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Last update 08 May 2025

PIAS3

Last update 08 May 2025

Basic Info

Synonyms

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

+ [4]

Introduction

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).

Drugs associated with PIAS3

CN117821404

Patent Mining

Target

PIAS3

Mechanism-

Active Org.

Xuzhou Medical University

Originator Org.

Xuzhou Medical University

Active Indication

Cognition Disorders [+1]

Inactive Indication-

Drug Highest PhaseDiscovery

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with PIAS3

100 Translational Medicine associated with PIAS3

0 Patents (Medical) associated with PIAS3

278

Literatures (Medical) associated with PIAS3

01 Feb 2025·3 Biotech

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

Article

Author: 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.

01 Dec 2024·Cellular and Molecular Life Sciences

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

Article

Author: 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.

27 Nov 2024·Oncogene

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

Article

Author: 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.

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PIAS3

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