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Interferon-gamma-activated STAT-1alpha suppresses MMP-9 gene transcription by sequestration of the coactivators

Zhendong Ma1, Mi Jung Chang, Reesha C Shah

  • 1Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL 35294-0005, USA.

Journal of Leukocyte Biology
|May 17, 2005
PubMed

Insights

Interferon-gamma (IFN-gamma) suppresses matrix metalloproteinase-9 (MMP-9) gene transcription via STAT-1alpha. This involves blocking coactivator CBP binding and inhibiting transcription complex assembly, crucial for cancer defense.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cancer Biology

Background:

  • Interferon-gamma (IFN-gamma) is a key cytokine in immune regulation and cancer defense.
  • The precise mechanisms by which IFN-gamma inhibits gene expression, particularly in cancer, remain unclear.
  • Matrix metalloproteinase-9 (MMP-9) is implicated in cancer progression and is a target for IFN-gamma regulation.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying IFN-gamma-mediated suppression of MMP-9 gene transcription.
  • To identify the specific signaling pathways and protein interactions involved in this regulatory process.
  • To understand how IFN-gamma influences transcription factor and coactivator dynamics at the MMP-9 gene locus.

Main Methods:

  • Investigated the role of Signal Transducer and Activator of Transcription-1alpha (STAT-1alpha) phosphorylation in MMP-9 suppression.
  • Assessed the interaction between STAT-1alpha, cyclic AMP response element-binding protein-binding protein (CBP), and the MMP-9 promoter using co-immunoprecipitation and chromatin immunoprecipitation assays.
  • Analyzed the effects of IFN-gamma on histone acetylation (H3/H4) and RNA Polymerase II (Pol II) recruitment to the MMP-9 promoter.

Main Results:

  • IFN-gamma-induced STAT-1alpha, phosphorylated on tyrosine 701, suppresses MMP-9 transcription.
  • IFN-gamma promotes the association of STAT-1alpha with CBP while decreasing CBP's binding to the MMP-9 promoter.
  • IFN-gamma inhibits MMP-9 transcription by reducing H3/H4 acetylation and blocking Pol II recruitment, without affecting CBP stability or chromatin remodeling.
  • IFN-gamma/STAT-1alpha interfere with the assembly of the MMP-9 transcription complex.

Conclusions:

  • IFN-gamma/STAT-1alpha signaling suppresses MMP-9 gene transcription through a multi-faceted mechanism.
  • The pathway involves disruption of coactivator recruitment and inhibition of essential transcription machinery assembly.
  • These findings provide critical insights into the molecular basis of IFN-gamma's anti-cancer effects mediated by gene expression regulation.

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