Signalling into the T-Cell Nucleus

Masuda, Esteban S.; Imamura, Ryu; Amasaki, Yoshiharu; Arai, Kohei; Arai, Naoko

doi:10.1016/s0898-6568(98)00019-9

Cited by 128 publications

(103 citation statements)

References 131 publications

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“…cAMP has been shown to inhibit transcription by preventing the binding of NFAT and NF-B factors to the IL-2 promoter (32). CsA has been shown to inhibit NFAT translocation to the nucleus by blocking calcineurin phosphatase activity (33,50). Factors such as NF-B and NFAT, translocate to the nucleus upon activation with very fast kinetics (6,40).…”

Section: Discussionmentioning

confidence: 99%

Chromatin Remodeling, Measured by a Novel Real-Time Polymerase Chain Reaction Assay, Across the Proximal Promoter Region of the IL-2 Gene

Rao¹,

Procko²,

Shannon³

2001

The Journal of Immunology

183

222

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The structure of chromatin and its remodeling following activation are important aspects of the control of inducible gene transcription. The IL-2 gene is induced in a cell specific-manner in T cells following an antigenic stimulus. We show, using a novel real-time PCR assay, that significant chromatin remodeling of the IL-2 proximal promoter region occurred upon stimulation of both the murine EL-4 T cell line and primary CD4+ T cells. Chromatin remodeling appears to be limited to the first 300 bp of the proximal promoter region as measured by micrococcal nuclease and restriction enzyme accessibility. Time course studies indicated that chromatin remodeling was observed at 1.5 h postinduction and was maintained for up to 16 h. The remodeling is reversible upon removal of the stimulus. The region immediately upstream from the transcription start site, however, remains accessible for up to 16 h. Upon restimulation, remodeling occurs much more rapidly, consistent with a more rapid rise in IL-2 mRNA levels. Using a number of pharmacological inhibitors we show that remodeling is dependent on the presence of specific transcription factors, but not on the modification of histones. The development of this novel chromatin accessibility assay based on real-time PCR has allowed rapid, sensitive, and quantitative measurements on the IL-2 gene following cellular activation in both T cell lines and primary cells.

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Section: Discussionmentioning

confidence: 99%

Chromatin Remodeling, Measured by a Novel Real-Time Polymerase Chain Reaction Assay, Across the Proximal Promoter Region of the IL-2 Gene

Rao¹,

Procko²,

Shannon³

2001

The Journal of Immunology

183

222

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“…Unstimulated (dephosphorylated) GSK3b is active and its phosphorylation activity appears to act as a general repressor on its substrates. Many substrates of GSK3b have been identified, including glycogen synthase, c-Jun, cyclin D1, b-catenin, nuclear factors of activated T-cells (NFATs), and Notch2 (Masuda et al, 1998;Espinosa et al, 2003). The inhibition of GSK3b by phosphorylation, leads to dephosphorylation activation of glycogen synthase, resulting in glycogen synthesis, and to activation of eIF-2B, which promotes protein synthesis (Rommel et al, 2001).…”

Section: Fibre Size: Mediators Of Muscle Hypertrophy/atrophymentioning

confidence: 99%

Key signalling factors and pathways in the molecular determination of skeletal muscle phenotype

Chang

2007

Animal

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The molecular basis and control of the biochemical and biophysical properties of skeletal muscle, regarded as muscle phenotype, are examined in terms of fibre number, fibre size and fibre types. A host of external factors or stimuli, such as ligand binding and contractile activity, are transduced in muscle into signalling pathways that lead to protein modifications and changes in gene expression which ultimately result in the establishment of the specified phenotype. In skeletal muscle, the key signalling cascades include the Ras-extracellular signal regulated kinase-mitogen activated protein kinase (Erk-MAPK), the phosphatidylinositol 3 0 -kinase (PI3K)-Akt1, p38 MAPK, and calcineurin pathways. The molecular effects of external factors on these pathways revealed complex interactions and functional overlap. A major challenge in the manipulation of muscle of farm animals lies in the identification of regulatory and target genes that could effect defined and desirable changes in muscle quality and quantity. To this end, recent advances in functional genomics that involve the use of micro-array technology and proteomics are increasingly breaking new ground in furthering our understanding of the molecular determinants of muscle phenotype.

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“…NFAT proteins are essential for T cell activation and therefore represent potential targets for new immunosuppressive therapies. Interestingly, recent data from mouse knockout studies indicate that NFAT genes encode proteins with potentially conf licting effects in T cell activation (11)(12)(13), suggesting the utility of targeting individual NFAT family members.…”

Section: Rugs That Destroy T Cells or Block Their Antigen-dependentmentioning

confidence: 99%

Chemical genetics to identify NFAT inhibitors: Potential of targeting calcium mobilization in immunosuppression

Natarajan

Feng

DeDecker

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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The development of more selective immunosuppressive agents to mitigate transplant rejection and autoimmune diseases requires effective strategies of blocking signaling pathways in T cells. Current immunosuppressive strategies use cyclosporin A (CsA) or FK506 to inhibit calcineurin, which dephosphorylates and promotes the nuclear import of nuclear factor of activated T cells (NFAT) transcription factors. These nuclear NFATs then transactivate cytokine genes that regulate proliferative responses of T cells. Both CsA and FK506 have debilitating side effects, including nephrotoxicity, hypertension, diabetes, and seizures, that argue for the development of alternative or complementary agents. To this end, we developed cell-based assays for monitoring NFAT dynamics in nonlymphoid cells to identify small molecules that inhibit NFAT nuclear import. Interestingly, we found that the majority of these small molecules suppress NFAT signaling by interfering with ''capacitative'' or ''store-operated'' calcium mobilization, thus raising the possibility that such mobilization processes are relevant targets in immunosuppression therapy. Further, these small molecules also show dose-dependent suppression of cytokine gene expression in T cells. Significantly, the IC50 of CsA in primary T cells was reduced by the addition of suboptimal concentrations of these compounds, suggesting the possibility that such small molecules, in combination with CsA, offer safer means of immunosuppression.capacitative calcium entry ͉ store-operated calcium channels ͉ cyclosporin A D rugs that destroy T cells or block their antigen-dependent activation have been the mainstays of treatment of organ transplant rejection (1). The latter group is represented chief ly by the natural products cyclosporin A (CsA) and FK506, both of which act by suppressing the protein phosphatase calcineurin (2-4). Calcineurin's activity depends on calcium signaling and plays an essential role in T cell signal transduction by controlling the nuclear import of the nuclear factor of activated T cells (NFAT) family of transcription factors. The NFATs are Rel-related transcription factors encoded by four genes (NFATc1-4) that are widely expressed in cells of the immune, cardiovascular, and nervous systems (4 -6). In resting cells, NFATs are localized to the cytoplasm due to a phosphorylation-dependent intramolecular masking of their nuclear location signals (NLSs) (7). During calcium signaling, calcineurin unmasks these NLSs, resulting in a rapid nuclear import of the dephosphorylated NFATs and transcriptional activation of cytokine genes (8). Besides unmasking the NLSs on the NFATs, calcineurin also masks their nuclear export signals, thereby preventing the futile cycling of these transcription factors across the nuclear envelope, thus ensuring their transcriptional functions in the nucleus (9, 10). NFAT proteins are essential for T cell activation and therefore represent potential targets for new immunosuppressive therapies. Interestingly, recent data from mouse knockout studie...

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Signalling into the T-Cell Nucleus

Cited by 128 publications

References 131 publications

Chromatin Remodeling, Measured by a Novel Real-Time Polymerase Chain Reaction Assay, Across the Proximal Promoter Region of the IL-2 Gene

Chromatin Remodeling, Measured by a Novel Real-Time Polymerase Chain Reaction Assay, Across the Proximal Promoter Region of the IL-2 Gene

Key signalling factors and pathways in the molecular determination of skeletal muscle phenotype

Chemical genetics to identify NFAT inhibitors: Potential of targeting calcium mobilization in immunosuppression

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