urokinase-Type Plasminogen Activator / genetics
Reg. No./Substance:
0/DNA-Binding Proteins; 0/Fos-Related Antigen-2; 0/Fosl2 protein, mouse; 0/Oligonucleotide Probes; 0/Proto-Oncogene Proteins c-jun; 0/Transcription Factor AP-1; 0/Transcription Factors; 16561-29-8/Tetradecanoylphorbol Acetate; EC Kinase Kinase Kinase 1; EC Plasminogen Activator

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

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