International Immunology, Vol. 16, No. 2, pp. 265-274,
February 2004
© 2004 Japanese Society for Immunology
Molecular basis of Stat1 and PU.1 cooperation in cytokine-induced Fc
receptor I promoter activation
1 Institute of Medical Technology, University of Tampere, 33014 Tampere, Finland 2 Department of Molecular Genetics and Microbiology, Shands Cancer Center, University of Florida, Gainesville, FL 32610, USA 3 Abramson Family Cancer Research Institute, Howard Hughes Medical Institute, University of Pennsylvania Cancer Center, Philadelphia, PA 19104, USA 4 Department of Clinical Microbiology, Tampere University Hospital, 33521 Tampere, Finland
Correspondence to: O. Silvennoinen, Institute of Medical Technology, University of Tampere, 33014 Tampere, Finland. E-mail: olli.silvennoinen{at}uta.fi
Transmitting editor: W. J. Leonard
The high-affinity receptor for IgG (Fc
RI) is a myeloid cell-specific and IFN--induced gene, and thereby serves as a paradigm for cytokine-induced cell type-specific gene responses. The expression of FcRI is regulated by PU.1 and Stat1 transcription factors. We established an experimental model to analyze the individual functions of Stat1 and PU.1 in cytokine-induced transcription of the natural FcRI promoter in U3A cells lacking both factors. PU.1 was required for both the basal activity and for the IFN--induced FcRI promoter activation, while Stat1 alone could not initiate transcription. In contrast, in the context of a heterologous promoter, PU.1 inhibited the Stat1-mediated transcription. Systematic analysis of Stat1 and PU.1 mutants and FcRI promoter elements revealed that activation of the promoter required the DNA binding, and the transactivation functions of both Stat1 and PU.1. PU.1 and Stat1 bound the promoter elements independently, and no physical interaction between the proteins was observed. The requirement of PU.1 for FcRI promoter activity was supported by demonstration of in vitro interaction between PU.1 and components of the basal transcription machinery TBP and RNA polymerase II. Deletion of the acidic transactivation domain of PU.1 greatly diminished both the FcRI promoter activity as well as the interaction with RNA polymerase II. In contrast, Stat1 did not interact with TBP or RNA polymerase II. These results define functional cooperativity between PU.1 and Stat1 in FcRI promoter activation where PU.1 serves as an amplifier and bridging factor with the basal transcription machinery.
Keywords: monocyte/macrophage, signal transduction, transcription factor
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