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The promyelocytic leukemia protein functions as a negative regulator of IFN-gamma signaling

Youn-Hee Choi1, Rosa Bernardi, Pier Paolo Pandolfi

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

Proceedings of the National Academy of Sciences of the United States of America
|November 24, 2006
PubMed

Insights

Promyelocytic leukemia (PML) protein negatively regulates interferon-gamma (IFN-gamma) signaling. PML deficiency enhances IFN-gamma-induced STAT-1alpha activity, suggesting PML inhibits STAT-1alpha DNA binding.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Biology

Background:

  • Interferon-gamma (IFN-gamma) is a key immunomodulatory cytokine.
  • STAT-1alpha is a transcription factor mediating IFN-gamma-induced gene expression.
  • Promyelocytic leukemia (PML) protein regulates gene transcription.

Purpose of the Study:

  • To investigate the role of PML in IFN-gamma signaling.
  • To determine how PML influences STAT-1alpha transcriptional activity.

Main Methods:

  • Comparison of IFN-gamma signaling in PML-wild-type (Pml(+/+)) and PML-deficient (Pml(-/-)) mouse embryonic fibroblasts (MEF).
  • Assessment of STAT-1alpha transcriptional activity and DNA-binding activity.
  • Analysis of endogenous IFN-gamma-regulated gene expression.
  • Investigation of PML-STAT-1alpha complex formation.

Main Results:

  • Pml(-/-) MEF showed enhanced IFN-gamma-induced STAT-1alpha transcriptional activity compared to Pml(+/+) MEF.
  • Reconstitution of PML in Pml(-/-) MEF reduced STAT-1alpha activity.
  • Numerous IFN-gamma-regulated genes were upregulated in Pml(-/-) MEF.
  • IFN-gamma-mediated STAT-1alpha DNA-binding activity was enhanced in Pml(-/-) cells.
  • IFN-gamma enhanced PML-STAT-1alpha complex formation in the nucleus.

Conclusions:

  • PML acts as an inhibitor of IFN-gamma signaling.
  • PML negatively regulates STAT-1alpha DNA binding and transcriptional activity.
  • PML plays a novel inhibitory role in the IFN-gamma signaling pathway.

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