A novel tumor necrosis factor-responsive transcription factor which recognizes a regulatory element in hemopoietic 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-alpha (TNF-alpha) treatment and that the CK-1 sequence from the G-CSF gene is a TNF-alpha-responsive enhancer in these cells. The NF-GMa protein is distinct from another TNF-alpha-responsive transcription factor, NF-kappa B, by several criteria. Firstly, several NF-kappa B-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-kappa B-binding element. These results demonstrate that NF-GMa is a novel transcription factor inducible by TNF-alpha and binds to a common element in HGF gene promoters.
Shannon
M F
MF
Division of Human Immunology, Institute of Medical and Veterinary Science, Adelaide, South Australia.
Pell
L M
LM
Lenardo
M J
MJ
Kuczek
E S
ES
Occhiodoro
F S
FS
Dunn
S M
SM
Vadas
M A
MA
D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D003115:Colony-Stimulating Factors / Q000235:genetics*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006133:Growth Substances / Q000235:genetics*; D006410:Hematopoiesis; D006801:Humans; D007378:Interleukins / Q000235:genetics*; D008969:Molecular Sequence Data; D015345:Oligonucleotide Probes; D011401:Promoter Regions, Genetic; D012689:Sequence Homology, Nucleic Acid; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D003115:Colony-Stimulating Factors; D006133:Growth Substances; D007378:Interleukins; D015345:Oligonucleotide Probes; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D013755:Tetradecanoylphorbol Acetate