NF-kappa B as inducible transcriptional activator of the granulocyte-macrophage colony-stimulating factor gene.

Abstract

The expression of the gene encoding the granulocyte-macrophage colony-stimulating factor (GM-CSF) is induced upon activation of T cells with phytohemagglutinin and active phorbolester and upon expression of tax,, a transactivating protein of the human T-ceil leukemia virus type I. The same agents induce transcription from the interleukin-2 receptor a-chain and interleukin-2 genes, depending on promoter elements that bind the inducible transcription factor NF-KB (or an NF-KB-like factor). We therefore tested the possibility that the GM-CSF gene is also regulated by a cognate motif for the NF-KB transcription factor. A recent functional analysis by Miyatake et al. (S. Miyatake, M. Seiki, M. Yoshida, and K. Arai, Mol. Cell. Biol. 8:5581-5587, 1988) described a short promoter region in the GM-CSF gene that conferred strong inducibility by T-cell-activating signals and tax1, but no NF-KB-binding motifs were identified. Using electrophoretic mobility shift assays, we showed binding of purified human NF-KB and of the NF-KB activated in Jurkat T cells to an oligonucleotide comprising the GM-CSF promoter element responsible for mediating responsiveness to T-cell-activating signals and tax,. As shown by a methylation interference analysis and oligonucleotide competition experiments, purified NF-KB binds at positions -82 to -91 (GGGAACTACC) of the GM-CSF promoter sequence with an affinity similar to that with which it binds to the biologically functional KB motif in the beta interferon promoter (GGGAAATTCC). Two KB-like motifs at positions -98 to -108 of the GM-CSF promoter were also recognized but with much lower affinities. Our data provide strong evidence that the expression of the GM-CSF gene following T-ceil activation is controlled by binding of the NF-KB transcription factor to a high-affinity binding site in the GM-CSF promoter.

Differentiation of Inflammatory Dendritic Cells Is Mediated by NF-κB1–Dependent GM-CSF Production in CD4 T Cells

“…In T cells, GM-CSF production is mainly controlled at the transcriptional level, is usually transient, and depends on activation through the TCR and costimulatory molecules, such as CD28 (42,43). These findings are consistent with the demonstration of NF-kB1 and c-Rel binding to the GM-CSF promoter (44,45). We conclude that the most likely reason for the Nfkb1 2/2 phenotype in the inflammation models is lack of NF-kB1/c-Rel heterodimer transcriptional activity in activated CD4 T cells.…”

Induction of cIAP-2 in Human Colon Cancer Cells through PKCδ/NF-κB

“…Selective activation of PKC␦ not only increased cIAP-2 promoter activity, but also increased transcription of other NF-B-dependent genes, such as GM-CSF, RANTES, and ICAM-1 promoters (56). Consistent with the activation of NF-B by PKC␦, the promoters of cIAP-2, IL-8, GM-CSF, RANTES, and ICAM-1 each contain NF-B-responsive elements (37,(57)(58)(59)(60). Activation of PKC␦ was associated with the binding of nuclear proteins to the NF-B oligonucleotide binding sequences as well as the trans activation of an NF-B reporter plasmid (56).…”

Bim and Noxa Are Candidates to Mediate the Deleterious Effect of the NF-κB Subunit RelA in Cerebral Ischemia

“…The sequence in the Bim promoter (GGGGCTTACC) deviates by a purine in position 8 from the consensus sequence. However, the same variation occurs in the NF-B motif of the GM-CSF (granulocyte/macrophage colony-stimulating factor) gene, which is a high-affinity binding site (Schreck and Baeuerle, 1990). …”