Modulation of the activation of Stat1 by the interferon-gamma receptor complex.
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.
Department of Molecular Genetics, Microbiology and Immunology, Robert Wood Johnson Medical School, The University of Medicine and Dentistry of New Jersey, 675 Hoes Lane West, Piscataway, 08855, USA.
Christopher D
CD
Krause
Wen
W
He
Sergei
S
Kotenko
Sidney
S
Pestka
D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D017471:Receptors, Interferon / Q000378:metabolism* / Q000502:physiology*; D050794:STAT1 Transcription Factor / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction; D015534:Trans-Activators; D014158:Transcription, Genetic; D014162:Transfection; D000096743:Interferon gamma Receptor
D007371:Interferon-gamma; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; D015534:Trans-Activators; D000096743:Interferon gamma Receptor