A NOVEL TUMOR NECROSIS FACTOR-RESPONSIVE TRANSCRIPTION FACTOR WHICH RECOGNIZES A REGULATORY ELEMENT IN HEMATOPOIETIC GROWTH-FACTOR GENES

A conserved DNA sequence element, termed cytokine 1 (CK-1), is found in the promoter regions of many hemopoietic growth factor (HGF) genes. Mutational analyses and modification interference experiments show that this sequence specifically binds a nuclear transcription factor, NF-GMa, which is a protein with a molecular mass of 43 kilodaltons. It interacts with different affinities with the CK-1-like sequence from a number of HGF genes, including granulocyte macrophage colony-stimulating factor (GM-CSF), granulocyte (G)-CSF, interleukin 3 (IL-3), and IL-5. We show here that the level of NF-GMa binding is induced in embryonic fibroblasts by tumor necrosis factor-α (TNF-α) treatment and that the CK-1 sequence from the G-CSF gene is a TNF-α-responsive enhancer in these cells. The NF-GMa protein is distinct from another TNF-α-responsive transcription factor, NF-κB, by several criteria. Firstly, several NF-κB-binding sites, although having sequence similarity with the CK-1 sequence, cannot compete efficiently for NF-GMa binding to CK-1. Secondly, the CK-1 sequence from both G-CSF and GM-CSF does not respond to phorbol ester treatment as would an NF-κB-binding element. These results demonstrate that NF-GMa is a novel transcription factor inducible by TNF-α and binds to a common element in HGF gene promoters.