scholarly journals Calcineurin-nuclear factor for activated T cells (NFAT) signaling in pathophysiology of wound healing

2021 ◽  
Vol 41 (1) ◽  
Author(s):  
Takahiro Manabe ◽  
Heamin Park ◽  
Takashi Minami
Keyword(s):  
Wound Healing ◽  
Immune Cell ◽  
Repair System ◽  
Nuclear Factor ◽  
Medical Studies ◽  
Activated T Cells ◽  
Mural Cells ◽  
Multiple Organs ◽  
Nfat Activation

AbstractWound healing occurred with serial coordinated processes via coagulation-fibrinolysis, inflammation following to immune-activation, angiogenesis, granulation, and the final re-epithelization. Since the dermis forms critical physical and biological barriers, the repair system should be rapidly and accurately functioned to keep homeostasis in our body. The wound healing is impaired or dysregulated via an inappropriate microenvironment, which is easy to lead to several diseases, including fibrosis in multiple organs and psoriasis. Such a disease led to the dysregulation of several types of cells: immune cells, fibroblasts, mural cells, and endothelial cells. Moreover, recent progress in medical studies uncovers the significant concept. The calcium signaling, typically the following calcineurin-NFAT signaling, essentially regulates not only immune cell activations, but also various healing steps via coagulation, inflammation, and angiogenesis. In this review, we summarize the role of the NFAT activation pathway in wound healing and discuss its overall impact on future therapeutic ways.

scholarly journals Human T-Cell Lymphotropic Virus Type 1 p12I Expression Increases Cytoplasmic Calcium To Enhance the Activation of Nuclear Factor of Activated T Cells

2002 ◽  
Vol 76 (20) ◽  
pp. 10374-10382 ◽  
Author(s):  
Wei Ding ◽  
Björn Albrecht ◽  
Robert E. Kelley ◽  
Natarajan Muthusamy ◽  
Seung-Jae Kim ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Calcium Release ◽  
Nuclear Factor ◽  
Cytoplasmic Calcium ◽  
Activated T Cells ◽  
Human T Cell ◽  
Nfat Activation

ABSTRACT Human T-cell lymphotropic virus type 1 (HTLV-1) establishes persistent infection and is associated with lymphoproliferative or neurodegenerative diseases. As a complex retrovirus, HTLV-1 contains typical structural and enzymatic genes, as well as regulatory and accessory genes encoded in the pX region. The early events necessary for HTLV-1 to establish infection in lymphocytes, its primary target cells, remain unresolved. Recent studies have demonstrated the importance of regulatory and accessory gene products in determining this virus-host interaction. Among these, pX open reading frame I, which encodes two proteins, p12I and p27I, is required for establishing persistent infection in vivo and for infection in quiescent primary lymphocytes. In addition, p12I localizes in the endoplasmic reticulum (ER) and cis-Golgi apparatus and associates with a calcium binding protein, calreticulin. We recently reported that p12I expression induces the calcium-responsive T-cell transcription factor, nuclear factor of activated T cells (NFAT), in the presence of phorbol ester activation. Based on these studies, we hypothesize that p12I may modulate calcium release from the ER. Here, we report that p12I expression increases basal cytoplasmic calcium and concurrently diminishes calcium available for release from the ER stores. Overexpression of calreticulin, a calcium buffer protein, blocked p12I-mediated NFAT activation independently of its ability to bind p12I. Chemical inhibition studies using inhibitors of inositol 1,4,5-triphosphate receptor and calcium release-activated calcium channels suggest that inositol 1,4,5-triphosphate receptor in the ER membrane and calcium release-activated calcium channels in the plasma membrane contribute to p12I-mediated NFAT activation. Collectively, our results are the first to demonstrate the role of p12I in elevating cytoplasmic calcium, an antecedent to T-cell activation, and further support the important role of this accessory protein in the early events of HTLV-1 infection.

scholarly journals The Ca2+ export pump PMCA clears near-membrane Ca2+ to facilitate store-operated Ca2+ entry and NFAT activation

2019 ◽  
Vol 12 (602) ◽  
pp. eaaw2627 ◽  
Author(s):  
Christina K. Go ◽  
Robert Hooper ◽  
Matthew R. Aronson ◽  
Bryant Schultz ◽  
Taha Cangoz ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Fate ◽  
T Cell Activation ◽  
Splice Variant ◽  
Cell Activation ◽  
Nuclear Factor ◽  
Activated T Cells ◽  
Plasma Membrane Calcium Atpase ◽  
Nfat Activation ◽  
Transcription Factor Nuclear Factor

Ca2+ signals, which facilitate pluripotent changes in cell fate, reflect the balance between cation entry and export. We found that overexpression of either isoform of the Ca2+-extruding plasma membrane calcium ATPase 4 (PMCA4) pump in Jurkat T cells unexpectedly increased activation of the Ca2+-dependent transcription factor nuclear factor of activated T cells (NFAT). Coexpression of the endoplasmic reticulum–resident Ca2+ sensor stromal interaction molecule 1 (STIM1) with the PMCA4b splice variant further enhanced NFAT activity; however, coexpression with PMCA4a depressed NFAT. No PMCA4 splice variant dependence in STIM1 association was observed, whereas partner of STIM1 (POST) preferentially associated with PMCA4b over PMCA4a, which enhanced, rather than inhibited, PMCA4 function. A comparison of global and near-membrane cytosolic Ca2+ abundances during store-operated Ca2+ entry revealed that PMCA4 markedly depressed near-membrane Ca2+ concentrations, particularly when PMCA4b was coexpressed with STIM1. PMCA4b closely associated with both POST and the store-operated Ca2+ channel Orai1. Furthermore, POST knockdown increased the near-membrane Ca2+ concentration, inhibiting the global cytosolic Ca2+ increase. These observations reveal an unexpected role for POST in coupling PMCA4 to Orai1 to promote Ca2+ entry during T cell activation through Ca2+ disinhibition.

scholarly journals The Essential Role of MEKK3 Signaling in Angiotensin II-induced Calcineurin/Nuclear Factor of Activated T-cells Activation

2005 ◽  
Vol 280 (44) ◽  
pp. 36737-36746 ◽  
Author(s):  
Shahrzad Abbasi ◽  
Bing Su ◽  
Rodney E. Kellems ◽  
JianHua Yang ◽  
Yang Xia
Keyword(s):  
T Cells ◽  
Angiotensin Ii ◽  
Essential Role ◽  
Nuclear Factor ◽  
Activated T Cells

scholarly journals Dynamic equilibrium between calcineurin and kinase activities regulates the phosphorylation state and localization of the nuclear factor of activated T-cells

1997 ◽  
Vol 324 (2) ◽  
pp. 597-603 ◽  
Author(s):  
John E. SCOTT ◽  
Valerie A. RUFF ◽  
Karen L. LEACH
Keyword(s):  
T Cells ◽  
Nuclear Localization ◽  
T Cell Activation ◽  
Cell Activation ◽  
Kinase Inhibitors ◽  
Dynamic Equilibrium ◽  
Nuclear Factor ◽  
Activated T Cells ◽  
Phosphorylation State

The nuclear factor of activated T-cells (NFATp) is a phosphorylated transcription factor that resides in the cytoplasm of unactivated T-cells. T-cell activation results in the activation of the phosphatase calcineurin (CaN), which leads to the dephosphorylation and subsequent nuclear localization of NFATp. We have investigated the role of kinases in the phosphorylation state and subcellular localization of NFATp. The phosphorylation state and nuclear/cytoplasmic location of NFATp were determined in unstimulated murine HT-2 cells treated with a panel of kinase inhibitors. Two of the seven kinase inhibitors, staurosporine (St) and bisindolylmaleimide I (BI), resulted in the dephosphorylation and nuclear localization of NFATp. These St-induced effects were inhibited by pretreatment with FK506, indicating that CaN activity was required for the observed effects on NFATp. Treatment of cells with ionomycin resulted in NFATp dephosphorylation and nuclear localization. Removal of ionomycin from the cells resulted in the reappearance of phosphorylated NFATp in the cytosol. St and BI also inhibited the re-accumulation of NFATp in the cytoplasm and its re-phosphorylation after ionomycin removal. The re-accumulation of NFATp in the cytosol after ionomycin withdrawal was shown to be energy- and temperature-dependent. Taken together, these results suggest that in unstimulated cells NFATp is actively maintained in the cytoplasm by kinases acting in opposition to basal CaN activity.

scholarly journals Mice Lacking the Calcineurin Inhibitor Rcan2 Have an Isolated Defect of Osteoblast Function

Endocrinology ◽  
2012 ◽  
Vol 153 (7) ◽  
pp. 3537-3548 ◽  
Author(s):  
J. H. Duncan Bassett ◽  
John G. Logan ◽  
Alan Boyde ◽  
Moira S. Cheung ◽  
Holly Evans ◽  
...  
Keyword(s):  
T Cells ◽  
Bone Development ◽  
Skeletal Development ◽  
Dominant Negative ◽  
Nuclear Factor ◽  
Activated T Cells ◽  
Osteoblast Function ◽  
And Function

Calcineurin-nuclear factor of activated T cells signaling controls the differentiation and function of osteoclasts and osteoblasts, and regulator of calcineurin-2 (Rcan2) is a physiological inhibitor of this pathway. Rcan2 expression is regulated by T3, which also has a central role in skeletal development and bone turnover. To investigate the role of Rcan2 in bone development and maintenance, we characterized Rcan2−/− mice and determined its skeletal expression in T3 receptor (TR) knockout and thyroid-manipulated mice. Rcan2−/− mice had normal linear growth but displayed delayed intramembranous ossification, impaired cortical bone formation, and reduced bone mineral accrual during development as well as increased mineralization of adult bone. These abnormalities resulted from an isolated defect in osteoblast function and are similar to skeletal phenotypes of mice lacking the type 2 deiodinase thyroid hormone activating enzyme or with dominant-negative mutations of TRα, the predominant TR isoform in bone. Rcan2 mRNA was expressed in primary osteoclasts and osteoblasts, and its expression in bone was differentially regulated in TRα and TRβ knockout and thyroid-manipulated mice. However, in primary osteoblast cultures, T3 treatment did not affect Rcan2 mRNA expression or nuclear factor of activated T cells c1 expression and phosphorylation. Overall, these studies establish that Rcan2 regulates osteoblast function and its expression in bone is regulated by thyroid status in vivo.

Regulation of nuclear factor of activated T cells by phosphotyrosyl-specific phosphatase activity: a positive effect on HIV-1 long terminal repeat–driven transcription and a possible implication of SHP-1

Blood ◽  
2001 ◽  
Vol 97 (8) ◽  
pp. 2390-2400 ◽  
Author(s):  
Jean-François Fortin ◽  
Benoit Barbeau ◽  
Gilles A. Robichaud ◽  
Marie-Ève Paré ◽  
Anne-Marie Lemieux ◽  
...  
Keyword(s):  
T Cells ◽  
Long Terminal Repeat ◽  
Nuclear Translocation ◽  
Interleukin 2 ◽  
Dominant Negative ◽  
Terminal Repeat ◽  
Nuclear Factor ◽  
Activated T Cells ◽  
Nfat Activation ◽  
Hiv 1

Abstract Although protein tyrosine phosphatase (PTP) inhibitors used in combination with other stimuli can induce interleukin 2 (IL-2) production in T cells, a direct implication of nuclear factor of activated T cells (NFAT) has not yet been demonstrated. This study reports that exposure of leukemic T cells and human peripheral blood mononuclear cells to bis-peroxovanadium (bpV) PTP inhibitors markedly induce activation and nuclear translocation of NFAT. NFAT activation by bpV was inhibited by the immunosuppressive drugs FK506 and cyclosporin A, as well as by a specific peptide inhibitor of NFAT activation. Mobility shift assays showed specific induction of the NFAT1 member by bpV molecules. The bpV-mediated NFAT activation was observed to be important for the up-regulation of the human immunodeficiency virus 1 (HIV-1) long terminal repeat (LTR) and the IL-2 promoter; NFAT1 was demonstrated to be particularly important in bpV-dependent positive action on HIV-1 LTR transcription. The active participation of p56lck, ZAP-70, p21ras, and calcium in the bpV-mediated signaling cascade leading to NFAT activation was confirmed, using deficient cell lines and dominant-negative mutants. Finally, overexpression of wild-type SHP-1 resulted in a greatly diminished activation of NFAT by bpV, suggesting an involvement of SHP-1 in the regulation of NFAT activation. These data were confirmed by constitutive NFAT translocation observed in Jurkat cells stably expressing a dominant-negative version of SHP-1. The study proposes that PTP activity attenuates constitutive kinase activities that otherwise would lead to constant NFAT activation and that this activation is participating in HIV-1 LTR stimulation by PTP inhibition.

Essential role of ROS-mediated NFAT activation in TNF-α induction by crystalline silica exposure

2006 ◽  
Vol 291 (2) ◽  
pp. L257-L264 ◽  
Author(s):  
Qingdong Ke ◽  
Jingxia Li ◽  
Jin Ding ◽  
Min Ding ◽  
Liying Wang ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Crystalline Silica ◽  
Dependent Manner ◽  
Activated T Cells ◽  
Silica Exposure ◽  
Tnf Α ◽  
Nfat Activation ◽  
Cytokine Tumor Necrosis Factor ◽  
Factor Α

Occupational exposure to crystalline silica has been associated with progressive pulmonary silicosis and lung cancer, but the underlying molecular mechanisms are not well understood. Previous studies have shown that crystalline silica exposure can generate reactive oxygen species (ROS) and induce the expression of the inflammatory cytokine tumor necrosis factor-α (TNF-α) in cells. TNF-α is believed to be critical in the development of silica-related diseases. Thus it will be of significance to understand the mechanisms of TNF-α induction by silica exposure. Given the fact that the transcription factor nuclear factor of activated T cells (NFAT) plays an important role in the regulation of TNF-α and can also be activated by ROS, in this study we investigated the potential role of ROS in silica-induced NFAT activity as well as TNF-α expression in Cl41 cells. The results showed that exposure of cells to silica led to NFAT transactivation and TNF-α induction, where superoxide anion radical (O2−·), but not H2O2, was involved. The knockdown of NFAT3 by its specific small interfering RNA significantly attenuated the silica-induced TNF-α transcription. This study demonstrated that silica was able to activate NFAT in an O2−·-dependent manner, which was required for TNF-α induction.

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