更新于：2024-05-01

NFATC4

nuclear factor of activated T cells 4

更新于：2024-05-01

基本信息

别名

NF-AT3、NF-ATc4、NFAT3

+ [4]

简介

Ca(2+)-regulated transcription factor that is involved in several processes, including the development and function of the immune, cardiovascular, musculoskeletal, and nervous systems (PubMed:7749981, PubMed:11514544, PubMed:11997522, PubMed:17875713, PubMed:17213202, PubMed:18668201, PubMed:25663301). Involved in T-cell activation, stimulating the transcription of cytokine genes, including that of IL2 and IL4 (PubMed:7749981, PubMed:18668201, PubMed:18347059). Along with NFATC3, involved in embryonic heart development. Involved in mitochondrial energy metabolism required for cardiac morphogenesis and function (By similarity). Transactivates many genes involved in the cardiovascular system, including AGTR2, NPPB/BNP (in synergy with GATA4), NPPA/ANP/ANF and MYH7/beta-MHC (By similarity). Involved in the regulation of adult hippocampal neurogenesis. Involved in BDNF-driven pro-survival signaling in hippocampal adult-born neurons. Involved in the formation of long-term spatial memory and long-term potentiation (By similarity). In cochlear nucleus neurons, may play a role in deafferentation-induced apoptosis during the developmental critical period, when auditory neurons depend on afferent input for survival (By similarity). Binds to and activates the BACE1/Beta-secretase 1 promoter, hence may regulate the proteolytic processing of the amyloid precursor protein (APP) (PubMed:25663301). Plays a role in adipocyte differentiation (PubMed:11997522). May be involved in myoblast differentiation into myotubes (PubMed:17213202). Binds the consensus DNA sequence 5'-GGAAAAT-3' (Probable). In the presence of CREBBP, activates TNF transcription (PubMed:11514544). Binds to PPARG gene promoter and regulates its activity (PubMed:11997522). Binds to PPARG and REG3G gene promoters (By similarity).

关联

100 项与 NFATC4 相关的临床结果

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100 项与 NFATC4 相关的转化医学

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0 项与 NFATC4 相关的专利（医药）

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384

项与 NFATC4 相关的文献（医药）

2024-02-08·Journal of clinical pharmacology

Genotype-Guided Model for Prediction of Tacrolimus Initial Dosing After Lung Transplantation.

Article

作者: Wenwen Du ; Xiaoxing Wang ; Dan Zhang ; Xianbo Zuo

The determination of the appropriate initial dose for tacrolimus is crucial in achieving the target concentration promptly and avoiding adverse effects and poor prognosis. However, the trial-and-error approach is still common practice. This study aimed to establish a prediction model for an initial dosing algorithm of tacrolimus in patients receiving a lung transplant. A total of 210 lung transplant recipients were enrolled, and 26 single nucleotide polymorphisms (SNP) from 18 genes that could potentially affect tacrolimus pharmacokinetics were genotyped. Associations between SNPs and tacrolimus concentration/dose ratio were analyzed. SNPs that remained significant in pharmacogenomic analysis were further combined with clinical factors to construct a prediction model for tacrolimus initial dose. The dose needed to reach steady state tacrolimus concentrations and achieve the target range was used to validate model prediction efficiency. Our final model consisted of 7 predictors-CYP3A5 rs776746, SLCO1B3 rs4149117, SLC2A2 rs1499821, NFATc4 rs1955915, alanine aminotransferase, direct bilirubin, and hematocrit-and explained 41.4% variance in the tacrolimus concentration/dose ratio. It achieved an area under the receiver operating characteristic curve of 0.804 (95% confidence interval, 0.746-0.861). The Hosmer-Lemeshow test yielded a nonsignificant P value of .790, suggesting good fit of the model. The predicted dose exhibited good correlation with the observed dose in the early postoperative period (r = 0.748, P less than .001). Our study provided a genotype-guided prediction model for tacrolimus initial dose, which may help to guide individualized dosing of tacrolimus in the lung transplant population in clinical practice.

2023-12-31·Clinical and experimental hypertension (New York, N.Y. : 1993)

CDN1163 alleviates SERCA2 dysfunction-induced pulmonary vascular remodeling by inhibiting the phenotypic transition of pulmonary artery smooth muscle cells.

Article

作者: Weimin Yu ; Qian Zhang ; Yixiang Qiu ; Hui Chen ; Xiaoyang Huang ; Li Xiao ; Gang Xu ; Siqi Li ; Pingping Hu ; Xiaoyong Tong

BACKGROUND AND PURPOSE:

Substitution of Cys⁶⁷⁴ (C674) in the sarcoplasmic/endoplasmic reticulum Ca²⁺ ATPase 2 (SERCA2) causes SERCA2 dysfunction which leads to activated inositol requiring enzyme 1 alpha (IRE1α) and spliced X-box binding protein 1 (XBP1s) pathway accelerating cell proliferation of pulmonary artery smooth muscle cells (PASMCs) followed by significant pulmonary vascular remodeling resembling human pulmonary hypertension. Based on this knowledge, we intend to investigate other potential mechanisms involved in SERCA2 dysfunction-induced pulmonary vascular remodeling.

EXPERIMENTAL APPROACH:

Heterozygous SERCA2 C674S knock-in (SKI) mice of which half of cysteine in 674 was substituted by serine to mimic the partial irreversible oxidation of C674 were used. The lungs of SKI mice and their littermate wild-type mice were collected for PASMC culture, protein expression, and pulmonary vascular remodeling analysis.

RESULTS:

SERCA2 dysfunction increased intracellular Ca²⁺ levels, which activated Ca²⁺-dependent calcineurin (CaN) and promoted the nuclear translocation and protein expression of the nuclear factor of activated T-lymphocytes 4 (NFAT4) in an IRE1α/XBP1s pathway-independent manner. In SKI PASMCs, the scavenge of intracellular Ca²⁺ by BAPTA-AM or inhibition of CaN by cyclosporin A can prevent PASMC phenotypic transition. CDN1163, a SERCA2 agonist, suppressed the activation of CaN/NFAT4 and IRE1α/XBP1s pathways, reversed the protein expression of PASMC phenotypic transition markers and cell cycle-related proteins, and inhibited cell proliferation and migration when given to SKI PASMCs. Furthermore, CDN1163 ameliorated pulmonary vascular remodeling in SKI mice.

CONCLUSIONS AND IMPLICATIONS:

SERCA2 dysfunction promotes PASMC phenotypic transition and pulmonary vascular remodeling by multiple mechanisms, which could be improved by SERCA2 agonist CDN1163.

2023-11-03·Human genomics

Comprehensive analysis of alternative splicing across multiple transcriptomic cohorts reveals prognostic signatures in prostate cancer.

Article

作者: Zhuofan Mou ; Jack Spencer ; John S McGrath ; Lorna W Harries

BACKGROUND:

Alternative splicing (AS) plays a crucial role in transcriptomic diversity and is a hallmark of cancer that profoundly influences the development and progression of prostate cancer (PCa), a prevalent and potentially life-limiting cancer among men. Accumulating evidence has highlighted the association between AS dysregulation and the onset and progression of PCa. However, a comprehensive and integrative analysis of AS profiles at the event level, utilising data from multiple high-throughput cohorts and evaluating the prognosis of PCa progression, remains lacking and calls for thorough exploration.

RESULTS:

We identified a differentially expressed retained intron event in ZWINT across three distinct cohorts, encompassing an original array-based dataset profiled by us previously and two RNA sequencing (RNA-seq) datasets. Subsequent in-depth analyses of these RNA-seq datasets revealed 141 altered events, of which 21 demonstrated a significant association with patients' biochemical recurrence-free survival (BCRFS). We formulated an AS event-based prognostic signature, capturing six pivotal events in genes CYP4F12, NFATC4, PIGO, CYP3A5, ALS2CL, and FXYD3. This signature effectively differentiated high-risk patients diagnosed with PCa, who experienced shorter BCRFS, from their low-risk counterparts. Notably, the signature's predictive power surpassed traditional clinicopathological markers in forecasting 5-year BCRFS, demonstrating robust performance in both internal and external validation sets. Lastly, we constructed a novel nomogram that integrates patients' Gleason scores with pathological tumour stages, demonstrating improved prognostication of BCRFS.

CONCLUSIONS:

Prediction of clinical progression remains elusive in PCa. This research uncovers novel splicing events associated with BCRFS, augmenting existing prognostic tools, thus potentially refining clinical decision-making.

项与 NFATC4 相关的新闻（医药）

2023-03-24

·生物谷

CCR：科学家首次发现，耐药卵巢癌能细胞“催眠”同伙，促进周围癌细胞集体耐药！

这项研究报告了一种新的化疗耐药机制，即化疗可促进静止态卵巢癌细胞表达大量FST，并以旁分泌的方式影响其邻近肿瘤细胞的增殖和耐药。通过敲除FST或使用FST中和抗体可提高肿瘤细胞或小鼠肿瘤模型对化疗药物卵巢癌是女性常见恶性肿瘤之一。由于卵巢位于盆腔较深部，缺乏早期筛查方法，多数患者确诊时已是晚期，具有病程复杂，易复发，远期生存率低等特点。因此，卵巢癌成为了女性生殖道肿瘤诊治中的“硬骨头”。手术和化疗是卵巢癌的常规治疗手段，其中约70%的患者经化疗后能够实现缓解，但大部分患者仍会对化疗药物耐药，最终导致卵巢癌治疗失败，但目前尚无较好的方法可以解决耐药问题。不过近日，美国匹兹堡大学Ronald Buckanovich教授团队发表于癌症领域著名期刊Clinical Cancer Research的最新研究[1]，为克服卵巢癌耐药带来了希望。该研究发现，化疗可通过激活转录因子NFATC4，使静止态卵巢癌细胞分泌大量卵泡抑制素（follistatin, FST），从而促进周围肿瘤细胞耐药；而靶向FST在临床前研究中逆转了卵巢癌细胞的耐药，并提高了卵巢癌小鼠模型的存活率和生存期。文章首页截图在肿瘤中，有部分暂停增殖、处于G0期的细胞，被称为静止态癌细胞。由于化疗主要针对快速分裂的细胞，静止态癌细胞由于分裂缓慢而对化疗药物耐受，既往研究已经证明，静止态癌细胞在多种癌症的耐药中扮演了重要角色[2]。静止态癌细胞在卵巢癌的化疗耐药中也起到重要作用[3]。Buckanovich教授团队在此前的工作中发现，转录因子NFATC4在卵巢癌肿瘤干细胞中高表达，化疗可激活NFATC4入核促进其发挥转录调控作用[4]，从而诱导细胞进入静止状态并发生耐药。但是，其中的具体机制尚不清楚。因此，研究团队这次首先通过体外实验，鉴定出受NFATC4调控的141个靶基因，其中RCAN1, CNN1, COL3A1, FST和ANO1的mRNA表达量上调最为明显。考虑到FST在卵巢的发育和功能中具有重要作用[5]，并且临床发现卵巢癌患者血清中的FST也出现升高[6]，研究团队决定探索NFATC4下游靶点FST的作用。体外细胞实验证实，NFATC4确实能调控FST蛋白表达，且对高级别浆液性卵巢癌（HGSOC）患者肿瘤组织中，不同分裂速度的癌细胞进行比较时，发现静止态癌细胞中FST表达量显著增高（P<0.01），可达到快速分裂细胞的23倍，由此可见，NFATC4对FST的调控作用主要发生于静止态肿瘤细胞中。用化疗药物顺铂或紫杉醇处理不同卵巢癌细胞系，可导致FST的mRNA表达量增加10-72倍，导致FST的蛋白表达量增加4-50倍，且静止态癌细胞是FST增加的主要来源，这部分细胞的FST分泌量大约是正常分裂癌细胞的3倍。不同化疗药物（紫杉醇，Taxol；顺铂，Ciplatin）处理后不同卵巢癌细胞系FST分泌量的变化情况同时，在卵巢癌肿瘤模型小鼠上也观察到化疗促进FST分泌的现象。那么这些大量分泌的FST，到底有什么用呢？研究显示，高浓度FST处理可导致体外培养的卵巢癌细胞数量明显减少（P<0.001）；进一步的分析发现，FST对细胞生长的影响是由于抑制增殖，且仅对快速分裂的细胞增殖产生明显作用，并不影响静止态癌细胞。不同浓度FST对不同卵巢癌细胞生长的影响前面提到过，许多化疗药物主要针对的是快速分裂的癌细胞，而一旦细胞增殖速度减慢，药效肯定会大打折扣！果然，研究团队发现FST能促进化疗耐药：与单独使用紫杉醇相比，联合FST处理时肿瘤细胞存活数量可提高1.5-2.5倍（P<0.05）。使用顺铂进行实验也得到相似结果，机制分析则显示，FST可通过ATF2信号转导通路促进化疗耐药。值得一提的是，研究者们还通过细胞共培养实验证明，静止态癌细胞产生的FST可以旁分泌的方式，抑制其邻近快速分裂癌细胞的增殖。打个比方来说，静止态癌细胞就像花的花芯，而相邻的细胞就像花瓣，当化疗药物来袭时，静止态癌细胞就分泌FST来保护整个“花朵”。在此过程中，更多的肿瘤细胞会进入静止状态，并进一步影响其周围更多的细胞，越来越多的耐药细胞也就随之产生，最终导致癌症复发。 FST可促进化疗药物（紫杉醇，Taxol；顺铂，Cisplatin）发生耐药接下来，研究团队尝试将FST作为治疗靶点，使用FST中和抗体或CRISPR-Cas9敲除FST，均能显著增加卵巢癌细胞对化疗药物的敏感性（P<0.01）；而为进一步评估敲除FST在体内的作用，研究者建立了卵巢癌移植瘤小鼠模型，并用紫杉醇进行治疗，结果显示，相比野生型小鼠，注射FST-KO细胞的小鼠存活率显著提高（P<0.0001），总生存期也明显延长。在化疗药物治疗同时FST敲除对移植瘤小鼠存活率和生存期的影响最后，研究团队还比较了化疗前后卵巢癌患者体内FST的变化情况：与化疗前相比，患者FST水平在化疗后24小时后增加了1-3倍；而对数百名卵巢癌患者的TCGA数据分析发现，高水平FST与较低的生存率相关，表明FST也有望作为逆转人卵巢癌耐药的新靶点。总的来说，这项研究报告了一种新的化疗耐药机制，即化疗可促进静止态卵巢癌细胞表达大量FST，并以旁分泌的方式影响其邻近肿瘤细胞的增殖和耐药。通过敲除FST或使用FST中和抗体可提高肿瘤细胞或小鼠肿瘤模型对化疗药物的敏感性。 FST介导的卵巢癌化疗耐药模式图本次研究对卵巢癌的治疗具有重要意义，化疗目前仍是不可手术卵巢癌的有效治疗手段，减少耐药和复发将大大改善患者预后，而且FST是一种分泌性蛋白，因此是中和抗体的理想靶点，期待相关抗体药物能早日被成功研发出来。