SIGNALS FOR ACTIVATION OF THE GM-CSF PROMOTER AND ENHANCER IN T-CELLS

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is one of th e many cytokines produced following T-cell activation. It is also prod uced in a variety of other cell types, in particular following activat ion by inflammatory mediators. Changes in the rate of transcription ar e important in the control of GM-CSF expression in T cells and in fibr oblasts and endothelial cells. The GM-CSF gene contains two distinct t ranscriptional control regions. These are the proximal promoter consis ting of the first 120 bp from the transcription start site and an enha ncer located approximately 3 kb upstream from the proximal promoter. D istinct regions of the proximal promoter respond to a wide array of si gnals such as phorbol myristate acetate (PMA) and Ca2+ ionophore or ph ytohemaglutinin (PHA), CD28 activation, human T leukemia virus (HTLV)- 1 tax, TNF, and interleukin 1 (IL-1). The transcription factors that m ediate these responses have mainly been defined, with the major induci ble proteins being the NF-kappa B/rel and AP-1 families of transcripti on factors. In contrast to the promoter, the enhancer responds only to PMA and Ca2+ ionophore signals and binds NFAT/AP-1 complexes that app ear to mediate its function.