scholarly journals Inversely proportional myelin growth due to altered Pmp22 gene dosage identifies PI3K/Akt/mTOR signaling as a novel therapeutic target in HNPP

2021 ◽  
Author(s):  
Doris Krauter ◽  
David Ewers ◽  
Timon J Hartmann ◽  
Stefan Volkmann ◽  
Theresa Kungl ◽  
...  
Keyword(s):  
Growth Regulation ◽  
Molecular Mechanisms ◽  
Motor Behavior ◽  
Gene Dosage ◽  
Mtor Signaling ◽  
Hereditary Neuropathy ◽  
Gene Encoding ◽  
Phosphatase And Tensin Homolog ◽  
Charcot Marie Tooth Disease ◽  
Tensin Homolog

Duplication of the gene encoding the myelin protein PMP22 causes the hereditary neuropathy Charcot-Marie-Tooth disease 1A (CMT1A), characterized by hypomyelination of medium to large peripheral axons. Conversely, haplo-insufficiency of PMP22 leads to focal myelin overgrowth in hereditary neuropathy with liability to pressure palsies (HNPP). However, the molecular mechanisms of myelin growth regulation by PMP22 remain obscure. Here, we found that the major inhibitor of the myelin growth signaling pathway PI3K/Akt/mTOR, phosphatase and tensin homolog (PTEN) is increased in abundance in CMT1A and decreased in HNPP rodent models. Indeed, treatment of DRG co-cultures from HNPP mice with PI3K/Akt/mTOR pathway inhibitors reduced focal hypermyelination and, importantly, treatment of HNPP mice with the mTOR inhibitor Rapamycin improved motor behavior, increased compound muscle amplitudes (CMAP) and reduced tomacula formation in the peripheral nerve. In Pmp22tg CMT1A mice, we uncovered that the differentiation defect of Schwann cells is independent from PI3K/Akt/mTOR activity, rendering the pathway insufficient as a therapy target on its own. Thus, while CMT1A pathogenesis is governed by dys-differentiation uncoupled from PI3K/Akt/mTOR signaling, targeting the pathway provides novel proof-of-principle for a therapeutic approach to HNPP.

scholarly journals Phosphatidylinositol 3-kinase regulatory subunit 1 and phosphatase and tensin homolog as therapeutic targets in breast cancer

Tumor Biology ◽  
2017 ◽  
Vol 39 (3) ◽  
pp. 101042831769552 ◽  
Author(s):  
Ebubekir Dirican ◽  
Mustafa Akkiprik
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Breast Cancer Progression ◽  
Regulatory Subunit ◽  
Phosphatidylinositol 3 Kinase ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Kinase Pathway ◽  
Phosphatidylinositol 3

Breast cancer is the most commonly diagnosed cancer among women in Turkey and worldwide. It is considered a heterogeneous disease and has different subtypes. Moreover, breast cancer has different molecular characteristics, behaviors, and responses to treatment. Advances in the understanding of the molecular mechanisms implicated in breast cancer progression have led to the identification of many potential therapeutic gene targets, such as Breast Cancer 1/2, phosphatidylinositol 3-kinase catalytic subunit alpha, and tumor protein 53. The aim of this review is to summarize the roles of phosphatidylinositol 3-kinase regulatory subunit 1 (alpha) (alias p85α) and phosphatase and tensin homolog in breast cancer progression and the molecular mechanisms involved. Phosphatase and tensin homolog is a tumor suppressor gene and protein. Phosphatase and tensin homolog antagonizes the phosphatidylinositol 3-kinase/AKT signaling pathway that plays a key role in cell growth, differentiation, and survival. Loss of phosphatase and tensin homolog expression, detected in about 20%–30% of cases, is known to be one of the most common tumor changes leading to phosphatidylinositol 3-kinase pathway activation in breast cancer. Instead, the regulatory subunit p85α is a significant component of the phosphatidylinositol 3-kinase pathway, and it has been proposed that a reduction in p85α protein would lead to decreased negative regulation of phosphatidylinositol 3-kinase and hyperactivation of the phosphatidylinositol 3-kinase pathway. Phosphatidylinositol 3-kinase regulatory subunit 1 protein has also been reported to be a positive regulator of phosphatase and tensin homolog via the stabilization of this protein. A functional genetic alteration of phosphatidylinositol 3-kinase regulatory subunit 1 that results in reduced p85α protein expression and increased insulin receptor substrate 1 binding would lead to enhanced phosphatidylinositol 3-kinase signaling and hence cancer development. Phosphatidylinositol 3-kinase regulatory subunit 1 underexpression was observed in 61.8% of breast cancer samples. Therefore, expression/alternations of phosphatidylinositol 3-kinase regulatory subunit 1 and phosphatase and tensin homolog genes have crucial roles for breast cancer progression. This review will summarize the biological roles of phosphatidylinositol 3-kinase regulatory subunit 1 and phosphatase and tensin homolog in breast cancer, with an emphasis on recent findings and the potential of phosphatidylinositol 3-kinase regulatory subunit 1 and phosphatase and tensin homolog as a therapeutic target for breast cancer therapy.

Quantitative measurement of duplicated DNA as a diagnostic test for Charcot-Marie-Tooth disease type 1a

1993 ◽  
Vol 39 (9) ◽  
pp. 1845-1849 ◽  
Author(s):  
G W Hensels ◽  
E A Janssen ◽  
J E Hoogendijk ◽  
L J Valentijn ◽  
F Baas ◽  
...  
Keyword(s):  
Preliminary Investigation ◽  
Sensory Neuropathy ◽  
Disease Type ◽  
Chromosome 17 ◽  
Hereditary Neuropathy ◽  
Chromosomal Dna ◽  
Gene Encoding ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Tooth Disease

Abstract Charcot-Marie-Tooth disease type 1 (CMT1) is a hereditary motor and sensory neuropathy. The autosomal dominant subtype is often linked with a large duplication on chromosome 17p11.2. The gene encoding the peripheral myelin protein PMP 22 (the critical gene in this subtype of CMT1) is located within this duplication. To detect this duplication in chromosomal DNA from individuals thought to have CMT1, we compared the hybridization signals of two DNA probes within this duplication (VAW412R3a and VAW409R3a) with the signal of a reference probe (E3.9). When duplication was present, the signals from the first two probes increased from 100% (for nonduplicated samples) to 145% and 142%, respectively. The day-to-day variance was 3.7% and 5.1%, respectively. We demonstrated this DNA duplication in 49 of 95 DNA samples from unrelated individuals thought to have CMT1. Moreover, because hereditary neuropathy with liability to pressure palsies (HNPP) is based on a DNA deletion in the same area of chromosome 17, this quantitative test may be useful in establishing the presence of HNPP. In a preliminary investigation, four unrelated patients with HNPP yielded test values of 63% and 54%, respectively, of those for nonduplicated samples (CV 19% and 18%, respectively; n = 4), suggesting a deletion in 17p11.2.

scholarly journals The Role of PTEN in Tumor Angiogenesis

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Stéphane Rodriguez ◽  
Uyen Huynh-Do
Keyword(s):  
Tumor Angiogenesis ◽  
Molecular Mechanisms ◽  
Tumor Formation ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Physiological Processes ◽  
Response To Chemotherapy ◽  
Independent Functions ◽  
Pi3 Kinase Pathway

During the past 20 years, the phosphatase and tensin homolog PTEN has been shown to be involved in major physiological processes, and its mutation or loss is often associated with tumor formation. In addition PTEN regulates angiogenesis not only through its antagonizing effect on the PI3 kinase pathway mainly, but also through some phosphatase-independent functions. In this paper we delineate the role of this powerful tumor suppressor in tumor angiogenesis and dissect the underlying molecular mechanisms. Furthermore, it appears that, in a number of cancers, the PTEN status determines the response to chemotherapy, highlighting the need to monitor PTEN expression and to develop PTEN-targeted therapies.

scholarly journals Molecular Analysis of AFP and HSA Interactions with PTEN Protein

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Mingyue Zhu ◽  
Bo Lin ◽  
Peng Zhou ◽  
Mengsen Li
Keyword(s):  
Molecular Docking ◽  
Molecular Mechanisms ◽  
Docking Study ◽  
Phosphatidylinositol 3 Kinase ◽  
Molecular Docking Study ◽  
Pten Protein ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Significant Homology ◽  
Modeling Data

Human cytoplasmic alpha-fetoprotein (AFP) has been classified as a member of the albuminoid gene family. The protein sequence of AFP has significant homology to that of human serum albumin (HSA), but its biological characteristics are vastly different from HSA. The AFP functions as a regulator in the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway, but HSA plays a key role as a transport protein. To probe their molecular mechanisms, we have applied colocalization, coimmunoprecipitation (co-IP), and molecular docking approaches to analyze the differences between AFP and HSA. The data from colocalization and co-IP displayed a strong interaction between AFP and PTEN (phosphatase and tensin homolog), demonstrating that AFP did bind to PTEN, but HSA did not. The molecular docking study further showed that the AFP domains I and III could contact with PTEN.In siliconsubstitutions of AFP binding site residues at position 490M/K and 105L/R corresponding to residues K490 and R105 in HSA resulted in steric clashes with PTEN residues R150 and K46, respectively. These steric clashes may explain the reason why HSA cannot bind to PTEN. Ultimately, the experimental results and the molecular modeling data from the interactions of AFP and HSA with PTEN will help us to identify targets for designing drugs and vaccines against human hepatocellular carcinoma.

scholarly journals Downregulation of PTEN promotes podocyte endocytosis of lipids aggravating obesity-related glomerulopathy

2020 ◽  
Vol 318 (3) ◽  
pp. F589-F599 ◽  
Author(s):  
Yuanyuan Shi ◽  
Chen Wang ◽  
Xiaoshuang Zhou ◽  
Yafeng Li ◽  
Yuehong Ma ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Glomerular Sclerosis ◽  
Filamentous Actin ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Stage Renal Disease ◽  
End Stage

With the increasing prevalence of obesity in adults worldwide, the incidence of obesity-related glomerulopathy (ORG) has increased yearly, becoming one of the leading causes of end-stage renal disease. Studies have demonstrated significant correlations between hyperlipidemia and impaired renal function in patients with ORG, indicating that hyperlipidemia causes damage in kidney cells. In podocytes, the endocytosis of lipids triggers an intracellular oxidative stress response that disrupts cellular integrity, resulting in proteinuria and glomerular sclerosis. However, the specific molecular mechanisms through which podocytes endocytose lipids remain unclear. Here, we demonstrated the enhanced endocytosis of lipids by podocytes from patients with ORG. This response was associated with decreased expression of phosphatase and tensin homolog (PTEN). In vitro silencing of PTEN promoted the endocytosis of low-density lipoprotein in mouse podocytes. Conversely, overexpression of PTEN inhibited the endocytosis of lipoproteins in podocytes. PTEN directly dephosphorylates and activates the actin-depolymerizing factor cofilin-1, leading to depolymerization of filamentous actin (F-actin), which is necessary for endocytosis. Notably, inhibition of PTEN resulted in the phosphorylation and inactivation of cofilin-1, leading to F-actin formation that enhanced the endocytosis of lipoproteins in podocytes. When hyperlipidemia was induced in mice with podocyte-specific deletion of PTEN, these mice recapitulated the major pathophysiological features of ORG. Thus, PTEN downregulation in podocytes may contribute to the pathogenesis of ORG.

scholarly journals Expression of MicroRNA-301a and its Functional Roles in Malignant Melanoma

2016 ◽  
Vol 40 (1-2) ◽  
pp. 230-244 ◽  
Author(s):  
Lei Cui ◽  
Yuejun Li ◽  
Xiaoxing Lv ◽  
Jinqing Li ◽  
Xiaolin Wang ◽  
...  
Keyword(s):  
Malignant Melanoma ◽  
Western Blot ◽  
Target Gene ◽  
Molecular Mechanisms ◽  
Luciferase Reporter ◽  
Phosphatase And Tensin Homolog ◽  
Functional Roles ◽  
Qrt Pcr ◽  
Tensin Homolog

Background/Aims: Although microRNA-301a has been reported to function as an oncogene in many human cancers, the roles of miR-301a in malignant melanoma (MM) is unclear. The present study aims to investigate the functional roles of miR-301a in MM and its possible molecular mechanisms. Methods: Quantitative real-time PCR (qRT-PCR) assay was performed to detect the expression of miR-301a in MM tissues, and analyze its correlation with metastasis and prognosis of MM patients. In vitro, miR-301a was ectopically expressed using overexpression and knock-down strategies, and the effects of miR-301a expression on growth, apoptosis, migration, invasion and chemosensitivity of MM cells were further investigated. Furthermore, the potential and functional target gene was identified by luciferase reporter, qRT-PCR, Western blot assays. Results: We showed that the expression of miR-301a was significantly upregulated in MM tissues, and upregulation of miR-301a correlated with metastasis and poor prognosis of MM patients. Transfection of miR-301a/inhibitor significantly inhibited growth, colony formation, migration, invasion and enhanced apoptosis and chemosensitivity in MM cells, while transfection of miR-301a/mimic could induce the inverse effects on phenotypes of MM cells. Luciferase reporter, qRT-PCR and Western blot assays showed that phosphatase and tensin homolog (PTEN) was a direct and functional target of miR-301a. It was also observed that the Akt and FAK signaling pathways were involved in miR-301/PTEN-promoting MM progression. Conclusion: Taken together, our study suggests that miR-301a may be used as a potential therapeutic target in the treatment of human MM.

Inhibition of the RKIP and PTEN-Transcription Repressor Snail in B-NHL by the Proteasome Inhibitor NPI-0052: Roles of RKIP and PTEN Induction in the Reversal of Resistance to TRAIL Apoptosis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3938-3938
Author(s):  
Stavroula Baritaki ◽  
Kam Yeung ◽  
Katherine Wu ◽  
Haiming Chen ◽  
James R. Berenson ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Kinase Inhibitor ◽  
Proteasome Inhibitors ◽  
Akt Pathway ◽  
Gene Products ◽  
Direct Role ◽  
Phosphatase And Tensin Homolog ◽  
Apoptotic Gene ◽  
Tensin Homolog ◽  
Survival Pathways

Abstract Abstract 3938 Poster Board III-874 Several strategies have been examined to reverse tumor cell resistance to immunotherapy. For instance, proteasome inhibitors such as Bortezomib, MG-132 and NPI-0052 have been reported to sensitize hematopoietic tumor cells to TRAIL-mediated apoptosis. NPI-0052 mediates its cytotoxic and sensitizing effects in lymphoma cells through the inhibition of the NF-κB and PI3K/Akt survival pathways. The molecular mechanisms and associated gene products involved in NPI-0052-induced inhibition of these pathways are not known. We have reported that NPI-0052 induced the expression of Raf-1 kinase inhibitor protein (RKIP) via inhibition of NF-κB activity and downstream the RKIP transcription repressor Snail (Baritaki et al., Oncogene. 2009, PMID: 19633685). Also, Snail has been reported to repress phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and allowing the Akt pathway to remain activated. Based on these findings, we hypothesized that treatment of B-NHL cells with NPI-0052 will result in the induction of both RKIP and PTEN through inhibition of Snail and, consequently, will result in the inhibition of the NF-κB and Akt pathways, respectively. Treatment of Ramos cells with NPI-0052 resulted in the inhibition of NF-κB activity and Snail expression along with the induction of both RKIP and PTEN expression, as assessed by western. The direct roles of RKIP and PTEN in B-NHL cell sensitization to TRAIL were demonstrated by the use of cells transfected with siRNA RKIP and siRNA PTEN, whereby reversal of sensitivity occurred. In contrast, Snail knockdown by siRNA Snail resensitized the cells to TRAIL apoptosis. The inhibition by NPI-0052 of both the NF-κB and PI3K/Akt pathways resulted downstream in the inhibition of transcription and/or activity of anti-apoptotic gene products such as Bcl-2 family members. The direct role of Bcl-2 family anti-apoptotic gene products in the reversal of resistance by NPI-0052 was demonstrated by the use of the Bcl-2 family chemical inhibitor 2MAM3. Altogether, these findings demonstrate that NPI-0052 modifies a tightly regulated loop in the resistance of B-NHL cells, namely, the constitutive activation of NF-κB and Akt survival pathways that crosstalk and induce Snail. Snail in turn, represses RKIP and PTEN and, thus, the cells continue to survive and proliferate. However, upon treatment with NPI-0052, the inhibition of PI3K/Akt and NF-κB activities results downstream in the inhibition of Snail and the inhibition of Snail, in turn, derepresses the transcription of both RKIP and PTEN. In a feedback loop, the induction of RKIP represses the NF-κB pathway and the induction of PTEN represses the PI3K/Akt pathway. Hence, the inhibition by NPI-0052 of the NF-κB/Akt/Snail/RKIP/PTEN regulatory resistance loop in B-NHL cells results in the reversal of resistance. Further, these findings identify several new targets for potential therapeutic intervention in the reversal of resistance. Disclosures: Berenson: Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau. Palladino:Nereus Pharmaceuticals: Employment, Equity Ownership.

α-synuclein accumulation in SH-SY5Y cell impairs autophagy in microglia by exosomes overloading miR-19a-3p

Epigenomics ◽  
2019 ◽  
Vol 11 (15) ◽  
pp. 1661-1677 ◽  
Author(s):  
Tianen Zhou ◽  
Danyu Lin ◽  
Ying Chen ◽  
Sudan Peng ◽  
Xiuna Jing ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Microarray Analysis ◽  
Experimental Verification ◽  
Neuronal Model ◽  
Mtor Signaling ◽  
Mtor Signaling Pathway ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Enhanced Expression

Aims: To reveal whether miRNAs in exosomes from α-synuclein transgenic SH-SY5Y cells are able to regulate autophagy in recipient microglia. Materials & methods: Microarray analysis and experimental verification were adopted to assess the significance of autophagy-associated miRNAs in exosomes from neuronal model of α-synucleinopathies. Results: We found that miR-19a-3p increased remarkably in the exosomes from α-synuclein gene transgenic SH-SY5Y cells. Further study inferred that α-synuclein gene transgenic SH-SY5Y cell-derived exosomes and miR-19a-3p mimic consistently inhibited the expression of phosphatase and tensin homolog and increased the phosphorylation of AKT and mTOR, both of which ultimately lead to the dysfunction of autophagy in recipient microglia. Conclusion: The data suggested that enhanced expression of miR-19a-3p in exosomes suppress autophagy in recipient microglia by targeting the phosphatase and tensin homolog/AKT/mTOR signaling pathway.

scholarly journals Targeting mTOR in Glioblastoma: Rationale and Preclinical/Clinical Evidence

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Carmen Mecca ◽  
Ileana Giambanco ◽  
Rosario Donato ◽  
Cataldo Arcuri
Keyword(s):  
Therapeutic Strategy ◽  
Molecular Mechanisms ◽  
Clinical Evidence ◽  
Survival Rates ◽  
Phosphatidylinositol 3 Kinase ◽  
Phosphatase And Tensin Homolog ◽  
Cellular Processes ◽  
Mechanistic Target Of Rapamycin ◽  
Tensin Homolog ◽  
Different Types

The mechanistic target of rapamycin (mTOR) drives several physiologic and pathologic cellular processes and is frequently deregulated in different types of tumors, including glioblastoma (GBM). Despite recent advancements in understanding the molecular mechanisms involved in GBM biology, the survival rates of this tumor are still disappointing, primarily due to the lack of efficacious treatments. The phosphatase and tensin homolog (PTEN)/phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mTOR pathway has emerged as a crucial player in GBM development and progression. However, to date, all the attempts to target this pathway with PI3K, AKT, or mTORC1 inhibitors failed to improve the outcome of patients with GBM. Despite these discouraging results, recent evidence pointed out that the blockade of mTORC2 might provide a useful therapeutic strategy for GBM, with the potential to overcome the limitations that mTORC1 inhibitors have shown so far. In this review, we analyzed the rationale of targeting mTOR in GBM and the available preclinical and clinical evidence supporting the choice of this therapeutic approach, highlighting the different roles of mTORC1 and mTORC2 in GBM biology.

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