Activation of lymphokine genes in T cells: Role of cis-acting DNA elements that respond to T cell activation signals

Arai, Naoko; Naito, Yoshiyuki; Watanabe, Mitsuo; Masuda, Esteban S.; Yamaguchi-Iwai, Yuko; Tsuboi, Akito; Heike, Toshio; Matsuda, Ikuo; Yokota, Kyoko; Koyano-Nakagawa, Naoko; Lee, Hyun Jun; Muramatsu, Masaaki; Yokota, Takashi; Arai, Ken

doi:10.1016/0163-7258(92)90054-4

Cited by 26 publications

(26 citation statements)

References 41 publications

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“…[59][60][61][62][63][64][65][66][67][68][69][70][71][72][73][74] These genetic elements lie within a region that extends to ෂ300 bp upstream of the transcription start site (Figure 2a). Inhibitory elements in the IL-3 promoter which suppress IL-3 transcription include a NIP (nuclear inhibitory protein) binding sequence located between bp −271 to −250.…”

Section: Transcriptional Regulation Of Il-3 Expressionmentioning

confidence: 99%

“…This results in the transactivation of cytokine gene expression, including IL-3 and GM-CSF whose promoters contain NF-AT binding sites. [59][60][61][62][63][64][65][66][67][68][69][70][71][72][73][74] The immunosuppressive drugs cyclosporin A (CsA) and FK506 mediate their activity by inhibiting calcineurin activation, thereby preventing the dephosphorylation of NF-ATc 58,74 ( Table 4). An illustration of the regulation of IL-3 gene expression is presented in Figure 1.…”

Section: Regulation Of Il-3 Expressionmentioning

confidence: 99%

“…Receptor aggregation is followed by a complex series of biochemical events leading to the activation of protein kinase C (PKC) and a rise in the concentration of intracellular Ca 2+ . [50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68] Activated PKC can phosphorylate and inactivate the repressor protein, inhibitor B (I-B), thus permitting IB to disassociate from nuclear factor-B (NF-B). 54 This allows NF-B to assume an active form ( Figure 1) which subsequently enters the nucleus and transactivates cytokine gene expression.…”

Section: Regulation Of Il-3 Expressionmentioning

confidence: 99%

“…Inactivation of GAP stimulates Ras activity, which results in an enhancement of activator-protein-1 (AP-1) binding activity. 61,[68][69][70] AP-1 can then stimulate cytokine gene expression, including IL-3 ( Figure 2a). Interestingly, the neurofibromatosis-1 (NF1) gene, a tumor suppressor frequently lost in juvenile chronic myelogenous leukemia (CML), is functionally related to GAP.…”

Section: Regulation Of Il-3 Expressionmentioning

confidence: 99%

“…PKC can activate the Ras pathway by inactivating the GTPase activating protein (GAP), a negative regulator of Ras. 61,[68][69][70] Ras is a member of a large multi-gene family, which encodes small GTP-binding proteins that serve as molecular switches. Inactivation of GAP stimulates Ras activity, which results in an enhancement of activator-protein-1 (AP-1) binding activity.…”

Section: Regulation Of Il-3 Expressionmentioning

confidence: 99%

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True

1999

Leukemia

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Over the past decade, there has been an exponential increase in our knowledge of how cytokines regulate signal transduction, cell cycle progression, differentiation and apoptosis. Research has focused on different biochemical and genetic aspects of these processes. Initially, cytokines were identified by clonogenic assays and purified by biochemical techniques. This soon led to the molecular cloning of the genes encoding the cytokines and their cognate receptors. Determining the structure and regulation of these genes in normal and malignant hematopoietic cells has furthered our understanding of neoplastic transformation. Furthermore, this has allowed the design of modified cytokines which are able to stimulate multiple receptors and be more effective in stimulating the repopulation of hematopoietic cells after myelosuppressive chemotherapy. The mechanisms by which cytokines transduce their regulatory signals have been evaluated by identifying the involvement of specific protein kinase cascades and their downstream transcription factor targets. The effects of cytokines on cell cycle regulatory molecules, which either promote or arrest cell cycle progression, have been more recently examined. In addition, the mechanisms by which cytokines regulate apoptotic proteins, which mediate survival vs death, are being elucidated. Identification and characterization of these complex, interconnected pathways has expanded our knowledge of leukemogenesis substantially. This information has the potential to guide the development of therapeutic drugs designed to target key intermediates in these pathways and effectively treat patients with leukemias and lymphomas. This review focuses on the current understanding of how hematopoietic cytokines such as IL-3, as well as its cognate receptor, are expressed and the mechanisms by which they transmit their growth regulatory signals. The effects of aberrant regulation of these molecules on signal transduction, cell cycle regulatory and apoptotic pathways in transformed hematopoietic cells are discussed. Finally, anti-neoplastic drugs that target crucial constituents in these pathways are evaluated.

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Section: Transcriptional Regulation Of Il-3 Expressionmentioning

confidence: 99%

Section: Regulation Of Il-3 Expressionmentioning

confidence: 99%

Section: Regulation Of Il-3 Expressionmentioning

confidence: 99%

Section: Regulation Of Il-3 Expressionmentioning

confidence: 99%

Section: Regulation Of Il-3 Expressionmentioning

confidence: 99%

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True

1999

Leukemia

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A common factor regulates both Th1- and Th2-specific cytokine gene expression.

et al. 1994

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Murine T helper cell clones are classified into two distinct subsets, T helper 1 (Th1) and T helper 2 (Th2), on the basis of cytokine secretion patterns. Th1 clones produce interleukin‐2 (IL‐2), tumor necrosis factor‐beta (TNF‐beta) and interferon‐gamma (IFN‐gamma), while Th2 clones produce IL‐4, IL‐5, IL‐6 and IL‐10. These subsets differentially promote delayed‐type hypersensitivity or antibody responses, respectively. The nuclear factor NF‐AT is induced in Th1 clones stimulated through the T cell receptor‐CD3 complex, and is required for IL‐2 gene induction. The NF‐AT complex consists of two components: NF‐ATp, which pre‐exists in the cytosol and whose appearance in the nucleus is induced by an increase of intracellular calcium, and a nuclear AP‐1 component whose induction is dependent upon activation of protein kinase C (PKC). Here we report that the induction of the Th2‐specific IL‐4 gene in an activated Th2 clone involves an NF‐AT complex that consists only of NF‐ATp, and not the AP‐1 component. On the basis of binding experiments we show that this ‘AP‐1‐less’ NF‐AT complex is specific for the IL‐4 promoter and does not reflect the inability of activated Th2 cells to induce the AP‐1 component. We propose that NF‐ATp is a common regulatory factor for both Th1 and Th2 cytokine genes, and that the involvement of PKC‐dependent factors, such as AP‐1, may help determine Th1‐/Th2‐specific patterns of gene expression.

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