Activity of Stat family transcription factors is developmentally controlled in cells of the macrophage lineage.
Stat family transcription factors are activated in response to a variety of cytokines to bind to a class of DNA elements termed gamma interferon activation site (GAS)-like elements. Here we investigate two GAS-binding transcription factors, the gamma-interferon activation factor (GAF) and the differentiation-induced factor (DIF) that are activated by interferon-gamma (IFN-gamma) in U937 cells. Treatment of U937 cells with phorbol ester (TPA) induces differentiation from a promonocyte into a monocyte stage of macrophage development. Monocytic differentiation led to an increased transcriptional response of GAS-containing genes to IFN-gamma. TPA treatment also caused a profound change in the IFN-gamma activation of GAF and DIF. GAF DNA-binding activity was activated much better in the monocyte stage and the GAF constituent Stat 1 showed increased phosphorylation. In contrast, DIF activation by IFN-gamma was found in promonocytes but was virtually absent in monocytes. Moreover, DIF activation was observed during TPA-induced monocytic differentiation and after treatment of macrophages with the macrophage differentiation factor CSF-1. Our data suggest DIF to be part of a developmental program leading to terminal macrophage differentiation and GAF to be a transcription factor bringing about the stronger activation response of mature macrophages to IFN-gamma.
Vienna Biocenter, Institute of Microbiology and Genetics, Austria.
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Eilers
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Decker
D002454:Cell Differentiation / Q000235:genetics; D004268:DNA-Binding Proteins / Q000502:physiology*; D006801:Humans; D050832:Interferon-Stimulated Gene Factor 3; D008222:Lymphokines / Q000502:physiology*; D016403:Lymphoma, Large B-Cell, Diffuse; D008264:Macrophages / Q000502:physiology*; D050794:STAT1 Transcription Factor; D015534:Trans-Activators / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D050832:Interferon-Stimulated Gene Factor 3; D008222:Lymphokines; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; C079868:gamma interferon activation factor; C050979:monocyte-macrophage differentiation factor