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High Level Class II trans-Activator Induction Does Not Occur with Transient Activation of the IFN- Signaling Pathway¹

Donna D. Eason^* and George Blanck^2,*,

^* Department of Biochemistry and Molecular Biology, College of Medicine, and Immunology Program, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, FL 33612

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- signaling pathway that in effect represents the differential sensitivities of STAT1, IFN-regulatory factor-1, and class II trans-activator (CIITA) to IFN-. Unlike developmental gene regulation, in which specificity of gene activation is a function of regulatory protein concentrations, specificity of gene activation in the IFN- signaling pathway is regulated by the duration of the activation of the primary IFN--regulatory protein, STAT1. This result most likely explains previously reported data indicating that a minimum amount of IFN- is required for MHC class II gene activation despite the fact that the level of the IFN--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- signaling. The possible implications of this result for tumorigenesis are discussed.

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