High level class II trans-activator induction does not occur with transient activation of the IFN-gamma signaling pathway.
Gene activation in early development is highly dependent on precise concentrations of trans-acting factors for the activation of different genes at differing points in the embryo. Thus, not only is the presence or absence of a particular trans-activator or repressor relevant in determining gene activation, but also the concentration of the regulatory protein must be above or below a certain threshold for proper gene regulation. Signaling pathways in somatic cells are thought to represent cascades of on/off switches, mediated most commonly by phosphorylation. Here we demonstrate a quantitative mechanism for regulating the level of a component of the IFN-gamma signaling pathway that in effect represents the differential sensitivities of STAT1, IFN-regulatory factor-1, and class II trans-activator (CIITA) to IFN-gamma. Unlike developmental gene regulation, in which specificity of gene activation is a function of regulatory protein concentrations, specificity of gene activation in the IFN-gamma signaling pathway is regulated by the duration of the activation of the primary IFN-gamma-regulatory protein, STAT1. This result most likely explains previously reported data indicating that a minimum amount of IFN-gamma is required for MHC class II gene activation despite the fact that the level of the IFN-gamma-inducible factor directly required for MHC class II induction, CIITA, directly correlates with the level of MHC class II expression. The induction of a high level of CIITA is dependent on sustained IFN-gamma signaling. The possible implications of this result for tumorigenesis are discussed.
Eason
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DD
Department of Biochemistry and Molecular Biology, College of Medicine, University of South Florida, Tampa, FL 33612, USA.
Blanck
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D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000378:metabolism; D004306:Dose-Response Relationship, Immunologic; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology*; D005802:Genes, MHC Class II; D006801:Humans; D050856:Interferon Regulatory Factor-1; D007371:Interferon-gamma / Q000378:metabolism / Q000502:physiology*; D009687:Nuclear Proteins; D010750:Phosphoproteins / Q000096:biosynthesis / Q000378:metabolism; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000235:genetics* / Q000276:immunology*; D013997:Time Factors; D015534:Trans-Activators / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D010750:Phosphoproteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D007371:Interferon-gamma