The Protein Phosphatase PPM1G Destabilizes HIF-1α Expression

Pyo, Jaehyuk; Ryu, Jaewook; Kim, Wootae; Choi, Jae-Sun; Jeong, Joo‐Won; Kim, Ja-Eun

doi:10.3390/ijms19082297

Cited by 5 publications

(5 citation statements)

References 61 publications

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“…Large sample size, high throughput, and multitumor data are necessary to identify key genes that cause cancer [2]. Some public medical databases, such as TCGA (The Cancer Genome Atlas), provide rich omics data, making it possible for us to explore in different omics levels [3][4][5]. More studies have focused on the exploration of tumor immunity and prognostic markers.…”

Section: Introductionmentioning

confidence: 99%

Clinical Value of PPM1G Gene in Survival Prognosis and Immune Infiltration of Hepatocellular Carcinoma

Xiao¹,

Cheng²,

Kuang

et al. 2022

Applied Bionics and Biomechanics

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Objective. Liver cancer is one of the most common malignancies, but its prognosis is still poor. Exploring potential biomarkers is an important direction of tumor research. We intend to use bioinformatics methods to explore potential biomarkers related to survival and prognosis of HCC. Methods. The mRNA and protein expressions of PPM1G in liver cancer were analyzed by HPA, TIMER, and UALCAN databases, and the effects of PPM1G on the prognosis of liver cancer patients were explored by the GEPIA database. We also explored the correlation between PPM1G expression and liver cancer immune infiltration through the TIMER database and further explored the potential protein interaction network of PPM1G through the STRING database. Results. The mRNA and protein expression of PPM1G gene in hepatocellular carcinoma tissues was lower than that in normal adjacent tissues. Liver cancer patients with high expression of PPM1G have a better prognosis than those with low expression of PPM1G. The expression of PPM1G is positively or negatively correlated with different immune cells of liver cancer, such as CD4+ T lymphocytes, CD8+ T lymphocytes, B cells, macrophages, and neutrophils. Conclusion. The liver cancer patients with high expression of PPM1G have a good prognosis, and PPM1G gene may be a potential immunotherapy target and prognostic marker of liver cancer.

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Section: Introductionmentioning

confidence: 99%

Clinical Value of PPM1G Gene in Survival Prognosis and Immune Infiltration of Hepatocellular Carcinoma

Xiao¹,

Cheng²,

Kuang

et al. 2022

Applied Bionics and Biomechanics

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“…Despite the wealth of information concerning kinases that control the HIF pathway, little is known about phosphatases involved in HIF regulation. Previous studies have implicated phosphatases SHIP‐1, PP2A and PPM1G in the control of HIF‐1α protein stability [16–18]. Using an siRNA screen, we have recently identified human phosphatase catalytic subunits, that affect HIF transcriptional activity under hypoxia [19].…”

Section: Introductionmentioning

confidence: 99%

Pyruvate dehydrogenase phosphatase 1 (PDP1) stimulates HIF activity by supporting histone acetylation under hypoxia

et al. 2022

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Cancer cells, when exposed to the hypoxic tumour microenvironment, respond by activating hypoxia-inducible factors (HIFs). HIF-1 mediates extensive metabolic re-programming, and expression of HIF-1a, its oxygenregulated subunit, is associated with poor prognosis in cancer. Here we analyse the role of pyruvate dehydrogenase phosphatase 1 (PDP1) in the regulation of HIF-1 activity. PDP1 is a key hormone-regulated metabolic enzyme that dephosphorylates and activates pyruvate dehydrogenase (PDH), thereby stimulating the conversion of pyruvate into acetyl-CoA. Silencing of PDP1 down-regulated HIF transcriptional activity and the expression of HIFdependent genes, including that of PDK1, the kinase that phosphorylates and inactivates PDH, opposing the effects of PDP1. Inversely, PDP1 stimulation enhanced HIF activity under hypoxia. Alteration of PDP1 levels or activity did not have an effect on HIF-1a protein levels, nuclear accumulation or interaction with its partners ARNT and NPM1. However, depletion of PDP-1 decreased histone H3 acetylation of HIF-1 target gene promoters and inhibited binding of HIF-1 to the respective hypoxia-response elements (HREs) under hypoxia. Furthermore, the decrease of HIF transcriptional activity upon PDP1 depletion could be reversed by treating the cells with acetate, as an exogenous source of acetyl-CoA, or the histone deacetylase (HDAC) inhibitor trichostatin A. These data suggest that the PDP1/PDH/ HIF-1/PDK1 axis is part of a homeostatic loop which, under hypoxia, preserves cellular acetyl-CoA production to a level sufficient to sustain chromatin acetylation and transcription of hypoxia-inducible genes.

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“…For instance, PPM1G blocks the initiation of protein translation by dephosphorylating 4E‐BP1 and p27 at T198, resulting in decreased cell volume and protein density 14,15 . It also degrades overexpressed HIF‐1 via the proteasomal pathway under acute oxidative stress 16 . Recently, the significance of PPM1G in liver diseases has been elucidated, as PPM1G complexes with WWP2 promote liver fibrosis by overactivating the Notch3/HES1 pathway and contributing to the growth of hepatocellular carcinoma by modulating SRSF3 phosphorylation 17‐19 .…”

Section: Introductionmentioning

confidence: 99%

“… 14 , 15 It also degrades overexpressed HIF‐1 via the proteasomal pathway under acute oxidative stress. 16 Recently, the significance of PPM1G in liver diseases has been elucidated, as PPM1G complexes with WWP2 promote liver fibrosis by overactivating the Notch3/HES1 pathway and contributing to the growth of hepatocellular carcinoma by modulating SRSF3 phosphorylation. 17 , 18 , 19 However, its importance in hepatic IRI still needs to be clarified.…”

Section: Introductionmentioning

confidence: 99%

PPM1G regulates hepatic ischemia/reperfusion injury through STING‐mediated inflammatory pathways in macrophages

Peng,

Huang,

Yang

et al. 2024

Immunity Inflam & Disease

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BackgroundIschemia/reperfusion injury (IRI) is generally unavoidable following liver transplantation. Here, we investigated the role of protein phosphatase, Mg2+/Mn2+ dependent 1G (PPM1G) in hepatic IRI.MethodsHepatic IRI was mimicked by employing a hypoxia/reperfusion (H/R) model in RAW 264.7 cells and a 70% warm ischemia model in C57BL/6 mice, respectively. In vitro, expression changes of tumor necrosis factor‐α and interleukin were detected by quantitative real‐time polymerase chain reaction (qRT‐PCR), western blot analysis, and enzyme‐linked immunosorbent assay. The protein expressions of PPM1G and the stimulator of interferon genes (STING) pathway components were analyzed by western blot. Interaction between PPM1G and STING was verified by coimmunoprecipitation (CO‐IP). Immunofluorescence was applied for detection of p‐IRF3. Flow cytometry, qRT‐PCR and western blot were utilized to analyze markers of macrophage polarization. In vivo, histological analyses of mice liver were carried out by TUNEL and H&E staining. Changes in serum aminotransferases were also detected.ResultsFollowing H/R intervention, a steady decline in PPM1G along with an increase in inflammatory cytokines in vitro was observed. Addition of plasmid with PPM1G sequence limited the release of inflammatory cytokines and downregulated phosphorylation of STING. CO‐IP validated the interaction between PPM1G and STING. Furthermore, inhibition of PPM1G with lentivirus enhanced phosphorylation of STING and its downstream components; meanwhile, p65, p38, and Jnk were also surged to phosphorylation. Expression of INOS and CD86 was surged, while CD206, Arg‐1, and IL‐10 were inhibited. In vivo, PPM1G inhibition further promoted liver damage, hepatocyte apoptosis, and transaminases release. Selective inhibition of STING with C‐176 partially reversed the activation of STING pathway and inflammatory cytokines in vitro. M1 markers were also suppressed by C‐176. In vivo, C‐176 rescued liver damage and transaminase release caused by PPM1G inhibition.ConclusionPPM1G suppresses hepatic IRI and macrophage M1 phenotype by repressing STING‐mediated inflammatory pathways.

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The Protein Phosphatase PPM1G Destabilizes HIF-1α Expression

Cited by 5 publications

References 61 publications

Clinical Value of PPM1G Gene in Survival Prognosis and Immune Infiltration of Hepatocellular Carcinoma

Clinical Value of PPM1G Gene in Survival Prognosis and Immune Infiltration of Hepatocellular Carcinoma

Pyruvate dehydrogenase phosphatase 1 (PDP1) stimulates HIF activity by supporting histone acetylation under hypoxia

PPM1G regulates hepatic ischemia/reperfusion injury through STING‐mediated inflammatory pathways in macrophages

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