Nuclear integration of JAK/STAT and Ras/AP-1 signaling by CBP and p300

Proc Natl Acad Sci U S A. 1997 Feb 18;94(4):1074-9. doi: 10.1073/pnas.94.4.1074.

Abstract

We report that interferon gamma (IFN-gamma) inhibits transcription of the macrophage scavenger receptor gene by antagonizing the Ras-dependent activities of AP-1 and cooperating ets domain transcription factors, apparently as a result of competition between AP-1/ets factors and activated STAT1 for limiting amounts of CBP and p300. Consistent with this model, STAT1 alpha interacts directly with CBP in cells, and microinjection of anti-CBP and anti-p300 antibodies blocks transcriptional responses to IFN-gamma. Cells lacking STAT1 fail to inhibit AP-1/ets activity, and overexpression of CBP both potentiates IFN-gamma-dependent transcription and relieves AP-1/ets repression. Thus, CBP and p300 integrate both positive and negative effects of IFN-gamma on gene expression by serving as essential coactivators of STAT1 alpha, modulating gene-specific responses to simultaneous activation of two or more signal transduction pathways.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acetyltransferases*
  • Animals
  • CREB-Binding Protein
  • Cell Cycle Proteins / metabolism
  • DNA-Binding Proteins / metabolism
  • Drug Antagonism
  • Histone Acetyltransferases
  • Humans
  • Interferon-gamma / pharmacology*
  • Macrophage Colony-Stimulating Factor / pharmacology*
  • Macrophages / drug effects*
  • Membrane Proteins*
  • Mice
  • Mice, Transgenic
  • Nuclear Proteins / metabolism
  • Receptors, Immunologic / genetics*
  • Receptors, Lipoprotein*
  • Receptors, Scavenger
  • STAT1 Transcription Factor
  • Scavenger Receptors, Class B
  • Signal Transduction*
  • Trans-Activators / metabolism
  • Transcription Factor AP-1 / metabolism
  • Transcription Factors / metabolism
  • Transcription, Genetic
  • p300-CBP Transcription Factors

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Membrane Proteins
  • Nuclear Proteins
  • Receptors, Immunologic
  • Receptors, Lipoprotein
  • Receptors, Scavenger
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • Scarb1 protein, mouse
  • Scavenger Receptors, Class B
  • Stat1 protein, mouse
  • Trans-Activators
  • Transcription Factor AP-1
  • Transcription Factors
  • Macrophage Colony-Stimulating Factor
  • Interferon-gamma
  • Acetyltransferases
  • CREB-Binding Protein
  • CREBBP protein, human
  • Crebbp protein, mouse
  • Histone Acetyltransferases
  • p300-CBP Transcription Factors
  • p300-CBP-associated factor