scholarly journals Redox Regulation of PTEN by Peroxiredoxins

Antioxidants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 302
Author(s):  
Thang Nguyen Huu ◽  
Jiyoung Park ◽  
Ying Zhang ◽  
Iha Park ◽  
Hyun Joong Yoon ◽  
...  
Keyword(s):  
Redox Regulation ◽  
Redox Homeostasis ◽  
Direct Interaction ◽  
Suppressor Gene ◽  
Cysteine Residue ◽  
Negative Regulator ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Tumor Suppressive Function ◽  
Phosphatidylinositol 4

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is known as a tumor suppressor gene that is frequently mutated in numerous human cancers and inherited syndromes. PTEN functions as a negative regulator of PI3K/Akt signaling pathway by dephosphorylating phosphatidylinositol (3, 4, 5)-trisphosphate (PIP3) to phosphatidylinositol (4, 5)-bisphosphate (PIP2), which leads to the inhibition of cell growth, proliferation, cell survival, and protein synthesis. PTEN contains a cysteine residue in the active site that can be oxidized by peroxides, forming an intramolecular disulfide bond between Cys124 and Cys71. Redox regulation of PTEN by reactive oxygen species (ROS) plays a crucial role in cellular signaling. Peroxiredoxins (Prxs) are a superfamily of peroxidase that catalyzes reduction of peroxides and maintains redox homeostasis. Mammalian Prxs have 6 isoforms (I-VI) and can scavenge cellular peroxides. It has been demonstrated that Prx I can preserve and promote the tumor-suppressive function of PTEN by preventing oxidation of PTEN under benign oxidative stress via direct interaction. Also, Prx II-deficient cells increased PTEN oxidation and insulin sensitivity. Furthermore, Prx III has been shown to protect PTEN from oxidation induced by 15s-HpETE and 12s-HpETE, these are potent inflammatory and pro-oxidant mediators. Understanding the tight connection between PTEN and Prxs is important for providing novel therapies. Herein, we summarized recent studies focusing on the relationship of Prxs and the redox regulation of PTEN.

scholarly journals Peroxiredoxin III Protects Tumor Suppressor PTEN from Oxidation by 15-Hydroperoxy-eicosatetraenoic Acid

2019 ◽  
Vol 2019 ◽  
pp. 1-8
Author(s):  
Ying Zhang ◽  
Jiyoung Park ◽  
Seong-Jeong Han ◽  
Yongwoon Lim ◽  
Iha Park ◽  
...  
Keyword(s):  
Redox Regulation ◽  
Lipid Peroxide ◽  
Lipid Peroxides ◽  
Mouse Embryonic Fibroblast ◽  
Cysteine Residue ◽  
Eicosatetraenoic Acid ◽  
Phosphatase And Tensin Homolog ◽  
Active Site Cysteine ◽  
Cellular Processes ◽  
Tensin Homolog

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a lipid and protein phosphatase that coordinates various cellular processes. Its activity is regulated by the reversible oxidation of an active-site cysteine residue by H2O2 and thioredoxin. However, the potential role of lipid peroxides in the redox regulation of PTEN remains obscure. To evaluate this, 15-hydroperoxy-eicosatetraenoic acid (15s-HpETE), a lipid peroxide, was employed to investigate its effect on PTEN using molecular and cellular-based assays. Exposure to 15s-HpETE resulted in the oxidation of recombinant PTEN. Reversible oxidation of PTEN was also observed in mouse embryonic fibroblast (MEF) cells treated with a 15s-HpETE and Lipofectamine mixture. The oxidative dimerization of thioredoxin was found simultaneously. In addition, the absence of peroxiredoxin III aggravated 15s-HpETE-induced PTEN oxidation in MEF cells. Our study provides novel insight into the mechanism linking lipid peroxidation to the etiology of tumorigenesis.

scholarly journals Intestinal epithelial-specific PTEN inactivation results in tumor formation

2011 ◽  
Vol 301 (5) ◽  
pp. G856-G864 ◽  
Author(s):  
Do-Sun Byun ◽  
Naseem Ahmed ◽  
Shannon Nasser ◽  
Joongho Shin ◽  
Sheren Al-Obaidi ◽  
...  
Keyword(s):  
Cell Fate ◽  
Intestinal Epithelium ◽  
Suppressor Gene ◽  
Major Effect ◽  
Tumor Formation ◽  
Negative Regulator ◽  
Intestinal Epithelial ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Pten Deletion

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a negative regulator of phosphatidylinositol 3-kinase (PI3K) signaling that is frequently inactivated in colorectal cancer through mutation, loss of heterozygosity, or epigenetic mechanisms. The aim of this study was to determine the effect of intestinal-specific PTEN inactivation on intestinal epithelial homeostasis and tumorigenesis. PTEN was deleted specifically in the intestinal epithelium, by crossing PTEN Lox/ Lox mice with villin Cre mice. PTEN was robustly expressed in the intestinal epithelium and maximally in the differentiated cell compartment. Targeted inactivation of PTEN in the intestinal epithelium of PTEN Lox/ Lox/villin Cre mice was confirmed by genotyping, immunohistochemistry, and qPCR. While intestinal-specific PTEN deletion did not have a major effect on cell fate determination or proliferation in the small intestine, it did increase phosphorylated (p) protein kinase B (AKT) expression in the intestinal epithelium, and 19% of animals developed small intestinal adenomas and adenocarcinomas at 12 mo of age. These tumors demonstrated pAKT and nuclear β-catenin staining, indicating simultaneous activation of the PI3K/AKT and Wnt signaling pathways. These findings demonstrate that, while PTEN inactivation alone has a minimal effect on intestinal homeostasis, it can facilitate tumor promotion upon deregulation of β-catenin/TCF signaling, further establishing PTEN as a bona fide tumor suppressor gene in intestinal cancer.

scholarly journals MIR22HG regulates miR-486/PTEN axis in bladder cancer to promote cell proliferation

2020 ◽  
Vol 40 (6) ◽  
Author(s):  
Qisheng Tang ◽  
Xue Jiang ◽  
Shanjin Ma ◽  
Lei Wang ◽  
Ruixiao Li ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Bladder Cancer ◽  
Direct Interaction ◽  
Luciferase Assay ◽  
Phosphatase And Tensin Homolog ◽  
Promote Cell Proliferation ◽  
Tensin Homolog ◽  
Two Factors ◽  
Tcga Dataset

Abstract The tumor suppressive role of MIR22HG has been studied in several types of cancer. We analyzed the TCGA dataset and found the down-regulation of MIR22HG in bladder cancer (BC). Bioinformatics analysis predicted the interaction between MIR22HG and miR-486. The direct interaction between MIR22HG and miR-486 was also confirmed by dual luciferase assay. However, overexpression of these two factors did not significantly affect the expression of each other. Interestingly, overexpression of MIR22HG led to up-regulated phosphatase and tensin homolog (PTEN), which is a target of miR-486. In cell proliferation assay, overexpression of MIR22HG and PTEN led to decreased rates of BC cell proliferation. Moreover, overexpression of miR-486 played an opposite role and attenuated the effects of overexpression of MIR22HG and PTEN. Therefore, MIR22HG regulates miR-486/PTEN axis to promote cell proliferation in BC.

scholarly journals Modeling PTEN overexpression-induced microcephaly in human brain organoids

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Navroop Dhaliwal ◽  
Wendy W.Y. Choi ◽  
Julien Muffat ◽  
Yun Li
Keyword(s):  
Human Brain ◽  
Human Genetics ◽  
Negative Regulator ◽  
Akt Inhibitor ◽  
Chromosome 10 ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Pi3k Signaling Pathway ◽  
Brain Organoid ◽  
Phosphoinositide 3 Kinase

AbstractThe phosphatase and tensin homolog (PTEN) protein, encoded by the PTEN gene on chromosome 10, is a negative regulator of the phosphoinositide 3-kinase (PI3K) signaling pathway. Loss of PTEN has been linked to an array of human diseases, including neurodevelopmental disorders such as macrocephaly and autism. However, it remains unknown whether increased dosage of PTEN can lead to human disease. A recent human genetics study identifies chromosome 10 microduplication encompassing PTEN in patients with microcephaly. Here we generated a human brain organoid model of increased PTEN dosage. We showed that mild PTEN overexpression led to reduced neural precursor proliferation, premature neuronal differentiation, and the formation of significantly smaller brain organoids. PTEN overexpression resulted in decreased AKT activation, and treatment of wild-type organoids with an AKT inhibitor recapitulated the reduced brain organoid growth phenotypes. Together, our findings provide functional evidence that PTEN is a dosage-sensitive gene that regulates human neurodevelopment, and that increased PTEN dosage in brain organoids results in microcephaly-like phenotypes.

scholarly journals Enhancing autophagy by redox regulation extends lifespan in Drosophila

2019 ◽  
Author(s):  
Helena M. Cochemé ◽  
Ivana Bjedov ◽  
Sebastian Grönke ◽  
Katja E. Menger ◽  
Andrew M. James ◽  
...  
Keyword(s):  
Redox Regulation ◽  
Redox Homeostasis ◽  
Model Organism ◽  
Fruit Fly ◽  
Cysteine Residue ◽  
Lifespan Extension ◽  
Post Translational Modification ◽  
Redox Signalling ◽  
Age Related

Redox signalling is an important modulator of diverse biological pathways and processes, and operates through specific post-translational modification of redox-sensitive thiols on cysteine residues 1–4. Critically, redox signalling is distinct from irreversible oxidative damage and functions as a reversible ‘redox switch’ to regulate target proteins. H2O2 acts as the major effector of redox signalling, both directly and through intracellular thiol redox relays 5,6. Dysregulation of redox homeostasis has long been implicated in the pathophysiology of many age-related diseases, as well as in the ageing process itself, however the underlying mechanisms remain largely unclear 7,8. To study redox signalling by H2O2in vivo and explore its involvement in metabolic health and longevity, we used the fruit fly Drosophila as a model organism, with its tractable lifespan and strong evolutionary conservation with mammals 9. Here we report that inducing an endogenous redox-shift, by manipulating levels of the H2O2-degrading enzyme catalase, improves health and robustly extends lifespan in flies, independently of oxidative stress resistance and dietary restriction. We find that the catalase redox-shifted flies are acutely sensitive to starvation stress, which relies on autophagy as a vital survival mechanism. Importantly, we show that autophagy is essential for the lifespan extension of the catalase flies. Furthermore, using redox-inactive knock-in mutants of Atg4a, a major effector of autophagy, we show that the lifespan extension in response to catalase requires a key redox-regulatory cysteine residue, Cys102 in Atg4a. These findings demonstrate that redox regulation of autophagy can extend lifespan, confirming the importance of redox signalling in ageing and as a potential pro-longevity target.

scholarly journals PTENSequence Analysis in Endometrial Hyperplasia and Endometrial Carcinoma in Slovak Women

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
H. Gbelcová ◽  
P. Bakeš ◽  
P. Priščáková ◽  
V. Šišovský ◽  
I. Hojsíková ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Endometrial Carcinoma ◽  
Endometrial Hyperplasia ◽  
Female Genital Tract ◽  
Suppressor Gene ◽  
Serous Carcinoma ◽  
Tissue Samples ◽  
Phosphatase And Tensin Homolog ◽  
Coding Regions ◽  
Tensin Homolog

Phosphatase and tensin homolog (PTEN) is a protein that acts as a tumor suppressor by dephosphorylating the lipid second messenger phosphatidylinositol 3,4,5-trisphosphate. Loss of PTEN function has been implicated in the pathogenesis of a number of different tumors, particularly endometrial carcinoma (ECa). ECa is the most common neoplasia of the female genital tract. Our study evaluates an association between the morphological appearance of endometrial hyperplasia and endometrial carcinoma and the degree ofPTENalterations. A total of 45 endometrial biopsies from Slovak women were included in present study. Formalin-fixed and paraffin-embedded tissue samples with simple hyperplasia (3), complex hyperplasia (5), atypical complex hyperplasia (7), endometrioid carcinomas G1 (20) and G3 (5), and serous carcinoma (5) were evaluated for the presence of mutations in coding regions ofPTENgene, the most frequently mutated tumor suppressor gene in endometrial carcinoma. 75% of the detected mutations were clustered in exons 5 and 8. Out of the 39 mutations detected in 24 cases, 20 were frameshifts and 19 were nonsense, missense, or silent mutations. Some specimens harboured more than one mutation. The results of current study on Slovak women were compared to a previous study performed on Polish population. The two sets of results were similar.

scholarly journals BRCA1-IRIS promotes human tumor progression through PTEN blockade and HIF-1α activation

2018 ◽  
Vol 115 (41) ◽  
pp. E9600-E9609 ◽  
Author(s):  
Andrew G. Li ◽  
Elizabeth C. Murphy ◽  
Aedin C. Culhane ◽  
Emily Powell ◽  
Hua Wang ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Human Cancer ◽  
Human Tumor ◽  
Suppressor Gene ◽  
Phosphatase And Tensin Homolog ◽  
Human Cancer Cells ◽  
Tensin Homolog ◽  
Multiple Protein ◽  
Gsk 3Β ◽  
Cancer Suppression

BRCA1 is an established breast and ovarian tumor suppressor gene that encodes multiple protein products whose individual contributions to human cancer suppression are poorly understood. BRCA1-IRIS (also known as “IRIS”), an alternatively spliced BRCA1 product and a chromatin-bound replication and transcription regulator, is overexpressed in various primary human cancers, including breast cancer, lung cancer, acute myeloid leukemia, and certain other carcinomas. Its naturally occurring overexpression can promote the metastasis of patient-derived xenograft (PDX) cells and other human cancer cells in mouse models. The IRIS-driven metastatic mechanism results from IRIS-dependent suppression of phosphatase and tensin homolog (PTEN) transcription, which in turn perturbs the PI3K/AKT/GSK-3β pathway leading to prolyl hydroxylase-independent HIF-1α stabilization and activation in a normoxic environment. Thus, despite the tumor-suppressing genetic origin of IRIS, its properties more closely resemble those of an oncoprotein that, when spontaneously overexpressed, can, paradoxically, drive human tumor progression.

scholarly journals Therapeutic Implications of Targeting AKT Signaling in Melanoma

2011 ◽  
Vol 2011 ◽  
pp. 1-20 ◽  
Author(s):  
SubbaRao V. Madhunapantula ◽  
Gavin P. Robertson
Keyword(s):  
Pi3k Pathway ◽  
Term Treatment ◽  
Negative Regulator ◽  
Phosphatase And Tensin Homolog ◽  
Key Enzymes ◽  
Therapeutic Implications ◽  
Cellular Processes ◽  
Tensin Homolog ◽  
Stage Disease ◽  
Long Term Treatment

Identification of key enzymes regulating melanoma progression and drug resistance has the potential to lead to the development of novel, more effective targeted agents for inhibiting this deadly form of skin cancer. The Akt3, also known as protein kinase B gamma, pathway enzymes regulate diverse cellular processes including proliferation, survival, and invasion thereby promoting the development of melanoma. Accumulating preclinical evidence demonstrates that therapeutic agents targeting these kinases alone or in combination with other pathway members could be effective for the long-term treatment of advanced-stage disease. However, currently, no selective and effective therapeutic agent targeting these kinases has been identified for clinical use. This paper provides an overview of the key enzymes of the PI3K pathway with emphasis placed on Akt3 and the negative regulator of this kinase called PTEN (phosphatase and tensin homolog deleted on chromosome 10). Mechanisms regulating these enzymes, their substrates and therapeutic implications of targeting these proteins to treat melanoma are also discussed. Finally, key issues that remain to be answered and future directions for interested researchers pertaining to this signaling cascade are highlighted.

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