Molecular regulation of the human IL-3 gene: inducible T cell-restricted expression requires intact AP-1 and Elf-1 nuclear protein binding sites.

Gottschalk, Lisa; Giannola, Diane; Emerson, Stephen G.

doi:10.1084/jem.178.5.1681

Cited by 76 publications

(59 citation statements)

References 59 publications

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“…We are interested in determining what factor(s) could be interacting with Elf-1 or other Ets factors binding the distal CD4 enhancer. Elf-1, in particular, has been reported to interact with AP-1 transcription factors in the inducible expression of the T-cell-specific interleukin-3 and GM-CSF genes (17,62). In both of these cases, the AP-1 factors and Elf-1 bind to sites that are directly adjacent to each other, mutation of either recognition sites reduces enhancer activity, and in the case of the GM-CSF promoter, the bindings by AP-1 and Elf-1 are cooperative (17,62).…”

Section: Discussionmentioning

confidence: 99%

“…Elf-1, in particular, has been reported to interact with AP-1 transcription factors in the inducible expression of the T-cell-specific interleukin-3 and GM-CSF genes (17,62). In both of these cases, the AP-1 factors and Elf-1 bind to sites that are directly adjacent to each other, mutation of either recognition sites reduces enhancer activity, and in the case of the GM-CSF promoter, the bindings by AP-1 and Elf-1 are cooperative (17,62). Even though an AP-1 recognition site is present in the CD4 enhancer and protected in DNase I footprinting experiments, the Ets and AP-1 recognition sites were separated by over 80 bp and mutation of the AP-1 recognition site had no significant effect on enhancer activity.…”

Section: Discussionmentioning

confidence: 99%

“…Two protein complexes (ETS-A and ETS-B) were able to bind specifically to the Ets binding site in EMSA studies, and the strongest complex (ETS-A) contains Elf-1, a recently identified Ets family transcription factor (58). Elf-1 has been shown to be expressed at high levels in T cells and has been implicated in the regulation of several activation and T-cell-specific cellular genes (interleukin-3 and GM-CSF genes) as well as in the regulation of T-cell-specific viruses (HIV-2 and HTLV-I) (4,17,37,64). From the results in our study, it is a reasonable conclusion that Elf-1 could be critically involved in the activity of the distal enhancer in the CD4 locus.…”

Section: Discussionmentioning

confidence: 99%

“…To date, however, reconstitution of the developmental pattern and T-cell subclass-specific expression of CD4 has been accomplished only through the use of large cosmid constructs that contain many kilobases of genomic DNA sequences within and around the human CD4 locus (2,14,31 We also determined that an Ets family transcription factor, Elf-1, is a dominant protein in T-cell nuclear extracts that binds to this site in vitro. Elf-1 has previously been shown to be required for the activation induced transcription of the T-cell-specific interleukin-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF) genes as well as in the regulation of the T-cell-specific human immunodeficiency virus type 2 (HIV-2) and human T-cell leukemia virus type I (HTLV-I) enhancers (4,17,37,64). Therefore, the involvement of Elf-1 in the regulation of the CD4 gene follows a previously established pattern for T-cell-specific gene regulation.…”

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confidence: 99%

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Elf-1 binds to a critical element in a second CD4 enhancer.

Wurster¹,

Siu²,

Leiden³

et al. 1994

Mol. Cell. Biol.

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The coordinated expression of CD4 and CD8 during T-cell development is tightly coupled with the maturation state of the T cell. Additionally, the mutually exclusive expression of these receptors in mature T cells is representative of the functional T-cell subclasses (CD4+ helper T cells versus CD8+ cytotoxic T cells). We have studied the regulation CD4 gene transcription during T-cell development in an attempt to gain an understanding of the molecular mechanisms involved in T-cell development and differentiation. Here we present the identification of a second transcriptional enhancer in the murine CD4 locus 24 kb upstream of the CD4 promoter. This enhancer is active in mature T cells and is especially active in CD4+ helper T cells. A number of nuclear proteins bind to elements in the minimal CD4 enhancer that includes consensus sites for AP-1, Spl, Gata, and Ets transcription factor families. We find that the Ets consensus site is crucial for enhancer activity and that the recently identified Ets factor, Elf-i, which is expressed at high levels in T cells and involved in the regulation of several other T-cell-specific genes, is a dominant protein in T-cell nuclear extracts that binds to this site.T-cell development involves the differentiation of functionally immature pre-T cells into mature, antigen-reactive effector cells (reviewed in reference 61). This process includes selection events in which the maturing T-cell population is depleted of self-reactive clones and enriched for those that can recognize foreign peptides bound by self-major histocompatibility complex (MHC). The development and selection of T-cell precursors occur in the thymus and are characterized by a coordinated expression of tissue-specific genes. Some of these genes encode cell surface molecules that directly promote T-cell differentiation and selection events. Understanding the molecular mechanisms responsible for the expression of these T-cellspecific genes is a window on the process of T-cell development.The CD4 glycoprotein is one of the surface molecules that is important as a receptor in the development and function of T cells (reviewed in references 39 and 46). In mature antigenspecific T cells, CD4 is expressed only on cells that have a T-cell receptor (TCR) specific for antigen associated with class II MHC molecules, while CD8, a cell surface protein functionally similar to CD4, is expressed only on T cells that recognize antigen bound to MHC class I molecules (56). The mutually exclusive expression of CD4 and CD8 on mature T cells also corresponds to T-cell function; CD4 is expressed primarily on helper T cells, while CD8 is expressed on cytotoxic T cells. CD4 participates in antigen recognition by binding to nonpolymorphic regions of class II MHC molecules, while the T-cell antigen receptor recognizes a specific peptide antigen that is bound by the MHC molecule (7). The CD4-MHC interaction serves to increase the avidity of the T cell to the antigenpresenting cell but also induces an intracellular signaling event through the CD4-...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Elf-1 binds to a critical element in a second CD4 enhancer.

Wurster¹,

Siu²,

Leiden³

et al. 1994

Mol. Cell. Biol.

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“…(Gegonne et al, 1993 (Gottschalk et al, 1993), and the HIV-2 long terminal repeat, in which two Ets-binding sites are close to an NF-KB site and to sites designated peri-Ets (pets) and peri-KB (Leiden et al, 1992;Markovitz et al, 1992;Clark et al, 1995 The integrity of EBS4 appears to be important for promoter activity. Deletion of EBS4 reduced the response of the promoter to PMA/ionomycin by approximately 60%, a result reminiscent of that found for the IL-3 promoter (Gottschalk et al, 1993), where deletion of the Elf-i binding caused a similar reduction in activity. Deletion of the adjacent AP-1 site in the IL-3 promoter abolished activity as did mutation of kB3 in the nfkbl reporter.…”

Section: Discussionmentioning

confidence: 99%

The nfkb1 promoter is controlled by proteins of the Ets family.

Lambert

Ludford-Menting

Deacon

et al. 1997

MBoC

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The gene encoding NFKB1 is autoregulated, responding to NF-KB/Rel activation through NF-KB binding sites in its promoter, which also contains putative sites for Ets proteins. One of the Ets sites, which we refer to as EBS4, is located next to an NF-KB/Rel binding site, kB3, which is absolutely required for activity of the promoter in Jurkat T cells in response to activation by phorbol 12-myristate 13-acetate (PMA), PMA/ionomycin, or the Tax protein from human T cell leukemia virus type I. We show that EBS4 is required for the full response of the nfkbl promoter to PMA or PMA/ionomycin in Jurkat cells. EBS4 is bound by Ets-1, Elf-1, and other species. Overexpression of Ets-1 augments the response to PMA/ionomycin and this is reduced by mutation of EBS4. Elf-1 has less effect in conjunction with PMA/ionomycin, but by itself activates the promoter 12-fold. This activation is only partly affected by mutation of EBS4, and a mutant promoter that binds Ets-1, but not Elf-1, at the EBS4 site responds to PMA/ionomycin as efficiently as the wild-type. Ets proteins may be responsible for fine-tuning the activity of the nfkbl gene in a cell-type-specific manner.

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Diverse transcription factors are involved in the quantitative regulation of transcriptional activation of χ promoters

Bemark

Leanderson

1997

Eur J Immunol

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Immunoglobulin kappa promoters show sequence divergence but conserved function between different subgroups. Here we show that three separate 5' elements are required for synergistic stimulation of transcription with the decamer in a kappa promoter. These sites are a 5' E-box, a 3' AT-rich region in the pentadecamer (pd) element, and the kappa-Y element. Elf-1 is a novel kappa-Y element ligand induced upon mitogenic stimulation of resting B lymphocytes. Furthermore, the 5' E2A-like E-box in the pd element could be substituted by an upstream stimulatory factor motif with conservation of function. Thus, the synergistic activation requirements of kappa transcription is strictly dependent on the quantitative presence of transcription factor-binding motifs 5' of the decamer, but these differ qualitatively in that they may bind an array of proteins with conserved function.

show abstract

Molecular regulation of the human IL-3 gene: inducible T cell-restricted expression requires intact AP-1 and Elf-1 nuclear protein binding sites.

Cited by 76 publications

References 59 publications

Elf-1 binds to a critical element in a second CD4 enhancer.

Elf-1 binds to a critical element in a second CD4 enhancer.

The nfkb1 promoter is controlled by proteins of the Ets family.

Diverse transcription factors are involved in the quantitative regulation of transcriptional activation of χ promoters

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