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.
Krause
Christopher D
CD
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.
He
Wen
W
Kotenko
Sergei
S
Pestka
Sidney
S
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