Nuclear Factor of Activated T Cells (NFAT)-dependent Transactivation Regulated by the Coactivators p300/CREB-binding Protein (CBP)

García-Rodríguez, Carmen; Rao, Anjana

doi:10.1084/jem.187.12.2031

Cited by 184 publications

(163 citation statements)

References 36 publications

(56 reference statements)

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“…30 Teleologically, the expression of CD154 by almost all IL-4-producing CD4 T cells may have evolved in conjunction with IL-4 expression to assist in critical B-cell functions such as immunoglobulin class switching. This expression would still have to be tightly regulated, because continued or prolonged CD154 expression contributes to autoimmunity in the form of SLE and other autoimmune disorders.…”

Section: Discussionmentioning

confidence: 99%

A T-cell-specific CD154 transcriptional enhancer located just upstream of the promoter

Brunner

Genin

et al. 2008

Genes Immun

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CD154 (CD40-ligand) is a critical immune regulator. CD154 expression is tightly regulated and largely restricted to activated CD4 T cells. Using DNase I hypersensitivity site (HSS) mapping, we identified two novel HSS mapping to the human CD154 promoter element and just upstream. Both HSS were activation independent and CD4 T-cell specific. Approximately 350 bp of DNA sequence flanking the upstream HSS site was highly conserved between mouse and man, and was rich in binding sites for GATA and NFAT proteins. Gel shift and chromatin immunoprecipitation assays demonstrated both NFAT1 and the Th2 factor, GATA-3, bound this enhancer element in vitro and in vivo, respectively. A PstI/XbaI 345 bp fragment of this region acted as a transcriptional enhancer of the CD154 promoter in primary human CD4 T cells. Overexpression of repressor of GATA and a dominant negative GATA-3 protein independently inhibited transcription, whereas overexpression of wild-type GATA-3 enhanced transcriptional activity, by this element in primary CD4 T cells. Moreover, more interleukin-4-producing CD4 T cells expressed CD154 following activation than interferon-g-producing CD4 T cells. Thus, we identified a novel T-cell-specific, GATA-3 responsive, CD154 transcriptional enhancer, which may contribute to increased propensity of Th2 cells to express CD154.

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Section: Discussionmentioning

confidence: 99%

A T-cell-specific CD154 transcriptional enhancer located just upstream of the promoter

Brunner

Genin

et al. 2008

Genes Immun

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“…The N-terminal transactivation domain of NFATp has been shown to recruit the coactivators p300/CBP (60), which are also bound by CREB after phosphorylation in response to calciuminduced signaling (61). NFATp-CBP interactions may involve the CREB-binding domain and the cysteine-histidine-rich region 3 of CBP (60).…”

Section: Discussionmentioning

confidence: 99%

“…NFATp-CBP interactions may involve the CREB-binding domain and the cysteine-histidine-rich region 3 of CBP (60). Thus, cooperative recruitment of a common coactivator by CREB, binding to the CRE, and NFATp, binding together with HNF-3␤ to G2, is a potential explanation for the effects of the internal deletion of either the CRE or G2 on glucagon promoter activity in HIT cells, which indicate that depolarization responsiveness conferred to the glucagon promoter by G2 or the CRE depends in part on the other element.…”

Section: Discussionmentioning

confidence: 99%

Characterization of a Novel Calcium Response Element in the Glucagon Gene

Fürstenau

Schwaninger²,

Blume

et al. 1999

Journal of Biological Chemistry

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To maintain blood glucose levels within narrow limits, the synthesis and secretion of pancreatic islet hormones is controlled by a variety of extracellular signals. Depolarization-induced calcium influx into islet cells has been shown to stimulate glucagon gene transcription through the transcription factor cAMP response element-binding protein that binds to the glucagon cAMP response element. By transient transfection of glucagon-reporter fusion genes into islet cell lines, this study identified a second calcium response element in the glucagon gene (G2 element, from ؊165 to ؊200). Membrane depolarization was found to induce the binding of a nuclear complex with NFATp-like immunoreactivity to the G2 element. Consistent with nuclear translocation, a comigrating complex was found in cytosolic extracts of unstimulated cells, and the induction of nuclear protein binding was blocked by inhibition of calcineurin phosphatase activity by FK506. A mutational analysis of G2 function and nuclear protein binding as well as the effect of FK506 indicate that calcium responsiveness is conferred to the G2 element by NFATp functionally interacting with HNF-3␤ binding to a closely associated site. Transcription factors of the NFAT family are known to cooperate with AP-1 proteins in T cells for calcium-dependent activation of cytokine genes. This study shows a novel pairing of NFATp with the cell lineage-specific transcription factor HNF-3␤ in islet cells to form a novel calcium response element in the glucagon gene.Activation of gene transcription allows cells to adapt to changes in environmental conditions through a new pattern of expressed proteins. In cells that are electrically excitable, calcium is an important intracellular second messenger that directs the genomic response of the cell. Transcription factors that have been shown to mediate calcium-induced gene transcription include CREB 1 (1-4), serum response factor (2, 5), and C/EBP␤ (6).Like neurons, endocrine cells of the pancreatic islets are electrically excitable and express L-type voltage-dependent calcium channels (7,8). By virtue of stimulation of glycogenolysis and gluconeogenesis in the liver, the islet hormone glucagon is an important regulator of blood glucose levels (9). Glucagonproducing islet cells show spontaneous electrical activity (10). Membrane electrical activity and calcium influx into glucagonproducing pancreatic islet cells is tightly controlled by extracellular messengers. Whereas L-arginine increases spike frequency (10), ␤-adrenergic cell-surface receptor stimulation by catecholamines through cAMP enhances the L-type calcium current, increasing the influx of calcium associated with each action potential (11). It is well known that membrane depolarization and calcium influx increase the cytosolic free calcium concentration, which stimulates hormone secretion by exocytosis (8, 12). The question is whether, and if so, how, this calcium signal reaches also into the nucleus and regulates gene transcription. Previous experiments have shown that membr...

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“…Under adverse conditions, blocking ERK1/2 enhances NFAT binding to the insulin gene promoter. NFAT is also known to bind to p300 and may recruit it under such circumstances (53).…”

Section: Discussionmentioning

confidence: 99%

Multiple chromatin-bound protein kinases assemble factors that regulate insulin gene transcription

Lawrence

Shao

McGlynn

et al. 2009

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

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During the onset of diabetes, pancreatic ␤ cells become unable to produce sufficient insulin to maintain blood glucose within the normal range. Proinflammatory cytokines have been implicated in impaired ␤ cell function. To understand more about the molecular events that reduce insulin gene transcription, we examined the effects of hyperglycemia alone and together with the proinflammatory cytokine interleukin-1␤ (IL-1␤) on signal transduction pathways that regulate insulin gene transcription. Exposure to IL-1␤ in fasting glucose activated multiple protein kinases that associate with the insulin gene promoter and transiently increased insulin gene transcription in ␤ cells. In contrast, cells exposed to hyperglycemic conditions were sensitized to the inhibitory actions of IL-1␤. Under these conditions, IL-1␤ caused the association of the same protein kinases, but a different combination of transcription factors with the insulin gene promoter and began to reduce transcription within 2 h; stimulatory factors were lost, RNA polymerase II was lost, and inhibitory factors were bound to the promoter in a kinase-dependent manner.ERK1/2 ͉ histone acetylation ͉ interleukin 1-␤

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Nuclear Factor of Activated T Cells (NFAT)-dependent Transactivation Regulated by the Coactivators p300/CREB-binding Protein (CBP)

Cited by 184 publications

References 36 publications

A T-cell-specific CD154 transcriptional enhancer located just upstream of the promoter

A T-cell-specific CD154 transcriptional enhancer located just upstream of the promoter

Characterization of a Novel Calcium Response Element in the Glucagon Gene

Multiple chromatin-bound protein kinases assemble factors that regulate insulin gene transcription

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