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MEKK1 plays a critical role in activating the transcription factor C/EBP-beta-dependent gene expression in response

Sanjit K Roy1, Junbo Hu, Qingjun Meng

  • 1Department of Microbiology and Immunology, Molecular and Cellular Biology Program, Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.

Proceedings of the National Academy of Sciences of the United States of America
|June 6, 2002
PubMed

Insights

Interferon-gamma (IFN-gamma) activates gene expression via the GATE element, regulated by MEKK1-MEK1-ERK1/2 kinases. This pathway is crucial for CCAAT/enhancer-binding protein-beta (C/EBP-beta)-driven transcription.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Immunology

Background:

  • Interferon-gamma (IFN-gamma) is a key cytokine regulating cellular responses.
  • Gene transcription is controlled by specific transcription factors and response elements.
  • CCAAT/enhancer-binding protein-beta (C/EBP-beta) is a transcription factor involved in cellular processes.

Purpose of the Study:

  • To elucidate the signaling pathway regulating C/EBP-beta-driven gene expression induced by IFN-gamma.
  • To identify the kinases involved in the activation of the gamma-IFN-activated transcriptional element (GATE).

Main Methods:

  • Utilized mutant cells, chemical inhibitors, and dominant-negative inhibitors.
  • Investigated the role of MEK1, ERK, Raf-1, and MEKK1 in GATE-driven gene expression.
  • Assessed the impact of MEKK1 deficiency or inhibition on ERK activation and gene expression.

Main Results:

  • GATE-driven gene expression is dependent on MEK1 and ERKs, but not Raf-1.
  • MEKK1 is essential for ERK activation and GATE-dependent gene expression.
  • Dominant-negative MEKK1 inhibits C/EBP-beta-driven gene expression stimulated by IFN-gamma.

Conclusions:

  • An IFN-gamma-stimulated signaling pathway involving MEKK1-MEK1-ERK1/2 kinases regulates C/EBP-beta-dependent gene expression.
  • This pathway is critical for the transcriptional activity mediated by the GATE element.

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