Deficiency in Protein Tyrosine Phosphatase PTP1B Shortens Lifespan and Leads to Development of Acute Leukemia

Sommer, Samantha Le; Morrice, Nicola; Pesaresi, Martina; Thompson, Dawn; Vickers, Mark A.; Murray, Graeme I.; Mody, Nimesh; Neel, Benjamin G.; Bence, Kendra K.; Wilson, Heather M.; Delibegović, Mirela

doi:10.1158/0008-5472.can-17-0946

Cited by 43 publications

(34 citation statements)

References 48 publications

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“…Indeed, PTP1B inhibition using antisense oligonucleotides enhances insulin sensitivity and decreases weight in T2D patients [ 14 ]. However, it is worth noting that myeloid-specific PTP1B deficiency in mice leads to the development of acute leukemia [ 72 ], suggesting the need for a targeted inhibitor delivery. Indeed, intracerebroventricular administration of a small-molecule PTPB inhibitor prevents binge drinking-induced systemic insulin resistance and glucose intolerance [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

Hepatic protein-tyrosine phosphatase 1B disruption and pharmacological inhibition attenuate ethanol-induced oxidative stress and ameliorate alcoholic liver disease in mice

et al. 2020

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Alcoholic liver disease (ALD) is a major health problem and a significant cause of liver-related death. Currently, the mainstay for ALD therapy is alcohol abstinence highlighting the need to develop pharmacotherapeutic approaches. Protein-tyrosine phosphatase 1B (PTP1B) is an established regulator of hepatic functions, but its role in ALD is mostly unexplored. In this study, we used mice with liver-specific PTP1B disruption as well as pharmacological inhibition to investigate the in vivo function of this phosphatase in ALD. We report upregulation of hepatic PTP1B in the chronic plus binge mouse model and, importantly, in liver biopsies of alcoholic hepatitis patients. Also, mice with hepatic PTP1B disruption attenuated ethanol-induced injury, inflammation, and steatosis compared with ethanol-fed control animals. Moreover, PTP1B deficiency was associated with decreased ethanol-induced oxidative stress in vivo and ex vivo . Further, pharmacological modulation of oxidative balance in hepatocytes identified diminished oxidative stress as a contributor to the salutary effects of PTP1B deficiency. Notably, PTP1B pharmacological inhibition elicited beneficial effects and mitigated hepatic injury, inflammation, and steatosis caused by ethanol feeding. In summary, these findings causally link hepatic PTP1B and ALD and define a potential therapeutic target for the management of this disease.

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Section: Discussionmentioning

confidence: 99%

Hepatic protein-tyrosine phosphatase 1B disruption and pharmacological inhibition attenuate ethanol-induced oxidative stress and ameliorate alcoholic liver disease in mice

et al. 2020

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“…Work form several groups has demonstrated that protein tyrosine phosphatases play a relevant role in the process of macrophage polarization acting, not only as negative regulators of pro-inflammatory signaling, but also as attenuators of anti-inflammatory pathways [21] , [33] , [34] , [35] , [36] , [37] . Moreover, in addition to immune regulation, an essential role for PTP1B in obesity-induced chronic low-grade inflammation and in other pathologies including diabetes, cancer, neuroinflammation, liver diseases or Rett syndrome, has been described as evidenced by the use of selective PTP1B inhibitors or animal models targeted for PTP1B [12] , [18] , [20] , [22] , [38] , [39] , [40] , [41] .…”

Section: Discussionmentioning

confidence: 99%

“…Thus, PTP1B seems to be a relevant target in the protection against ionizing radiation. Indeed, absence of PTP1B reduces life-span and enhances the appearance of lymphoproliferative disorders in mice [18] . Also, these results are in agreement with previous data on the role of myeloid cell irradiation (macrophages among them) in oncogenic treatments [42] , [43] , [44] .…”

Section: Discussionmentioning

confidence: 99%

“…PTP1B is also involved in the regulation of cytokine signaling pathways, controlling in this way cell outcomes [14] , [15] , [16] , [17] . Moreover, PTP1B mRNA levels are regulated by different pro- and anti-inflammatory stimuli, such as LPS or IL4 [18] , [19] , [20] , [21] . Through these mechanisms PTP1B has been involved in atherogenesis and cardiovascular diseases [4] , [22] , [23] , liver diseases [1] , neuroinflammation [3] and in endoplasmic reticulum stress [24] ; however, conflictive data have been reported regarding its involvement in cancer [18] , [25] , [26] , [27] , [28] .…”

Section: Introductionmentioning

confidence: 99%

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Protection against gamma-radiation injury by protein tyrosine phosphatase 1B

et al. 2018

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Protein tyrosine phosphatase 1B (PTP1B) is widely expressed in mammalian tissues, in particular in immune cells, and plays a pleiotropic role in dephosphorylating many substrates. Moreover, PTP1B expression is enhanced in response to pro-inflammatory stimuli and to different cell stressors. Taking advantage of the use of mice deficient in PTP1B we have investigated the effect of γ-radiation in these animals and found enhanced lethality and decreased respiratory exchange ratio vs. the corresponding wild type animals. Using bone-marrow derived macrophages and mouse embryonic fibroblasts (MEFs) from wild-type and PTP1B-deficient mice, we observed a differential response to various cell stressors. PTP1B-deficient macrophages exhibited an enhanced response to γ-radiation, UV-light, LPS and S-nitroso-glutathione. Macrophages exposed to γ-radiation show DNA damage and fragmentation, increased ROS production, a lack in GSH elevation and enhanced acidic β-galactosidase activity. Interestingly, these differences were not observed in MEFs. Differential gene expression analysis of WT and KO macrophages revealed that the main pathways affected after irradiation were an up-regulation of protein secretion, TGF-β signaling and angiogenesis among other, and downregulation of Myc targets and Hedgehog signaling. These results demonstrate a key role for PTP1B in the protection against the cytotoxicity of irradiation in intact animal and in macrophages, which might be therapeutically relevant.

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“…Metabolic reprogramming also has a significant impact on the progression, treatment and prognosis of AML (10,11). More precisely, there are abnormalities in the metabolic processes of AML such as glycolysis, amino acid metabolism, fatty acid metabolism, epigenetic modification and autophagy pathway (12).…”

Section: Introductionmentioning

confidence: 99%

Comprehensive Analysis of Prognostic Markers for Acute Myeloid Leukemia Based on Four Metabolic Genes

Zhang

Wang

et al. 2020

Front. Oncol.

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Background: Metabolic reprogramming is the core characteristic of tumors during the development of tumors, and cancer cells can rely on metabolic changes to support their rapid growth. Nevertheless, an overall analysis of metabolic markers in acute myeloid leukemia (AML) is absent and urgently needed. Methods: Within this work, genetic expression, mutation data and clinical data of AML were queried from Genotype-Tissue Expression (GTEx) database, The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database. The tumor samples of TCGA were randomly divided into a training group (64 samples) and an internal validation group (64 samples) at one time, and the tumor samples of GEO served as two external validation groups (99 samples, 374 samples). According to the expression levels of survival-associated metabolic genes, we divided all TCGA tumor samples into high, medium and low metabolism groups, and evaluated the immune cell activity in the tumor microenvironment of the three metabolism groups by single-sample gene set enrichment analysis (ssGSEA) algorithm. Finally, we examined the mutations and prognostic effects of each model gene. Results: Four metabolism-related genes were screened and applied to construct a prognostic model for AML, giving excellent results. As for the area under the curve (AUC) value of receiver operating characteristic (ROC) curve, the training group was up to 0.902 (1-year), 0.81 (3-year), and 0.877 (5-year); and the internal and external validation groups also met the expected standards, showing high potency in predicting patient outcome. Univariate and multivariate prognostic analyses indicated that the riskScore obtained from our prognostic model was an independent prognostic factor. ssGSEA analysis revealed the high metabolism group had higher immune activity. Single and multiple gene survival analysis validated that each model gene had significant effects on the overall survival of AML patients. Conclusions: In our study, a high-efficiency prognostic prediction model was built and validated for AML patients. The results showed that metabolism-related genes could become potential prognostic biomarkers for AML.

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Deficiency in Protein Tyrosine Phosphatase PTP1B Shortens Lifespan and Leads to Development of Acute Leukemia

Cited by 43 publications

References 48 publications

Hepatic protein-tyrosine phosphatase 1B disruption and pharmacological inhibition attenuate ethanol-induced oxidative stress and ameliorate alcoholic liver disease in mice

Hepatic protein-tyrosine phosphatase 1B disruption and pharmacological inhibition attenuate ethanol-induced oxidative stress and ameliorate alcoholic liver disease in mice

Protection against gamma-radiation injury by protein tyrosine phosphatase 1B

Comprehensive Analysis of Prognostic Markers for Acute Myeloid Leukemia Based on Four Metabolic Genes

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