Regulation of the Zinc Finger- encoding EGR-1 Gene by Granulocyte-Macrophage Colony-stimulating Factor in Human U-937 Monocytic Leukemia Cells: Involvement of a Pertussis Toxin-sensitive G Protein’

The EGR-1 gene is an immediate early response gene encoding a zinc finger DNA-binding protein. The present studies have examined the regulation of EGR-1 gene expression in human U-937 monocytic leukemia cells treated with granulocyte-macrophage colonystimulating factor (GM-CSF). The results demonstrate that GM-CSF rapidly and transiently increases EGR-1 gene expression in U-937 cells. Similar findings were obtained in GM-CSF-treated human monocytes. We also show that the regulation of EGR-1 expression by GM-CSF is a pertussis toxin-sensitive event. The results of nuclear run-on assays further demonstrate that the EGR-1 gene is constitutively transcribed in untreated U-937 cells and that GM-CSF has little effect on this rate of transcription. Inhibition of protein synthesis with cycloheximide also had no detectable effect on EGR-1 gene transcription but was associated with superinduction of EGR-1 mRNA levels in GM-CSFtreated cells. Moreover, the half-life of GM-CSFinduced EGR-1 transcripts was prolonged from 33 to 70 mm following inhibition of protein synthesis. Taken together, the results indicate that GM-CSF activates signaling pathways which regulate EGR-1 gene expression through a pertussis toxin-sensitive G protein and that these events increase EGR-1 mRNA levels by a posttranscriptional mechanism. This GM-CSFdependent regulation of EGR-1 expression may provide a mechanism for transducing signals to the nucleus that are involved in the control of gene transcription.