PDE12

Last update 08 May 2025

Basic Info

Synonyms

2-PDE, 2'-PDE, 2',5'-phosphodiesterase 12

+ [5]

Introduction

Enzyme that cleaves 2',5'-phosphodiester bond linking adenosines of the 5'-triphosphorylated oligoadenylates, triphosphorylated oligoadenylates referred as 2-5A modulates the 2-5A system. Degrades triphosphorylated 2-5A to produce AMP and ATP (PubMed:26055709). Also cleaves 3',5'-phosphodiester bond of oligoadenylates (PubMed:21666256, PubMed:26055709, PubMed:30389976). Plays a role as a negative regulator of the 2-5A system that is one of the major pathways for antiviral and antitumor functions induced by interferons (IFNs). Suppression of this enzyme increases cellular 2-5A levels and decreases viral replication in cultured small-airway epithelial cells and Hela cells (PubMed:26055709).

100 Clinical Results associated with PDE12

100 Translational Medicine associated with PDE12

0 Patents (Medical) associated with PDE12

Literatures (Medical) associated with PDE12

01 Jan 2025·Translational Cancer Research

Oxidative phosphorylation-related genes for prognosis and tumor microenvironment in breast cancer

Article

Author: Dong, Shu-Feng ; Wang, Chun-Lei ; Xia, Man-Zhi

BackgroundOxidative phosphorylation (OXPHOS) is a major energy resource occurring in mitochondria. Targeting OXPHOS-related genes has emerged as potential targets for cancer therapy. This study aimed to explore the significance of OXPHOS-related genes in breast cancer (BRCA).MethodsDifferentially expressed genes (DEGs) related to OXPHOS in BRCA were identified using packages of Limma and VennDiagram using the data from public databases. A prognostic model based on differentially expressed OXPHOS-related genes was constructed using least absolute shrinkage and selection operator Cox regression analyses and then evaluated through Kaplan-Meier and receiver operator characteristic (ROC) curves. Additionally, gene set variate analysis (GSVA) and gene set enrichment analysis (GSEA) were performed to explore the potential pathways involved in BRCA. Furthermore, the tumor microenvironment (TME) difference between low- and high-risk BRCA groups was investigated. The prognostic significance of hub genes was then examined. We conducted a protein-protein interaction (PPI) network to uncover the potential gene interactions and identify key genes, whose expressions were validated in cells.ResultsOur analyses revealed 234 differentially expressed OXPHOS-related genes, from which a nine-gene (ATP5PF, FOXP3, IGF2, IREB2, MIEF2, NOTCH1, PDE12, SHC1, and UCP3) prognostic model was constructed. Patients in the high-risk group exhibited poorer survival outcomes and a suppressed immune microenvironment compared to the low-risk group. Additionally, except for IGF2, abnormal expression levels of hub genes were significantly associated with poor prognosis of BRCA patients. GSVA and GSEA highlighted the involvement of TME-related pathways, such as transforming growth factor beta (TGF-β) and mechanistic target of rapamycin (mTOR) signaling pathways. PPI network identified 4 common genes that interacted with all hub genes. The in vitro experiment on the key genes showed a consistent result with the bioinformatics finding.ConclusionsOur study provides insights into the prognostic biomarkers and molecular mechanisms in BRCA, offering potential therapeutic avenues and guiding personalized treatment strategies for improved patient outcomes.

01 Mar 2024·European Journal of Pharmacology

PDE12 disrupts mitochondrial oxidative phosphorylation and mediates mitochondrial dysfunction to induce oral mucosal epithelial barrier damage in oral submucous fibrosis

Article

Author: Shi, Yuqing ; Chen, Cailian ; Xie, Jinmei ; Chen, Linlin ; Luo, Hai-Bin ; Luo, Wen ; Xie, Xi ; Wei, Qihui

Oral submucous fibrosis (OSF) is a chronic oral mucosal disease. The pathological changes of OSF include epithelial damage and subepithelial matrix fibrosis. This study aimed to reveal the epithelial injury mechanism of OSF. A histopathological method was used to analyze oral mucosal tissue from OSF patients and OSF rats. The expression of PDE12 in the oral epithelium was analyzed by immunohistochemistry. The epithelial-mesenchymal transition (EMT) and tight junction proteins in arecoline-treated HOKs were explored by western blotting. Epithelial leakage was assessed by transepithelial electrical resistance and lucifer yellow permeability. The expression of PDE12 and the mitochondrial morphology, mitochondrial permeability transition pore opening, mitochondrial membrane potential, and mitochondrial reactive oxygen species (mtROS) were evaluated in arecoline-induced HOKs. Oxidative phosphorylation (OXPHOS) complexes and ATP content were also explored in HOKs. The results showed significant overexpression of PDE12 in oral mucosal tissue from OSF patients and rats. PDE12 was also overexpressed and aggregated in mitochondria in arecoline-induced HOKs, resulting in dysfunction of OXPHOS and impaired mitochondrial function. An EMT, disruption of tight junctions with epithelial leakage, and extracellular matrix remodeling were also observed. PDE12 overexpression induced by PDE12 plasmid transfection enhanced the mtROS level and interfered with occludin protein localization in HOKs. Interestingly, knockdown of PDE12 clearly ameliorated arecoline-induced mitochondrial dysfunction and epithelial barrier dysfunction in HOKs. Therefore, we concluded that overexpression of PDE12 impaired mitochondrial OXPHOS and mitochondrial function and subsequently impaired epithelial barrier function, ultimately leading to OSF. We suggest that PDE12 may be a new potential target against OSF.

01 Jul 2023·The Journal of general virology

Inhibition of phosphodiesterase 12 results in antiviral activity against several RNA viruses including SARS-CoV-2.

Article

Author: Thomas, Howard ; Wand, Matthew ; Beasley, David W C ; Carroll, Miles W ; Dejnirattisai, Wanwissa ; Tree, Julia A ; Mongkolsapaya, Juthathip ; Sadiq, Fouzia ; Karayiannis, Peter ; Thursz, Mark ; Screaton, Gavin ; Matthews, Ian ; Elmore, Michael J

The 2',5'- oligoadenylate synthetase (OAS) - ribonuclease L (RNAseL) - phosphodiesterase 12 (PDE12) pathway is an essential interferon-induced effector mechanism against RNA virus infection. Inhibition of PDE12 leads to selective amplification of RNAseL activity in infected cells. We aimed to investigate PDE12 as a potential pan-RNA virus antiviral drug target and develop PDE12 inhibitors that elicit antiviral activity against a range of viruses. A library of 18 000 small molecules was screened for PDE12 inhibitor activity using a fluorescent probe specific for PDE12. The lead compounds (CO-17 or CO-63) were tested in cell-based antiviral assays using encephalomyocarditis virus (EMCV), hepatitis C virus (HCV), dengue virus (DENV), West Nile virus (WNV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in vitro. Cross reactivity of PDE12 inhibitors with other PDEs and in vivo toxicity were measured. In EMCV assays, CO-17 potentiated the effect of IFNα by 3 log₁₀. The compounds were selective for PDE12 when tested against a panel of other PDEs and non-toxic at up to 42 mg kg^-1 in rats in vivo. Thus, we have identified PDE12 inhibitors (CO-17 and CO-63), and established the principle that inhibitors of PDE12 have antiviral properties. Early studies suggest these PDE12 inhibitors are well tolerated at the therapeutic range, and reduce viral load in studies of DENV, HCV, WNV and SARS-CoV-2 in human cells and WNV in a mouse model.

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PDE12

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