Abstract
Class II transactivator (CIITA) is required for both constitutive and inducible expression of MHC class II genes. IFN-γ induced expression of CIITA in various cell types is directed by CIITA type IV promoter. The two transactivators, STAT1 and IRF-1, mediate the IFN-γ activation of the type IV promoter by binding to the GAS and IRF-E of the promoter, respectively. In addition to IRF-1, IRF-2, another member of the IRF family, also activates the human CIITA type IV promoter, and IRF-2 cooperates with IRF-1 to activate the promoter in transient transfection assays. IRF-1 and IRF-2 can co-occupy the IRF-E of the human CIITA type IV promoter. To understand the effect of loss of IRF-2 on the endogenous CIITA expression, we assayed for CIITA expression in IRF-2 knock-out mice. Both basal and IFN-γ induced CIITA expression were reduced in IRF-2 knock-out mice. At least half of the amount of inducible CIITA mRNA depends on IRF-2. The reduction of IFN-γ induced CIITA mRNA in IRF-2 knock-out mice was due to the reduction of the type IV CIITA mRNA induction. The reduction of basal CIITA mRNA was apparently due to the reduction of CIITA mRNA originating from other promoters. These data indicate that IRF-2, like IRF-1, plays a critical role in the regulation of the endogenous CIITA gene. The implications in understanding the previously described phenotypes of IRF-2 defective mice are discussed.
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Acknowledgements
We thank Sue Plyte and Tak Mak (Amgen Institute) for providing the IRF-2 KO mice, Sue Corbitt and R Engelman (College of Medicine Animal Facility, University of South Florida) for help with animal care, Marybeth Colter and the H Lee Moffitt Cancer Center Molecular Biology Core Facility for assistance with DNA sequencing. We also thank Donna Eason for helpful discussion and Ping Lai for technical assistance. This work was supported by grants from National Cancer Institute (RO1CA81497-01) and American Cancer Society (RPG-98-184-01-CIM).
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Xi, H., Goodwin, B., Shepherd, A. et al. Impaired class II transactivator expression in mice lacking interferon regulatory factor-2. Oncogene 20, 4219–4227 (2001). https://doi.org/10.1038/sj.onc.1204556
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DOI: https://doi.org/10.1038/sj.onc.1204556
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