Modulation of the activation of Stat1 by the interferon-gamma receptor complex

Cell Res. 2006 Jan;16(1):113-23. doi: 10.1038/sj.cr.7310015.

Abstract

The activation of Stat1 by the interferon-gamma (IFN-gamma) receptor complex is responsible for the transcription of a significant portion of IFN-gamma induced genes. Many of these genes are responsible for the induction of an apoptotic state in response to IFN-gamma. In the absence of Stat1 activation, IFN-gamma instead induces a proliferative response. Modifying Stat1 activation by IFN-gamma may have pharmacological benefits. We report that the rate of activation of Stat1 can be altered in HeLa cells by overexpressing either the IFN-gammaR1 chain or the IFN-gammaR2 chain. These alterations occur in hematopoietic cell lines: Raji cells and monocytic cell lines, which have average and above-average IFN-gammaR2 surface expression, activate Stat1 similarly to HeLa cells and HeLa cells overexpressing IFNgammaR2, respectively. The rapid Stat1 activation seen in HeLa cells can be inhibited by overexpressing a chimeric IFN-gammaR2 chain that does not bind Jak2 or (when high concentrations of IFN-gamma are used) by overexpressing IFN-gammaR1. These data are consistent with a model in which the recruitment of additional Jak2 activity to a signaling complex accelerates the rate of Stat1 activation. We conclude that the rate of activation of Stat1 in cells by IFN-gamma can be modified by regulating either receptor chain and speculate that pharmacological agents which modify receptor chain expression may alter IFN-gamma receptor signal transduction.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Gene Expression Regulation / drug effects*
  • HeLa Cells
  • Humans
  • Interferon gamma Receptor
  • Interferon-gamma / pharmacology
  • Receptors, Interferon / metabolism*
  • Receptors, Interferon / physiology*
  • STAT1 Transcription Factor / metabolism*
  • STAT1 Transcription Factor / physiology
  • Signal Transduction
  • Trans-Activators
  • Transcription, Genetic*
  • Transfection

Substances

  • Receptors, Interferon
  • STAT1 Transcription Factor
  • Trans-Activators
  • Interferon-gamma