scholarly journals A potential role for nuclear factor of activated T-cells in receptor tyrosine kinase and G-protein-coupled receptor agonist-induced cell proliferation

2002 ◽  
Vol 368 (1) ◽  
pp. 183-190 ◽  
Author(s):  
Chandrahasa R. YELLATURU ◽  
Salil K. GHOSH ◽  
R.K. RAO ◽  
Lisa K. JENNINGS ◽  
Aviv HASSID ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Dna Synthesis ◽  
G Protein ◽  
Receptor Tyrosine Kinase ◽  
Binding Activity ◽  
Nuclear Factor ◽  
Activated T Cells ◽  
Dna Binding Activity ◽  
G Protein Coupled

We have studied the role of nuclear factor of activated T-cells (NFAT) transcription factors in the induction of vascular smooth muscle cell (VSMC) growth by platelet-derived growth factor-BB (PDGF-BB) and thrombin, the receptor tyrosine kinase (RTK) and G-protein-coupled receptor (GPCR) agonists, respectively. NFATc1 but not NFATc2 or NFATc3 was translocated from the cytoplasm to the nucleus upon treatment of VSMCs with PDGF-BB or thrombin. Translocation of NFATc1 was followed by an increase in NFAT—DNA binding activity and NFAT-dependent reporter gene expression. Cyclosporin A (CsA), a potent and specific inhibitor of calcineurin, a calcium/calmodulin-dependent serine phosphatase involved in the dephosphorylation and activation of NFATs, blocked NFAT—DNA binding activity and NFAT-dependent reporter gene expression induced by PDGF-BB and thrombin. CsA also completely inhibited PDGF-BB- and thrombin-induced VSMC growth, as measured by DNA synthesis and cell number. In addition, forced expression of the NFAT-competing peptide VIVIT for calcineurin binding significantly attenuated the DNA synthesis induced by PDGF-BB and thrombin in VSMCs. Together, these findings for the first time demonstrate a role for NFATs in RTK and GPCR agonist-induced growth in VSMCs.

A novel monitoring of immunosuppression in recipients with DNA-binding activity of nuclear factor in activated T cells

1997 ◽  
Vol 29 (1-2) ◽  
pp. 1172-1173
Author(s):  
K. Akioka ◽  
H. Nakajima ◽  
I. Fujiwara ◽  
N. Yoshimura ◽  
T. Matsuda ◽  
...  
Keyword(s):  
T Cells ◽  
Dna Binding ◽  
Binding Activity ◽  
Nuclear Factor ◽  
Activated T Cells ◽  
Dna Binding Activity

scholarly journals STIM2 targets Orai1/STIM1 to the AKAP79 signaling complex and confers coupling of Ca2+entry with NFAT1 activation

2020 ◽  
Vol 117 (28) ◽  
pp. 16638-16648 ◽  
Author(s):  
Ga-Yeon Son ◽  
Krishna Prasad Subedi ◽  
Hwei Ling Ong ◽  
Lucile Noyer ◽  
Hassan Saadi ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Endoplasmic Reticulum ◽  
Plasma Membrane ◽  
Nuclear Factor ◽  
Activated T Cells ◽  
Unique Role ◽  
Signaling Complex ◽  
Contact Sites ◽  
Channel Function

The Orai1 channel is regulated by stromal interaction molecules STIM1 and STIM2 within endoplasmic reticulum (ER)-plasma membrane (PM) contact sites. Ca2+signals generated by Orai1 activate Ca2+-dependent gene expression. When compared with STIM1, STIM2 is a weak activator of Orai1, but it has been suggested to have a unique role in nuclear factor of activated T cells 1 (NFAT1) activation triggered by Orai1-mediated Ca2+entry. In this study, we examined the contribution of STIM2 in NFAT1 activation. We report that STIM2 recruitment of Orai1/STIM1 to ER-PM junctions in response to depletion of ER-Ca2+promotes assembly of the channel with AKAP79 to form a signaling complex that couples Orai1 channel function to the activation of NFAT1. Knockdown of STIM2 expression had relatively little effect on Orai1/STIM1 clustering or local and global [Ca2+]iincreases but significantly attenuated NFAT1 activation and assembly of Orai1 with AKAP79. STIM1ΔK, which lacks the PIP2-binding polybasic domain, was recruited to ER-PM junctions following ER-Ca2+depletion by binding to Orai1 and caused local and global [Ca2+]iincreases comparable to those induced by STIM1 activation of Orai1. However, in contrast to STIM1, STIM1ΔK induced less NFAT1 activation and attenuated the association of Orai1 with STIM2 and AKAP79. Orai1-AKAP79 interaction and NFAT1 activation were recovered by coexpressing STIM2 with STIM1ΔK. Replacing the PIP2-binding domain of STIM1 with that of STIM2 eliminated the requirement of STIM2 for NFAT1 activation. Together, these data demonstrate an important role for STIM2 in coupling Orai1-mediated Ca2+influx to NFAT1 activation.

scholarly journals Interleukin-7 Upregulates the Interleukin-2–Gene Expression in Activated Human T Lymphocytes at the Transcriptional Level by Enhancing the DNA Binding Activities of Both Nuclear Factor of Activated T Cells and Activator Protein-1

Blood ◽  
1997 ◽  
Vol 90 (7) ◽  
pp. 2690-2700 ◽  
Author(s):  
Sonja I. Gringhuis ◽  
Lou F.M.H. de Leij ◽  
Emmy W. Verschuren ◽  
Peter Borger ◽  
Edo Vellenga
Keyword(s):  
T Lymphocytes ◽  
Dna Binding ◽  
Binding Activity ◽  
Transcriptional Level ◽  
Nuclear Factor ◽  
Activator Protein 1 ◽  
Activated T Cells ◽  
Dna Binding Activity ◽  
Interleukin 7 ◽  
Activated T Lymphocytes

Abstract In the present report, we studied the role of the stromal-derived cytokine interleukin-7 (IL-7) in the IL-2–gene regulation in activated T lymphocytes. Production of IL-2 requires the formation of transcription factors involved in the IL-2 –gene regulation. T-cell receptor (TCR)/CD3 engagement results in the activation of nuclear factor of activated T cells (NFAT), activator protein-1 (AP-1), and nuclear factor κB (NFκB), whereas the CD28 responsive complex (CD28RC) is activated in response to the CD28 signal. Costimulation of phytohemagglutinin/anti-CD28 activated T lymphocytes with IL-7 induces a fivefold enhanced IL-2–mRNA accumulation and a 2.5-fold enhanced protein secretion. The IL-2–gene transcription rate is increased 3.4-fold, indicating that the effect of IL-7 is in part mediated at the transcriptional level. The molecular mechanisms underlying the IL-7 effect involve the upregulation of the DNA binding activity of NFAT (60%) and AP-1 (120%), without affecting the activities of NFκB and CD28RC, which was confirmed by transfection assays. We also show that the IL-7–induced enhancement of the AP-1–DNA binding activity is not cyclosporin A-sensitive. Since AP-1 is part of the NFAT complex, we conclude that the IL-7–signaling pathway is involved in the activation of the fos and jun proteins of which AP-1 consists.

scholarly journals UV-A-induced decrease in nuclear factor-κB activity in human keratinocytes

1999 ◽  
Vol 338 (3) ◽  
pp. 607-613 ◽  
Author(s):  
Mojgan DJAVAHERI-MERGNY ◽  
Marie-Pierre GRAS ◽  
Jean-Louis MERGNY ◽  
Louis DUBERTRET
Keyword(s):  
Gene Expression ◽  
Dna Binding ◽  
Uv Radiation ◽  
Human Keratinocytes ◽  
Nuclear Factor Κb ◽  
Binding Activity ◽  
Luciferase Reporter ◽  
Nuclear Factor ◽  
Protein Subunits ◽  
Dna Binding Activity

Previous reports have demonstrated an increase in nuclear factor-κB (NF-κB) activity in response to UV radiation. These studies have essentially focused on the DNA-damaging fraction of solar UV radiation (UV-B and UV-C). In contrast, the effects of UV-A radiation (320–400 nm) on NF-κB are not well known. In this study, we present evidence that UV-A radiation induces a marked decrease in NF-κB DNA-binding activity in NCTC 2544 human keratinocytes. In addition, NCTC 2544 keratinocytes pretreated with UV-A fail to respond to NF-κB inducers. Moreover, UV-A radiation induces a decrease in NF-κB-driven luciferase reporter gene expression in NCTC 2544 keratinocytes. The expression of the gene encoding IκBα (IκB is the NF-κB inhibitor), which is closely associated with NF-κB activity, is also reduced (3-fold) upon UV-A treatment. Our results indicate that the UV-A-induced decrease in NF-κB DNA-binding activity is associated with a decrease in the levels of the p50 and p65 protein subunits. This is the first evidence that an oxidative stress, such as UV-A radiation, may induce a specific decrease in NF-κB activity in mammalian cells, probably through degradation of NF-κB protein subunits. These findings suggest that UV-A could modulate the NF-κB-dependent gene expression.

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