The structure and expression of the murine gene encoding granulocyte-macrophage colony stimulating factor: evidence for utilisation of alternative promoters.

Stanley, E. Richard; Metcalf, Donald; Sobieszczuk, Peter; Gough, Nicholas M.; Dunn, Ashley R.

doi:10.1002/j.1460-2075.1985.tb03972.x

Cited by 122 publications

(54 citation statements)

References 35 publications

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“…Activating signals ultimately result in cellular proliferation, and transcriptional induction and secretion of a number of cytokines including IL-2 (interleukin-2), IL-3, IFNg (interferon-gamma) and GM ± CSF (granulocytemacrophage colony-stimulating factor) (Stanley et al, 1985;Miyajima et al, 1988;Arai et al, 1990). These cytokines direct the e ector functions of various cell types involved in an immune response, including B cells, macrophages, mast cells, eosinophils and neutrophils.…”

Section: Introductionmentioning

confidence: 99%

ETS1, NFκB and AP1 synergistically transactivate the human GM – CSF promoter

et al. 1997

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Activation of helper T cells results in coordinate expression of a number of cytokines involved in di erentiation, proliferation and activation of the haematopoietic system. Granulocyte-macrophage colony stimulating factor (GM ± CSF) is one such cytokine, whose increased expression results mostly from increases in transcription. Cis-acting elements with NFkB, AP1 and ETS-like binding motifs have been identi®ed in the promoter region of the GM ± CSF gene, and are important or essential for transcriptional activity following T cell activation. ETS1 is a transcription factor of the ETS family that is expressed in T cells. We have previously shown that ETS1 can transactivate GM ± CSF in Jurkat T cells, but only after the cells have been stimulated by treatment with PMA and ionomycin, agents that mimic T cell activation. Thus we proposed that ETS1, which is expressed constitutively in Jurkat cells, may act in concert with PMA/ionomycin inducible factors. Here we show that ETS1 can transactivate a GM ± CSF reporter construct in unstimulated Jurkat cells, providing that either NFkB or AP1 transcription factors are supplied by co-transfection. We con®rm that binding of endogenous NFkB and AP1 is induced following PMA/ionomycin treatment of T cells. Transactivation by ETS1, NFkB and AP1 is synergistic, and mutation of the individual binding sites reveals that the transcriptional activities of these factors are interdependent. Our results suggest that constitutive ETS1, and inducible NFkB and AP1, cooperate as part of a higher order transcriptional complex in activated T cells.

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Section: Introductionmentioning

confidence: 99%

ETS1, NFκB and AP1 synergistically transactivate the human GM – CSF promoter

et al. 1997

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“…9A). This sequence has been identified in several lymphokinecytokine genes, such as human and mouse granulocytemacrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor, and IL-3 genes (5,32,40,45) (Fig. 9A).…”

Section: Discussionmentioning

confidence: 99%

Structures of human genes coding for cytokine LD78 and their expression.

Nakao¹,

Nomiyama²,

Shimada³

1990

Mol. Cell. Biol.

113

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LD78 is a member of a newly identified superfamily of small inducible proteins involved in inflammatory responses, wound healing, and tumorigenesis. Southern blot analysis of the EcoRI-digested human genomic DNAs, using previously isolated LD78 cDNA as a probe, showed that in each individual there are 4.2-and 4.8-kilobase-pair (kb) fragments and that some have an additional 6.5-kb fragment. The 4.2-kb fragment contained genomic DNA sequences corresponding to the LD78 cDNA and was named the LD78a gene. The 4.8-kb fragment contained similar sequences, showing 94% homology to the LD78a gene, and was named the LD78j gene. The LD78a gene was present in a single or a few copies per haploid genome, whereas the copy number of the LD78, gene and of the 6.5-kb fragment hybridizable to LD78 cDNA varied among the samples tested. Treatment of human myeloid cell lines HL-60 and U937 with phorbol 12-myristate 13-acetate (PMA) increased within 2 h cellular levels of the RNA hybridizable to LD78 cDNA. The human glioma cell line U105MG and primary culture of human fibroblasts also expressed the hybridizable RNA in response to PMA. Addition of cycloheximide had no apparent effect on this response in U937 cells and inhibited the response in fibroblasts, whereas it stimulated the response in HL-60 and U1O5MG cells. mRNA phenotyping experiments revealed that the LD78a and LD78I8 genes were both transcribed in PMA-stimulated U937 cells.We formerly isolated a cDNA clone, named pLD78, from a cDNA library constructed on the poly(A)+ RNA of human tonsillar lymphocytes stimulated with phorbol 12-myristate 13-acetate (PMA) and phytohemagglutinin, using a differential screening procedure (33). Sequence analysis of the pLD78 cDNA revealed that it codes for a protein of 92 amino acid residues, including a putative leader sequence. To obtain information on the function of this LD78 protein, we made a computer search of nucleotide and protein sequence data bases and found that it has significant similarity to small inducible mammalian proteins forming a new cytokine superfamily (for reviews, see references 4, 34, and 49). Although the exact functions of the members of this cytokine superfamily are unknown, a monocyte-derived neutrophil chemotactic factor, now called interleukin-8 (IL-8), is one of the best-characterized proteins (21).Among the members of the superfamily, LD78 has 75% sequence similarity with murine macrophage inflammatory protein la (MIP-lot) (10), also called murine L2G25B (20). Accordingly, we presume that LD78 is a human counterpart of murine MIP-la. Murine MIP-la has already been demonstrated to have inflammatory and chemokinetic properties (11,50). Recently, we found that high levels of LD78 gene transcripts are present in acute nonlymphotic as well as lymphotic leukemic cells; hence, LD78 is also probably involved in the neoplastic transformation of hematopoietic cells (51).We have now obtained evidence for at least three different LD78-like genes in the human genome. Among them, we isolated and characterized two highly ho...

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“…There is limited evidence that certain coordinate control mechanisms might involve transcriptional control of multiple cytokine genes (21), while posttranscriptional control mechanisms are also believed to be important. For example, the mRNA products of many cytokine genes have AU-rich nucleotide sequences in the 3'-untranslated region that confer instability upon the mRNA transcript (22,23), and cytokine induction after stimulation is associated with increased mRNA half-life (7,17,22).…”

Section: Introductionmentioning

confidence: 99%