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Phosphatase and tensin homologue deleted on chromosome ten (PTEN) as a molecular target in lung epithelial wound repair.

ABSTRACT: Epithelial injury contributes to lung pathogenesis. Our work and that of others have identified the phosphoinositide-3 kinase (PI3K)/Akt pathway as a vital component of survival in lung epithelia. Therefore, we hypothesized that pharmacological inhibition of PTEN, a major suppressor of this pathway, would enhance wound closure and restore lung epithelial monolayer integrity following injury.We evaluated the ability of two bisperoxovanadium derivatives, bpV(phen) and bpV(pic), in differentiated primary human airway epithelia and BEAS2B cultures for their ability to inhibit PTEN, activate the PI3K/Akt pathway and restore epithelial monolayer integrity following mechanical injury.BpV(phen) and bpV(pic) induced Akt phosphorylation in primary and BEAS2B cells in a dose and time dependent manner. Minimal toxicity was observed as measured by lactate dehydrogenase (LDH) release. To verify that Akt phosphorylation is specifically induced by PTEN inhibition, the PTEN positive cell line, DU145, and two PTEN negative cell lines, LNCaP and PC3, were examined. PTEN positive cells demonstrated a dose responsive increase in Akt phosphorylation whereas PTEN negative cells showed no response indicating that bpV(phen) directly suppresses PTEN without affecting auxiliary pathways. Next, we observed that exposure to either compound resulted in accelerated wound closure following mechanical injury. Similar effects were observed after transfection with a dominant negative isoform of PTEN and PTEN specific siRNA.From these studies, we conclude that PTEN is a valid target for future studies directed at restoring epithelial barrier function after lung injury.

SUBMITTER: Lai JP

PROVIDER: S-EPMC2189995 | biostudies-other | 2007 Dec

REPOSITORIES: biostudies-other

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Loss of phosphatase activity in PTEN (phosphatase and tensin homolog deleted on chromosome ten) results in endometrial carcinoma in humans: An in-silico study.

Project description:The tumour suppressor gene, PTEN (Phosphatase and Tensin homolog deleted on chromosome Ten), can act as both protein phosphatase and lipid phosphatase, is known to play a vital role in Pi3k signalling pathway. In humans, it is located at 10q23. Loss of its phosphatase and catalytic activity is associated with various types of cancers. This study focuses on evolution, understanding the somatic missense mutation in a particular residue of PTEN and understanding the molecular mechanism that leads to endometrial carcinoma through molecular docking. Mutational analysis of H123 position indicates that the missense mutation at first position of the codon CAC by G or T, result in aspartic acid or tyrosine instead of histidine and can have negative effect on the function of PTEN. Alongside, structural analysis showed mutated PTEN has lower stability than the normal. Additionally, SNPs dataset for endometrial carcinoma suggests H123 as strongly mutated residue. The mutation in phosphatase domain of PTEN along with its effect and interaction with substrate TLA1352 were systematically studied through molecular docking. Molecular interaction study reveals that the optimal substrate binding site in PTEN is unable to interact with the substrate in the mutated condition. This observation drew attention on the impact of mutation on disease biology and enabled us to conduct follow-up studies to retrieve novel molecular targets, such as mutated protein domain and modified Asp and Tyr sites, to design effective therapies to either prevent endometrial carcinoma or impede its progression.

| S-EPMC7002800 | biostudies-literature

Negative regulation of myofibroblast differentiation by PTEN (Phosphatase and Tensin Homolog Deleted on chromosome 10).

Project description:RationaleMyofibroblasts are primary effector cells in idiopathic pulmonary fibrosis (IPF). Defining mechanisms of myofibroblast differentiation may be critical to the development of novel therapeutic agents.ObjectiveTo show that myofibroblast differentiation is regulated by phosphatase and tensin homolog deleted on chromosome 10 (PTEN) activity in vivo, and to identify a potential mechanism by which this occurs.MethodsWe used tissue sections of surgical lung biopsies from patients with IPF to localize expression of PTEN and alpha-smooth muscle actin (alpha-SMA). We used cell culture of pten(-/-) and wild-type fibroblasts, as well as adenoviral strategies and pharmacologic inhibitors, to determine the mechanism by which PTEN inhibits alpha-SMA, fibroblast proliferation, and collagen production.ResultsIn human lung specimens of IPF, myofibroblasts within fibroblastic foci demonstrated diminished PTEN expression. Furthermore, inhibition of PTEN in mice worsened bleomycin-induced fibrosis. In pten(-/-) fibroblasts, and in normal fibroblasts in which PTEN was inhibited, alpha-SMA, proliferation, and collagen production was upregulated. Addition of transforming growth factor-beta to wild-type cells, but not pten(-/-) cells, resulted in increased alpha-SMA expression in a time-dependent fashion. In pten(-/-) cells, reconstitution of PTEN decreased alpha-SMA expression, proliferation, and collagen production, whereas overexpression of PTEN in wild-type cells inhibited transforming growth factor-beta-induced myofibroblast differentiation. It was observed that both the protein and lipid phosphatase actions of PTEN were capable of modulating the myofibroblast phenotype.ConclusionsThe results indicate that in IPF, myofibroblasts have diminished PTEN expression. Inhibition of PTEN in vivo promotes fibrosis, and PTEN inhibits myofibroblast differentiation in vitro.

| S-EPMC1434700 | biostudies-literature

The phosphatase and tensin homologue deleted on chromosome 10 mediates radiosensitivity in head and neck cancer.

Project description:BackgroundFor locally advanced squamous cell carcinoma of the head and neck (HNSCC), the recurrence rate after surgery and postoperative radiotherapy is between 20 and 40%, and the 5-year overall survival rate is approximately 50%. Presently, no markers exist to accurately predict treatment outcome. Expression of proteins in the human epidermal growth factor receptor (EGFR) pathway has been reported as a prognostic marker in several types of cancer.MethodsThe aim of this study was to investigate the prognostic value of proteins in the EGFR pathway in HNSCC. For this purpose, we collected surgically resected tissue of 140 locally advanced head and neck cancer patients, all treated with surgery and postoperative radiotherapy.ResultsIn a multivariate analysis, expression of the phosphatase and tensin homologue deleted on chromosome 10 (PTEN) was significantly related to worse locoregional control (LRC; HR: 2.2, 95% CI: 1.1-4.6; P=0.03), independent of lymph node metastases (HR: 5.6, 95% CI: 1.2-27.4; P=0.03) and extranodal spread (HR: 2.7; 95% CI: 1.2-6.5; P=0.02). In vitro clonogenic radiosensitivity assays confirmed that overexpression of PTEN resulted in increased radioresistance.ConclusionOur study is the first report showing that expression of PTEN mediates radiosensitivity in vitro and that increased expression in advanced HNSCC predicts worse LRC.

| S-EPMC2883706 | biostudies-literature

Neuroprotective and anti-inflammatory roles of the phosphatase and tensin homolog deleted on chromosome Ten (PTEN) Inhibition in a Mouse Model of Temporal Lobe Epilepsy.

Project description:Excitotoxic damage represents the major mechanism leading to cell death in many human neurodegenerative diseases such as ischemia, trauma and epilepsy. Caused by an excess of glutamate that acts on metabotropic and ionotropic excitatory receptors, excitotoxicity activates several death signaling pathways leading to an extensive neuronal loss and a consequent strong activation of astrogliosis. Currently, the search for a neuroprotective strategy is aimed to identify the level in the signaling pathways to block excitotoxicity avoiding the loss of important physiological functions and side effects. To this aim, PTEN can be considered an ideal candidate: downstream the excitatory receptors activated in excitotoxicity (whose inhibition was shown to be not clinically viable), it is involved in neuronal damage and in the first stage of the reactive astrogliosis in vivo. In this study, we demonstrated the involvement of PTEN in excitotoxicity through its pharmacological inhibition by dipotassium bisperoxo (picolinato) oxovanadate [bpv(pic)] in a model of temporal lobe epilepsy, obtained by intraperitoneal injection of kainate in 2-month-old C57BL/6J male mice. We have demonstrated that inhibition of PTEN by bpv(pic) rescues neuronal death and decreases the reactive astrogliosis in the CA3 area of the hippocampus caused by systemic administration of kainate. Moreover, the neurotoxin administration increases significantly the scanty presence of mitochondrial PTEN that is significantly decreased by the administration of the inhibitor 6 hr after the injection of kainate, suggesting a role of PTEN in mitochondrial apoptosis. Taken together, our results confirm the key role played by PTEN in the excitotoxic damage and the strong anti-inflammatory and neuroprotective potential of its inhibition.

| S-EPMC4264755 | biostudies-literature

Sex differences in skeletal muscle phosphatase and tensin homolog deleted on chromosome 10 (PTEN) levels: a cross-sectional study.

Project description:Women have higher adiposity but maintain insulin sensitivity when compared to men. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) inhibits insulin signaling, but it is not known if PTEN regulate insulin resistance in a sex-specific manner. In this cross-sectional study, muscle biopsies from participants in the Molecular Study of Health and Risk in Ethnic Groups (Mol-SHARE) were used to test for sex differences in PTEN expression. Quantitative real-time PCR was performed to determine PTEN gene expression (n = 53), and western blotting detected total and phosphorylated PTEN protein (n = 36). Study participants were comparable in age and body mass index. Women had higher fat mass percentage compared to men (40.25 ± 9.9% in women versus 27.6 ± 8.8% in men; mean difference -0.18, 95%CI (-0.24, -0.11), p-value <0.0001), with similar HOMA-IR (2.46 ± 2.05 in men versus 2.34 ± 3.06 in women; mean difference 0.04; 95% CI (-0.12, 0.21), p-value 0.59). Women had significant downregulation of PTEN gene expression (p-value 0.01) and upregulation of PTEN protein phosphorylation (inactivation) (p-value 0.001) when compared to men after correction for age, ethnicity, HOMA-IR, fat mass and sex. We conclude that the downregulation of muscle PTEN may explain the retention of insulin sensitivity with higher adiposity in women compared to men.

| S-EPMC4366049 | biostudies-literature

Different conformations of phosphatase and tensin homolog, deleted on chromosome 10 (PTEN) protein within the nucleus and cytoplasm of neurons.

Project description:PTEN is a critical gene involved in the regulation of many cellular processes. The product of this gene has dual phosphatase activity and is able to dephosphorylate the 5' end of the phosphatidylinositol (3,4,5)-trisphosphate. Within the cellular nucleus, this protein has been associated with regulation of the expression of many genes, although the mechanism of this regulation remains unclear. In this paper, two specific oligonucleotide aptamers were developed and selected, using the SELEX procedure, according to their ability to detect the PTEN protein in different subcellular compartments of neurons. While one aptamer was able to detect PTEN in the nucleus, the other recognized PTEN in the cytoplasm. The recognition pattern of PTEN by both aptamers was confirmed using antibodies in western blots of the proteins purified from mouse cerebellar homogenates and subcellular fractions. Additionally, we demonstrated that the two aptamers recognized different epitopes of the target peptide. The results presented here could not be fully explained by the canonical phosphatase structure of PTEN, suggesting the existence of different conformations of phosphatase in the nucleus and the cytoplasm.

| S-EPMC3084716 | biostudies-literature

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) inhibition by 4-hydroxynonenal leads to increased Akt activation in hepatocytes.

Project description:The production of reactive aldehydes such as 4-hydroxynonenal (4-HNE) is proposed to be an important factor in the etiology of alcoholic liver disease. To understand the effects of 4-HNE on homeostatic signaling pathways in hepatocytes, cellular models consisting of the human hepatocellular carcinoma cell line (HepG2) and primary rat hepatocytes were evaluated. Treatment of both HepG2 cells and primary hepatocytes with subcytotoxic concentrations of 4-HNE resulted in the activation of Akt within 30 min as demonstrated by increased phosphorylation of residues Ser473 and Thr308. Quantification and subsequent immunocytochemistry of phosphatidylinositol-3,4,5-trisphosphate [PtdIns(3,4,5)P(3)[rsqb] resulted in a 6-fold increase in total PtdIns(3,4,5)P(3) and increased immunostaining at the plasma membrane after 4-HNE treatment. Cotreatment of HepG2 cells with 4-HNE and the phosphatidylinositol 3-kinase (PI3K) inhibitor 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (Ly294002) or the protein phosphatase 2A (PP2A) inhibitor okadaic acid revealed that the mechanism of activation of Akt is PI3K-dependent and PP2A-independent. Using biotin hydrazide detection, it was established that the incubation of HepG2 cells with 4-HNE resulted in increased carbonylation of the lipid phosphatase known as "phosphatase and tensin homolog deleted on chromosome 10" (PTEN), a key regulator of Akt activation. Activity assays both in HepG2 cells and recombinant PTEN revealed a decrease in PTEN lipid phosphatase activity after 4-HNE application. Mass spectral analysis of 4-HNE-treated recombinant PTEN detected a single 4-HNE adduct. Subsequent analysis of Akt dependent physiological consequences of 4-HNE in HepG2 cells revealed significant increases in the accumulation of neutral lipids. These results provide a potential mechanism of Akt activation and cellular consequences of 4-HNE in hepatocytes.

| S-EPMC3102545 | biostudies-literature

miR-486 Promotes Capan-2 Pancreatic Cancer Cell Proliferation by Targeting Phosphatase and Tensin Homolog Deleted on Chromosome 10 (PTEN).

Project description:Introduction: Pancreatic cancer is one of the most common malignant digestive system tumors. Current treatment options for pancreatic cancer cannot achieve the expected curative effect. MicroRNAs (miRNAs and miRs) participate in many biological and pathological processes. miR-486 has been reported to be involved in diverse types of malignant tumors; however, its role in pancreatic cancer remains unclear. Material and Methods: miR-486 mimics and inhibitors were transfected into Capan-2 cells to increase or decrease the expression of miR-486. Western blot was used to detect protein expression levels. EdU proliferation assay and flow cytometry were applied to identify changes in proliferation. In combination with a PTEN overexpression plasmid, miR-486 mimics were used to determine whether PTEN upregulation abolished the proliferative effect of miR-486. Results: Overexpression of miR-486 promoted proliferation and cell cycle progression of Capan-2 cells. Conversely, the proliferation and cell cycle of Capan-2 cells were attenuated after inhibition of miR-486. Using a combination of bioinformatics and Western blot analysis, PTEN was identified as a downstream target gene of miR-486. The effect of miR-486 on Capan-2 cell proliferation could be abolished by PTEN overexpression. Conclusions: miR-486 promotes the proliferation of Capan-2 cells by targeting PTEN. Inhibition of miR-486 might be a novel therapy for pancreatic cancer.

| S-EPMC6588128 | biostudies-literature

Pten (phosphatase and tensin homologue gene) haploinsufficiency promotes insulin hypersensitivity.

Project description:AIMS/HYPOTHESIS: Insulin controls glucose metabolism via multiple signalling pathways, including the phosphatidylinositol 3-kinase (PI3K) pathway in muscle and adipose tissue. The protein/lipid phosphatase Pten (phosphatase and tensin homologue deleted on chromosome 10) attenuates PI3K signalling by dephosphorylating the phosphatidylinositol 3,4,5-trisphosphate generated by PI3K. The current study was aimed at investigating the effect of haploinsufficiency for Pten on insulin-stimulated glucose uptake. MATERIALS AND METHODS: Insulin sensitivity in Pten heterozygous (Pten(+/-)) mice was investigated in i.p. insulin challenge and glucose tolerance tests. Glucose uptake was monitored in vitro in primary cultures of myocytes from Pten(+/-) mice, and in vivo by positron emission tomography. The phosphorylation status of protein kinase B (PKB/Akt), a downstream signalling protein in the PI3K pathway, and glycogen synthase kinase 3beta (GSK3beta), a substrate of PKB/Akt, was determined by western immunoblotting. RESULTS: Following i.p. insulin challenge, blood glucose levels in Pten(+/-) mice remained depressed for up to 120 min, whereas glucose levels in wild-type mice began to recover after approximately 30 min. After glucose challenge, blood glucose returned to normal about twice as rapidly in Pten(+/-) mice. Enhanced glucose uptake was observed both in Pten(+/-) myocytes and in skeletal muscle of Pten(+/-) mice by PET. PKB and GSK3beta phosphorylation was enhanced and prolonged in Pten(+/-) myocytes. CONCLUSIONS/INTERPRETATION: Pten is a key negative regulator of insulin-stimulated glucose uptake in vitro and in vivo. The partial reduction of Pten due to Pten haploinsufficiency is enough to elicit enhanced insulin sensitivity and glucose tolerance in Pten(+/-) mice.

| S-EPMC1781097 | biostudies-other

Phosphatase and tensin homologue deleted on chromosome 10 deficiency accelerates tumor induction in a mouse model of ErbB-2 mammary tumorigenesis.

Project description:Loss of the tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN) and amplification or elevated expression of ErbB-2 are both involved in human breast cancer. To directly test the importance of these genetic events in mammary tumorigenesis, we have assessed whether mammary-specific disruption of PTEN could cooperate with activation of ErbB-2. Transgenic mice expressing ErbB-2 under the transcriptional control of its endogenous promoter (ErbB-2(KI)) were interbred with mice carrying conditional PTEN alleles and an MMTV/Cre transgene. Loss of one or both PTEN alleles resulted in a dramatic acceleration of mammary tumor onset and an increased occurrence of lung metastases in the ErbB-2(KI) strain. Tumor progression in PTEN-deficient/ErbB-2(KI) strains was associated with elevated ErbB-2 protein levels, which were not due to ErbB-2 amplification or to a dramatic increase in ErbB-2 transcripts. Moreover, the PTEN-deficient/ErbB-2(KI)-derived mouse mammary tumors display striking morphologic heterogeneity in comparison with the homogeneous pathology of the ErbB-2(KI) parental strain. Therefore, inactivation of PTEN would not only have a dramatic effect on ErbB-2-induced mammary tumorigenesis but would also lead to the formation of mammary tumors that, in part, display pathologic and molecular features associated with the basal-like subtype of primary human breast cancer.

| S-EPMC2752841 | biostudies-literature

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