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更新于：2025-05-07

PIAS3

更新于：2025-05-07

基本信息

别名

E3 SUMO-protein ligase PIAS3、E3 SUMO-protein transferase PIAS3、FLJ14651

+ [4]

简介

Functions as an E3-type small ubiquitin-like modifier (SUMO) ligase, stabilizing the interaction between UBE2I and the substrate, and as a SUMO-tethering factor. Plays a crucial role as a transcriptional coregulation in various cellular pathways, including the STAT pathway and the steroid hormone signaling pathway. Involved in regulating STAT3 signaling via inhibiting STAT3 DNA-binding and suppressing cell growth. Enhances the sumoylation of MTA1 and may participate in its paralog-selective sumoylation (PubMed:21965678, PubMed:9388184). Sumoylates CCAR2 which promotes its interaction with SIRT1 (PubMed:25406032). Diminishes the sumoylation of ZFHX3 by preventing the colocalization of ZFHX3 with SUMO1 in the nucleus (PubMed:24651376).

关联

项与 PIAS3 相关的药物

CN117821404

专利挖掘

靶点

PIAS3

作用机制-

在研机构

徐州医科大学

原研机构

徐州医科大学

在研适应症

认知障碍 [+1]

非在研适应症-

最高研发阶段药物发现

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 PIAS3 相关的临床结果

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100 项与 PIAS3 相关的转化医学

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0 项与 PIAS3 相关的专利（医药）

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278

项与 PIAS3 相关的文献（医药）

2025-02-01·3 Biotech

NF-κB signaling is the major inflammatory pathway for inducing insulin resistance

Article

作者: Bhargav, Anasuya ; Fatima, Firdaus ; Joshi, Sweta ; Mobeen, Ahmed ; Faruq, Mohammed ; Ramachandran, Srinivasan ; Arif, Yusra

Insulin resistance is major factor in the development of metabolic syndrome and type 2 diabetes (T2D). We extracted 430 genes from literature associated with both insulin resistance and inflammation. The highly significant pathways were Toll-like receptor signaling, PI3K-Akt signaling, cytokine-cytokine receptor interaction, pathways in cancer, TNF signaling, and NF-kappa B signaling. Among the 297 common genes in all datasets of various T2D patients' tissues including blood, muscle, liver, pancreas, and adipose tissues, 71% and 60% of these genes were differentially expressed in pancreas (GSE25724) and liver (GSE15653), respectively. A total of 169 genes contain highly conserved motifs for various transcription factors involved in immune response, thereby suggesting coordinated expression. Through co-expression analysis, we obtained three modules. The respective modules had 78, 158, and 55 genes, and TRAF2, HMGA1, and RGS5 as hub genes. Further, we used the BioNSi pathways simulation tool and identified the following five KEGG pathways perturbed in four or more tissues, namely Toll-like receptor signaling pathway, RIG-1-like receptor signaling pathway, pathways in cancer, NF-kappa B signaling pathway, and insulin resistance pathway. The genes NFKBIA and IKBKB are common to all these five pathways. In addition, using the NF-κB computational activation model, we identified that the reversal of NF-κB constitutive activation through overexpression of NFKB1 (P50 homodimer), PPARG, PIAS3 could reduce insulin resistance by almost half of its original value. To conclude, co-expression studies, gene expression network simulation, and NF-κB computational modeling substantiate the causal role of NF-κB pathway in insulin resistance. These results taken together with other published evidence suggests that the TNF-TRAF2-IKBKB-NF-κB axis could be explored as a potential target in combination with available metabolic targets in the management of insulin resistance.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13205-024-04202-4.

2024-12-01·Cellular and Molecular Life Sciences

Disrupting PIAS3-mediated SUMOylation of MLK3 ameliorates poststroke neuronal damage and deficits in cognitive and sensorimotor behaviors

Article

作者: Hu, Lulu ; Shao, Mengwen ; Chen, Rourou ; Zhang, Bingge ; Xu, Yan ; Jiang, Yu ; Meng, Li ; Wang, Baixue ; Du, Caiping ; Li, Meng

AbstractActivated small ubiquitin-like modifiers (SUMOs) have been implicated in neuropathological processes following ischemic stroke. However, the target proteins of SUMOylation and their contribution to neuronal injury remain to be elucidated. MLK3 (mixed-lineage kinase 3), a member of the mitogen-activated protein kinase kinase kinase (MAPKKK) family, is a critical regulator of neuronal lesions following cerebral ischemia. Here, we found that SUMOylation of MLK3 increases in both global and focal ischemic rodent models and primary neuronal models of oxygen and glucose deprivation (OGD). SUMO1 conjugation at the Lys401 site of MLK3 promoted its activation, stimulated its downstream p38/c-Jun N-terminal kinase (JNK) cascades, and led to cell apoptosis. The interaction of MLK3 with PIAS3, a SUMO ligase, was elevated following ischemia and reperfusion. The PINIT domain of PIAS3 was involved in direct interactions with MLK3. Overexpression of the PINIT domain of PIAS3 disrupted the MLK3-PIAS3 interaction, inhibited SUMOylation of MLK3, suppressed downstream signaling, and reduced cell apoptosis and neurite damage. In rodent ischemic models, the overexpression of the PINIT domain reduced brain lesions and alleviated deficits in learning, memory, and sensorimotor functions. Our findings demonstrate that brain ischemia-induced MLK3 SUMOylation by PIAS3 is a potential target against poststroke neuronal lesions and behavioral impairments.

2024-11-27·Oncogene

Obesity-induced extracellular vesicles proteins drive the endometrial cancer pathogenesis: therapeutic potential of HO-3867 and Metformin

Article

作者: Suarez, Adrian ; Cohn, David E. ; Koga, Hironori ; O'Malley, David M ; Cosgrove, Casey ; Zingarelli, Roman ; Selvendiran, Karuppaiyah ; Wallbillich, John ; Dorayappan, Kalpana Deepa Priya ; Bognar, Balazs ; Cohn, David E ; Maxwell, G. Larry ; Anbalagan, Muralidharan ; Sakaue, Takahiko ; O’Malley, David M. ; Maxwell, G Larry ; Khadraoui, Wafa ; Wanner, Ross

AbstractEndometrial cancer (EC) is the leading gynecologic malignancy in the United States with obesity implicated in 57% of cases. This research investigates the molecular complexities of extracellular vesicles (EV) secretion as carriers of oncogenic protein and their involvement in obesity-mediated EC. An understanding of these mechanisms is pivotal for unraveling pathways relevant to obesity-associated EC, thereby guiding the development of innovative prevention and treatment strategies. Our exploration revealed a significant increase in EV secretion carrying oncogenic proteins (TMEM205, STAT5, and FAS) in adipose and uterine tissues/serum samples from obese EC patients compared to control (without cancer). We identified alterations in EV-regulating proteins (Rab7, Rab11, and Rab27a) in obesity-mediated EC patients, adipose/uterine tissues, and serum samples. Through a 24-week analysis of the effects of a 45% kcal high-fat diet (HFD) on mice, we observed increased body weight, increased adipose tissue, enlarged uterine horns, and increased inflammation in the HFD group. This correlated with elevated levels of EV secretion and increased expression of oncogenic proteins TMEM205, FAS, and STAT5 and downregulation of the tumor suppressor gene PIAS3 in adipose and uterine tissues. Furthermore, our study confirmed that adipocyte derived EV increased EC cell proliferation, migration and xenograft tumor growth. Additionally, we identified that the small molecule inhibitors (HO-3867) or Metformin inhibited EV secretion in vitro and in vivo, demonstrating significant inhibition of high glucose or adipocyte-mediated EC cell proliferation and a reduction in body weight and adipose tissue accumulation when administered to HFD mice. Moreover, HO-3867 or Metformin treatment inhibited HFD induced hyperplasia (precursor of EC) by altering the expression of EV-regulated proteins and decreasing oncogenic protein expression levels. This study provides critical insights into the mechanisms underpinning obesity-mediated EV secretion with oncogenic protein expression, shedding light on their role in EC pathogenesis. Additionally, it offers pre-clinical evidence supporting the initiation of novel studies for EV-targeted therapies aimed at preventing obesity-mediated EC.

项与 PIAS3 相关的新闻（医药）

2022-09-19

·佰傲谷BioValley

JAK-STAT通路与肿瘤免疫

30年前，JAK-STAT通路被人们发现，之后在转化与应用方面被持续关注。在细胞因子刺激下，这条通路调控着体内多种生物学活动、介导了几乎所有的免疫反应，不仅是免疫防御，还包括促进肿瘤细胞存活、免疫逃逸以及持续性炎症（特应性皮炎）的过程。JAK-STAT简介非受体酪氨酸激酶（JAK），包括JAK1/2/3和Tyk2。信号转导及激活转录因子（STAT），包括STAT1/2/3/4/5a/5b/6。细胞因子是JAK-STAT的主要激活信号，通过与膜上受体结合，使JAKs激活并介导STAT磷酸化入核，以调控靶基因的转录。细胞因子信号 → 激活JAK → STAT磷酸化后入核 → 调控转录Signal Transduct Target Ther. 2021 Nov 26;6(1):402. JAK-STAT与肿瘤免疫在不同的刺激信号下，JAK-STAT通路能够介导产生不同的效应，根据TME中的多种信号，发挥出抗肿瘤和促肿瘤双重作用。1. 抗肿瘤功能在多种细胞中，STAT-JAK都会响应抗瘤信号。在NK细胞中IFN-α/β信号：通过STAT1、STAT2介导NK细胞免疫应答。IL-2、IL-15信号：通过STAT5信号维持NK细胞稳态、增殖、功能。IL-12信号：通过STAT1、STAT3、STAT4使NK细胞产生INF-γ、穿孔素、颗粒酶介导细胞毒性。在T细胞中IFNα/β信号：通过STAT4促进抗原相关CD8T细胞扩增和细胞毒性作用。IL-12和IFN-γ信号：通过STAT1、STAT4诱导T-BET产生，能够促进T细胞进一步分泌IFN-γ。并且还能促进T细胞向Th1细胞分化，阻止向Th2、Th17、Treg等免疫抑制性亚群分化。细胞死亡后通过触发JAK-STAT信号以刺激IRG的TLR感测，能够与TCR协同增强T细胞分泌细胞因子。在肿瘤细胞中IFN-γ作用于与肿瘤细胞，通过STAT1激活caspase-1/3/8和FAS，从而诱导肿瘤细胞凋亡。2. 促肿瘤功能响应促瘤信号的主要为STAT3和STAT5。STAT3是响应促瘤信号的主要转录因子。生长因子、多种细胞因子、集落刺激因子IL-6是STAT3最主要的激活信号：通过介导IL-6-gp130与IL-6-IL-60这两个复合体形成，进而驱动肿瘤细胞以JAK-STAT依赖性的跨内皮迁移。IL-10能够通过STAT3抑制APC细胞阻断T细胞功能，促进Treg细胞分化。IL-6、IL-10导致STAT3表达升高，而升高的STAT3能够通过正反馈环路进一步促进IL-6、IL-10分泌，最终导致利于肿瘤生长环境的形成。此外，在STAT3信号激活后还能够抑制STAT1、IRF7、IRF9基因的表达，从而抑制Ⅰ型IFN信号，最终也促进免疫抑制性TME形成。STAT5在乳腺癌和前列腺癌中，STAT5与Foxp3结合，能够维持其过表达的同时促进Treg细胞发育。IL-8通过激活过表达的STAT5与乳腺癌细胞存活、化疗耐药以及转移有关。与STAT3一样，过度激活的STAT5也能够抑制IFNα信号对STAT1的激活，影响下游反应。3. 负性调节信号在JAK-STAT通路中，为了维持正确的信号传递，各层面存在多种稳态调控机制，包括负调控信号。负调控因子同样具有促瘤与抗瘤双重作用。SOCS1是维持T细胞稳态的细胞因子信号转导抑制物。它能够结合并促进JAK与STAT分解，在STAT激活时SOCS的快速诱导是决定JAK-STAT信号强度的关键。其表达缺失与肿瘤细胞PD-L1高表达有关。PIAS是细胞因子激活的STAT蛋白抑制物，能够物理阻断核内激活的STAT与DNA结合，从而阻止信号诱导。PIAS1能够抑制Ⅰ/Ⅱ型IFN→STAT1信号传递，在多种恶心肿瘤中表达升高。PIAS3被沉默时，会导致STAT3过度激活。PTP蛋白质酪氨酸磷酸酶，包括SHP1/2、DUSP2、CD45。能够去磷酸化JAK, STAT上的酪氨酸残基，以促进它们快速地重新激活。SHP1通过抑制STAT3和NFκB信号在肝癌中发挥抗瘤作用。SHP2抑制剂与PD-1抑制剂联用能够发挥短暂的抗瘤反应。小结JAK-STAT通路看似是一个简单的线性过程，但在信号传递过程中通路上的所有成员都会参与调控。通路中复杂调控机制的存在，使STAT及辅助分子表达、结构、功能方面的微小改动就可以对免疫信号和肿瘤进展产生深远的影响。推荐阅读IL-6：肿瘤炎症、癌症转移核心分子参考资料Hu X et al. The JAK/STAT signaling pathway: from bench to clinic. Signal Transduct Target Ther. 2021 Nov 26;6(1):402. Yu H et al. Revisiting STAT3 signalling in cancer: new and unexpected biological functions. Nat Rev Cancer. 2014 Nov;14(11):736-46. Thomas SJ et al. The role of JAK/STAT signalling in the pathogenesis, prognosis and treatment of solid tumours. Br J Cancer. 2015 Jul 28;113(3):365-71.Kiu H et al. Biology and significance of the JAK/STAT signalling pathways. Growth Factors. 2012 Apr;30(2):88-106.Niu GJ et al. Protein Inhibitor of Activated STAT (PIAS) Negatively Regulates the JAK/STAT Pathway by Inhibiting STAT Phosphorylation and Translocation. Front Immunol. 2018 Oct 26;9:2392.Zhao M et al. SHP2 inhibition triggers anti-tumor immunity and synergizes with PD-1 blockade. Acta Pharm Sin B. 2019 Mar;9(2):304-315.

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