Last update 01 Nov 2024

NFAT1

Last update 01 Nov 2024

Basic Info

Synonyms

NF-ATc2, NF-ATP, NFAT pre-existing subunit

+ [6]

Introduction

Plays a role in the inducible expression of cytokine genes in T-cells, especially in the induction of the IL-2, IL-3, IL-4, TNF-alpha or GM-CSF (PubMed:15790681). Promotes invasive migration through the activation of GPC6 expression and WNT5A signaling pathway (PubMed:21871017). Is involved in the negative regulation of chondrogenesis (PubMed:35789258).

Drugs associated with NFAT1

NFAT inhibitor(Imagene)

Target

NFAT1

Mechanism

NFAT1 inhibitors

Active Org.

IMAGENE Co., Ltd.

Originator Org.

IMAGENE Co., Ltd.

Active Indication-

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

MA242

Target

MDM2 x NFAT1

Mechanism

MDM2 inhibitors [+1]

Active Org.

University of Houston

Originator Org.

University of Houston

Active Indication

Breast Cancer

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with NFAT1

100 Translational Medicine associated with NFAT1

0 Patents (Medical) associated with NFAT1

1,144

Literatures (Medical) associated with NFAT1

01 Dec 2024·Molecular and Cellular Endocrinology

Extragonadal function of follicle-stimulating hormone: Evidence for a role in endothelial physiology and dysfunction

Article

Author: Marino, Saralea ; Ferlin, Alberto ; Foresta, Carlo ; Pannella, Micaela ; Bayraktar, Erva ; Rocca, Maria Santa ; Di Nisio, Andrea ; Bortolozzi, Mario

AIMSFollicle-stimulating hormone (FSH) plays a fundamental role in reproduction stimulating ovarian folliculogenesis, Sertoli cells function and spermatogenesis. However, the recent identification of FSH receptor (FSHR) also in extra-gonadal tissues has suggested that FSH activity may not be limited only to fertility regulation, with conflicting results on the possible role of FSH in endothelial cells. The aim of this study was to investigate FSH role on endothelial function in Human Umbilical Vein Endothelial Cells (HUVECs).RESULTSEndothelial Nitric oxide synthase (eNOS) expression, eNOS phosphorylation and Nitric Oxide (NO) production resulted increased after the stimulation of HUVEC with recombinant human FSH (rhFSH) at 3.6x10³ ng/ml, with increasing Calcium release from intracellular stores. Furthermore, IP₃ production increased after rhFSH stimulation despite PTX treatment and NFAT1 was observed prevalently in nucleus. We observed a statistical difference between untreated cells and cells stimulated with 0.36x10³ ng/ml and between cells stimulated with 0.36x10³ ng/ml and cells stimulated with 1.8x10³ ng/ml at 4 and 8 h by Wound healing assay, respectively. Furthermore, a higher cellular permeability was observed in stimulated cells, with atypical VE-cadherin distribution, as well as filamentous actin.CONCLUSIONSOur findings suggest that FSH at high concentrations elicits a signalling that could compromise the endothelial membrane. Indeed, VE-cadherin anomalies may severely affect the endothelial barrier, resulting in an increased membrane permeability. Although NO is an important vasodilatation factor, probably an excessive production could impact on endothelial functionality, partially explaining the increased risk of cardiovascular diseases in menopausal women and men with hypogonadism.

01 Nov 2024·Arteriosclerosis, Thrombosis, and Vascular Biology

Rap1A Modulates Store-Operated Calcium Entry in the Lung Endothelium: A Novel Mechanism Controlling NFAT-Mediated Vascular Inflammation and Permeability

Article

Author: Kosuru, Ramoji ; Zhang, David X. ; Sharma, Guru Prasad ; Trebak, Mohamed ; Kastrup, Christian J. ; Mammoto, Tadanori ; Yang, Kai ; Romito, Olivier ; Chrzanowska, Magdalena ; Ferraresso, Francesca ; Goldspink, Paul H. ; Ghadrdoost Nakhchi, Behshid ; Mammoto, Akiko

BACKGROUND:Store-operated calcium entry mediated by STIM (stromal interaction molecule)-1–Orai1 (calcium release-activated calcium modulator 1) is essential in endothelial cell (EC) functions, affecting signaling, NFAT (nuclear factor for activated T cells)-induced transcription, and metabolic programs. While the small GTPase Rap1 (Ras-proximate-1) isoforms, including the predominant Rap1B, are known for their role in cadherin-mediated adhesion, EC deletion of Rap1A after birth uniquely disrupts lung endothelial barrier function. Here, we elucidate the specific mechanisms by which Rap1A modulates lung vascular integrity and inflammation.METHODS:The role of EC Rap1A in lung inflammation and permeability was examined using in vitro and in vivo approaches.RESULTS: We explored Ca 2+ signaling in human ECs following siRNA-mediated knockdown of Rap1A or Rap1B. Rap1A knockdown, unlike Rap1B, significantly increased store-operated calcium entry in response to a GPCR (G-protein–coupled receptor) agonist, ATP (500 µmol/L), or thapsigargin (250 nmol/L). This enhancement was attenuated by Orai1 channel blockers 10 μmol/L BTP2 (N-[4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-4-methyl-1,2,3-thiadiazole-5-carboxamide), 10 μmol/L GSK-7975A, and 5 μmol/L Gd 3+ . Whole-cell patch clamp measurements revealed enhanced Ca 2+ release-activated Ca 2+ current density in siRap1A ECs. Rap1A depletion in ECs led to increased NFAT1 nuclear translocation and activity and elevated levels of proinflammatory cytokines (CXCL1 [C-X-C motif chemokine ligand 1], CXCL11 [C-X-C motif chemokine 11], CCL5 [chemokine (C-C motif) ligand 5], and IL-6 [interleukin-6]). Notably, reducing Orai1 expression in siRap1A ECs normalized store-operated calcium entry, NFAT activity, and endothelial hyperpermeability in vitro. EC-specific Rap1A knockout (Rap1A iΔEC ) mice displayed an inflammatory lung phenotype with increased lung permeability and inflammation markers, along with higher Orai1 expression. Delivery of siRNA against Orai1 to lung endothelium using lipid nanoparticles effectively normalized Orai1 levels in lung ECs, consequently reducing hyperpermeability and inflammation in Rap1A iΔEC mice. CONCLUSIONS: Our findings uncover a novel role of Rap1A in regulating Orai1-mediated Ca 2+ entry and expression, crucial for NFAT-mediated transcription and endothelial inflammation. This study distinguishes the unique function of Rap1A from that of the predominant Rap1B isoform and highlights the importance of normalizing Orai1 expression in maintaining lung vascular integrity and modulating endothelial functions.

01 Oct 2024·International Journal of Radiation Oncology*Biology*Physics

ORAI2 is Important for the Development of Early-Stage Postirradiation Fibrosis in Salivary Glands

Article

Author: Tang, Patrick M K ; Li, Honglin ; Li, Chunjie ; Tang, Patrick MK ; Huang, Guangzhao ; Ding, Zhangfan ; Wang, Lei ; Cao, Yubin ; Zhao, Guile ; Wang, Guanru

PURPOSEAlthough postirradiation hyposalivation significantly impairs patient quality of life, the underlying mechanisms driving radiation-induced salivary gland fibrosis and hyposalivation remain poorly understood. This study aims to explore the role of calcium-mediated signaling pathways in radiation-induced salivary gland fibrosis.METHODS AND MATERIALSPrimary human submandibular gland (SG) cells and C57BL/6J female mouse SGs were exposed to irradiation to model fibrosis development. Following 15 Gy irradiation exposure, RNA sequencing and bioinformatic analysis were conducted on mouse SGs. The effects of store-operated calcium entry (SOCE) inhibition using SKF96365 and YM58483 on fibrosis markers were assessed in vitro and in vivo. Additionally, the involvement of ORAI2 protein and the newly identified JNK/NFAT1/transforming growth factor β1 (TGF-β1) signaling axis in SG fibrosis was explored.RESULTSWe identified that the calcium release-activated calcium modulator ORAI2 was important in promoting early-stage postirradiation fibrosis in SGs. Calcium channel signaling was activated in both human patients and irradiated C57BL/6J female mice SGs. Inhibition of SOCE signaling effectively blocked fibrosis in an ORAI2-dependent manner 30 days after irradiation. Our mechanistic studies revealed a novel ORAI2/JNK/NFAT1 axis within the SOCE pathway critical in driving TGF-β1-mediated fibrogenesis. Encouragingly, pharmacologic inhibition of NFAT1 significantly mitigated radiation-induced SG fibrosis and restored saliva flow to 84.61% of normal levels in treated mice 30 days after irradiation, without detectable side effects.CONCLUSIONSOur findings highlight the significance of the ORAI2-mediated calcium signaling pathway, specifically via the ORAI2/JNK/NFAT1 axis, in promoting TGF-β1 expression and contributing to the development of early-stage salivary gland fibrosis following irradiation exposure. Targeting the ORAI2/JNK/NFAT1 axis emerges as a promising therapeutic strategy to alleviate radiation-induced hyposalivation and fibrosis, potentially improving the quality of life for patients undergoing radiation therapy.

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NFAT1

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