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MEKK1 regulates the AP-1 dimer repertoire via control of JunB transcription and Fra-2 protein stability

Oncogene volume 24, pages 801–809 (2005)Cite this article

Abstract

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.

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Authors and Affiliations

  1. Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC, 27599-7365, USA

    Bruce D Cuevas, Mark T Uhlik & Gary L Johnson

  2. Department of Pediatrics, School of Medicine, University of Colorado Health Sciences Center, Denver, CO, 80262, USA

    Timothy P Garrington

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  1. Bruce D Cuevas
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  2. Mark T Uhlik
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Correspondence to Bruce D Cuevas or Gary L Johnson.

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Cuevas, B., Uhlik, M., Garrington, T. et al. MEKK1 regulates the AP-1 dimer repertoire via control of JunB transcription and Fra-2 protein stability. Oncogene 24, 801–809 (2005). https://doi.org/10.1038/sj.onc.1208239

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