Regulation of human interleukin-2 gene: Functional DNA sequences in the 5′ flanking region for the gene expression in activated T lymphocytes

Fujita, Takashi; Shibuya, H.; Ohashi, Tetsuo; Yamanishi, Kiyofumi; Taniguchi, Tadatsugu

doi:10.1016/0092-8674(86)90660-4

Cited by 275 publications

(143 citation statements)

References 31 publications

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“…PCNA-LUC constructs were transfected transiently into EL4 cells by the DEAE-dextran method as previously described (4,20), except that the cells were harvested for assay 18 h after transfection when luciferase activity was expressed maximally. L2 cells in a G, resting state grown in IL-2-free DMEM-CM were transfected by the DEAE-dextran method.…”

Section: Methodsmentioning

confidence: 99%

Promoter activity of the proliferating-cell nuclear antigen gene is associated with inducible CRE-binding proteins in interleukin 2-stimulated T lymphocytes.

Huang¹,

Shipman-Appasamy²,

Orten³

et al. 1994

Mol. Cell. Biol.

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The proliferating-cell nuclear antigen (PCNA) gene encodes an auxiliary factor of DNA polymerase delta and functions in DNA replication during S phase. It is expressed at much higher levels in proliferating cells than in quiescent cells. We have studied the regulatory role of the 5'-flanking sequence of the murine PCNA gene in interleukin 2 (IL-2)-responsive cloned T cells (L2). Analysis of a set of deletion constructs in transient transfection assays measuring heterologous reporter gene (luciferase) activity demonstrated that the 182-bp 5'-flanking region provides full promoter activity in IL-2-stimulated L2 cells. While many elements contribute to PCNA promoter strength in IL-2-stimulated cells, the largest decrease in activity occurred with deletion of the tandem CRE (cyclic AMP response element) binding sites located at nucleotides -37 to -52. With a gel mobility shift assay, several IL-2-inducible DNA-protein complexes were detected, including CREB (CREbinding) and ATFI (activating transcription factor) proteins that are specific for the PCNA-CRE sequence.Methylation interference analysis confirmed specific binding of these proteins to the CRE sites. Mutation at the PCNA-CRE motif abolishes IL-2-inducible binding and reduces substantially PCNA promoter activity.These results indicate that IL-2-stimulated PCNA transcription may be partially mediated by these CRE-binding proteins.The activation of antigen-specific T lymphocytes from Go to S phase usually requires several signals. Initially, antigen interacts with the T-cell antigen receptor, which leads to the transition from Go to GI and the expression of interleukin 2 (IL-2) receptor and lymphokines including IL-2. Further GI progression requires additional signals provided by the interaction of IL-2 with its high-affinity receptor, which results in the expression of genes related to G, activation, and binding of prolactin to its receptor, which results in entry into S phase and DNA replication (11,14,35,38,67).One of the genes expressed during IL-2-driven G, progression is proliferating-cell nuclear antigen (PCNA) (49, 69). PCNA was originally described as a proliferation-associated nuclear antigen that was thought to be expressed in a cellcycle-specific manner (8,47). While PCNA is an auxiliary protein for DNA polymerase delta (leading-strand polymerase) (9, 59) and PCNA-associated immunofluorescence closely parallels [3H]thymidine incorporation during cell cycle progression (42), synthesis and expression of PCNA can be detected in all phases of the cell cycle (G11SG2/M) in proliferating cells, suggesting that the protein is easily extractable when it is not associated with the polymerase (10, 49). Beach and coworkers showed recently that D-type cyclins can directly interact with PCNA and suggested this interaction as one possible mechanism by which the cell cycle machinery could * Corresponding author. Present address:

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Section: Methodsmentioning

confidence: 99%

Promoter activity of the proliferating-cell nuclear antigen gene is associated with inducible CRE-binding proteins in interleukin 2-stimulated T lymphocytes.

Huang¹,

Shipman-Appasamy²,

Orten³

et al. 1994

Mol. Cell. Biol.

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“…The regulatory regions of the human IL-2 promoter have been studied in detail and it was initially established that ϳ300 nt upstream from the start of transcription was sufficient for maximal activity in transient transfection assays in Jurkat T cells (9,10). Within this minimal promoter region, two major TCR responsive regions were identified in the human gene and termed Ag-responsive elements (ARRE), 4 ARRE-1 and ARRE-2 (Ref.…”

Section: T He Generation Of T Cell-mediated Immune Responses Ismentioning

confidence: 99%

The Human IL-2 Gene Promoter Can Assemble a Positioned Nucleosome That Becomes Remodeled Upon T Cell Activation

Attema

Reeves

Murray

et al. 2002

The Journal of Immunology

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Controlled production of the cytokine IL-2 plays a key role in the mammalian immune system. Expression from the gene is tightly regulated with no detectable expression in resting T cells and a strong induction following T cell activation. The IL-2 proximal promoter (+1 to −300) contains many well-defined transcriptional activation elements that respond to T cell stimulation. To determine the role of chromatin structure in the regulation of interleukin-2 gene transcription, nucleosome assembly across the IL-2 promoter region was examined using in vitro chromatin reconstitution assays. The IL-2 promoter assembles a nucleosome that is both translationally and rotationally positioned, spanning some of the major functional control elements. The binding of transcription factors to these elements, with the exception of the architectural protein HMGA1, was occluded by the presence of the nucleosome. Analysis of the chromatin architecture of the IL-2 gene in Jurkat T cells provided evidence for the presence of a similarly positioned nucleosome in vivo. The region encompassed by this nucleosome becomes remodeled following activation of Jurkat T cells. These observations suggest that the presence of a positioned nucleosome across the IL-2 proximal promoter may play an important role in maintaining an inactive gene in resting T cells and that remodeling of this nucleosome is important for gene activation.

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“…The consensus sequence was also found in the control region of IL2 (Fujita et al, 1986) and polyoma DNA (Zenke et al, 1986) and c-fos (Piette and Yaniv, 1987). The P motif which binds the transcription factor AP1 mediates transcriptional induction in response to phorbol ester tumor promoters and cAMP elevating agents.…”

Section: Introductionmentioning

confidence: 95%

Regulatory elements of the human vimentin gene: activation during proliferation

Paulin¹,

Lilienbaum²,

Duprey³

et al. 1990

Reprod. Nutr. Dévelop.

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Regulation of human interleukin-2 gene: Functional DNA sequences in the 5′ flanking region for the gene expression in activated T lymphocytes

Cited by 275 publications

References 31 publications

Promoter activity of the proliferating-cell nuclear antigen gene is associated with inducible CRE-binding proteins in interleukin 2-stimulated T lymphocytes.

Promoter activity of the proliferating-cell nuclear antigen gene is associated with inducible CRE-binding proteins in interleukin 2-stimulated T lymphocytes.

The Human IL-2 Gene Promoter Can Assemble a Positioned Nucleosome That Becomes Remodeled Upon T Cell Activation

Regulatory elements of the human vimentin gene: activation during proliferation

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