scholarly journals mTOR pathway in human cardiac hypertrophy caused by LEOPARD syndrome: a different role compared with animal models?

2019 ◽  
Vol 14 (1) ◽  
Author(s):  
Hao Cui ◽  
Lei Song ◽  
Changsheng Zhu ◽  
Ce Zhang ◽  
Bing Tang ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Ribosomal Protein ◽  
Animal Studies ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Pathway ◽  
Leopard Syndrome ◽  
Ribosomal Protein S6 ◽  
Phosphoinositide 3 Kinase ◽  
Mtor Complex 1 ◽  
Normal Controls

Abstract Background Animal studies suggested that blocking the activation of the mammalian target of rapamycin (mTOR) pathway might be effective to treat cardiac hypertrophy in LEOPARD syndrome (LS) caused by PTPN11 mutations. Results In the present study, mTOR pathway activity was examined in human myocardial samples from two patients with LS, four patients with hypertrophic cardiomyopathy (HCM), and four normal controls. The two patients with LS had p.Y279C and p.T468 M mutations of the PTPN11 gene, respectively. Although PTPN11 mutation showed initially positive regulation on phosphoinositide 3-kinase, overall the mTOR complex 1 pathway showed widely attenuated activity in LS. This included mildly hypophosphorylated mTOR and ribosomal protein S6 kinase and significantly hypophosphorylated Akt308 and ribosomal protein S6, which is similar to HCM. Akt473 is a basal molecule of the mTOR complex 2 pathway. Akt473 was less affected and showed hyperactivity in LS compared with HCM and normal controls. Additionally, MAPK/ERK kinase and ERK1/2 were significantly more phosphorylated in both HCM and LS than normal controls. Conclusions In LS, the mTOR signaling pathway shows similar activity to HCM and is attenuated compared with normal controls. Thus, caution should be applied when using rapamycin to treat heart hypertrophy in LS.

Blebbistatin induces chondrogenesis of single mesenchymal cells via PI3K/PDK1/mTOR/p70S6K pathway

Biologia ◽  
2017 ◽  
Vol 72 (6) ◽  
Author(s):  
Hyoin Kim ◽  
Dong Hyun Kim ◽  
Bohyeon Jeong ◽  
Ju-Hee Kim ◽  
Sun-Ryung Lee ◽  
...  
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Mesenchymal Cells ◽  
Akt Inhibitor ◽  
Dependent Protein Kinase ◽  
Ribosomal Protein S6 ◽  
Monolayer Cultures ◽  
Pi3k Inhibition ◽  
Dependent Protein ◽  
Phosphoinositide 3 Kinase ◽  
Mtor Complex 1

AbstractRearrangement of the actin cytoskeleton plays an inductive role in chondrogenic differentiation. Our previous study showed that blebbistatin, an inhibitor of myosin II, removes actin stress fibres and induces chondrogenesis of mesenchymal cells in monolayer cultures. In the present study, we investigated signalling pathways implicated in the induction of chondrogenesis by dissolving actin stress fibres after blebbistatin treatment. Blebbistatin increased the activity of phosphoinositide 3-kinase (PI3K). Inhibition of PI3K with LY294002 blocked blebbistatin-induced chondrogenesis without affecting blebbistatin-induced reorganization of actin filaments. Blebbistatin also upregulated the phosphorylation of phosphoinositide-dependent protein kinase 1 (PDK1), and inhibition of PDK1 with GSK2334470 suppressed blebbistatin-induced chondrogenesis, indicating that removal of actin stress fibres by blebbistatin induced chondrogenesis by activating PI3K/PDK1. Although inhibition of Akt activity by Akt inhibitor IV blocked blebbistatin-induced chondrogenesis, phosphorylation of Akt was not affected by blebbistatin. Blebbistatin increased the phosphorylation of mammalian target of rapamycin (mTOR) at Ser2448 and p70 ribosomal protein S6 kinase (p70S6K). Inhibition of mTOR with rapamycin almost completely abolished the phosphorylation of p70S6K. Inhibition of mTOR complex 1 (mTORC1) and complex 2 (mTORC2) with pp242 diminished phosphorylation of Akt at Ser473, whereas inhibition of mTORC1 with rapamycin did not. However, blebbistatin did not affect the phosphorylation of mTOR at Ser2481. Taken together, the present results suggest that blebbistatin induces chondrogenesis by activating the PI3K/PDK1/mTOR/p70S6K pathway. Our data also indicate that Akt activity is essential for chondrogenesis but is regulated by mTORC2, which is independent of blebbistatin treatment.

Blocking the mTOR pathway: a drug discovery perspective

2011 ◽  
Vol 39 (2) ◽  
pp. 451-455 ◽  
Author(s):  
Carlos Garcia-Echeverria
Keyword(s):  
Drug Discovery ◽  
Cancer Patients ◽  
Cancer Biology ◽  
Human Cancer ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Inhibitors ◽  
Mechanisms Of Action ◽  
Mtor Pathway ◽  
Lipid Kinase ◽  
Phosphoinositide 3 Kinase

Substantial drug discovery efforts have been devoted, over the last few years, to identifying and developing mTOR (mammalian target of rapamycin) kinase modulators. This has resulted in a number of mTOR inhibitors with different mechanisms of action and/or distinct protein and lipid kinase selectivity profiles. As briefly reviewed in the present paper, these compounds have provided us with a better understanding of the roles of mTOR and other phosphoinositide 3-kinase/mTOR pathway components in human cancer biology, and a few of them have already demonstrated clinical benefit in cancer patients.

scholarly journals Phosphoproteomic Analysis of Neonatal Regenerative Myocardium Revealed Important Roles of Checkpoint Kinase 1 via Activating Mammalian Target of Rapamycin C1/Ribosomal Protein S6 Kinase b-1 Pathway

Circulation ◽  
2020 ◽  
Vol 141 (19) ◽  
pp. 1554-1569 ◽  
Author(s):  
Yi Fan ◽  
Yiwei Cheng ◽  
Yafei Li ◽  
Bingrui Chen ◽  
Zimu Wang ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Ribosomal Protein ◽  
Mammalian Target Of Rapamycin ◽  
Border Zone ◽  
Target Of Rapamycin ◽  
Cardiomyocyte Proliferation ◽  
S6 Kinase ◽  
Ribosomal Protein S6 ◽  
Ribosomal Protein S6 Kinase

Background: In mammals, regenerative therapy after myocardial infarction is hampered by the limited regenerative capacity of adult heart, whereas a transient regenerative capacity is maintained in the neonatal heart. Systemic phosphorylation signaling analysis on ischemic neonatal myocardium might be helpful to identify key pathways involved in heart regeneration. Our aim was to define the kinase-substrate network in ischemic neonatal myocardium and to identify key pathways involved in heart regeneration after ischemic insult. Methods: Quantitative phosphoproteomics profiling was performed on infarct border zone of neonatal myocardium, and kinase-substrate network analysis revealed 11 kinases with enriched substrates and upregulated phosphorylation levels, including checkpoint kinase 1 (CHK1) kinase. The effect of CHK1 on cardiac regeneration was tested on Institute of Cancer Research CD1 neonatal and adult mice that underwent apical resection or myocardial infarction. Results: In vitro, CHK1 overexpression promoted whereas CHK1 knockdown blunted cardiomyocyte proliferation. In vivo, inhibition of CHK1 hindered myocardial regeneration on resection border zone in neonatal mice. In adult myocardial infarction mice, CHK1 overexpression on infarct border zone upregulated mammalian target of rapamycin C1/ribosomal protein S6 kinase b-1 pathway, promoted cardiomyocyte proliferation, and improved cardiac function. Inhibiting mammalian target of rapamycin activity by rapamycin blunted the neonatal cardiomyocyte proliferation induced by CHK1 overexpression in vitro. Conclusions: Our study indicates that phosphoproteome of neonatal regenerative myocardium could help identify important signaling pathways involved in myocardial regeneration. CHK1 is found to be a key signaling responsible for neonatal regeneration. Myocardial overexpression of CHK1 could improve cardiac regeneration in adult hearts by activating the mammalian target of rapamycin C1/ribosomal protein S6 kinase b-1 pathway. Thus, CHK1 might serve as a potential novel target in myocardial repair after myocardial infarction.

scholarly journals Recent Updates on the Involvement of PI3K/AKT/mTOR Molecular Cascade in the Pathogenesis of Hyperproliferative Skin Disorders

2021 ◽  
Vol 8 ◽  
Author(s):  
Laura Mercurio ◽  
Cristina Albanesi ◽  
Stefania Madonna
Keyword(s):  
Cell Carcinoma ◽  
Mammalian Cells ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Pathway ◽  
Mtor Signaling ◽  
Keratinocyte Differentiation ◽  
Current Status ◽  
Regulatory Subunit ◽  
Skin Disorders ◽  
Phosphoinositide 3 Kinase

PhosphoInositide-3 Kinase (PI3K) represents a family of different classes of kinases which control multiple biological processes in mammalian cells, such as cell growth, proliferation, and survival. Class IA PI3Ks, the main regulators of proliferative signals, consists of a catalytic subunit (α, β, δ) that binds p85 regulatory subunit and mediates activation of AKT and mammalian Target Of Rapamycin (mTOR) pathways and regulation of downstream effectors. Dysregulation of PI3K/AKT/mTOR pathway in skin contributes to several pathological conditions characterized by uncontrolled proliferation, including skin cancers, psoriasis, and atopic dermatitis (AD). Among cutaneous cancers, basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC) display PI3K/AKT/mTOR signaling hyperactivation, implicated in hyperproliferation, and tumorigenesis, as well as in resistance to apoptosis. Upregulation of mTOR signaling proteins has also been reported in psoriasis, in association with enhanced proliferation, defective keratinocyte differentiation, senescence-like growth arrest, and resistance to apoptosis, accounting for major parts of the overall disease phenotypes. On the contrary, PI3K/AKT/mTOR role in AD is less characterized, even though recent evidence demonstrates the relevant function for mTOR pathway in the regulation of epidermal barrier formation and stratification. In this review, we provide the most recent updates on the role and function of PI3K/AKT/mTOR molecular axis in the pathogenesis of different hyperproliferative skin disorders, and highlights on the current status of preclinical and clinical studies on PI3K-targeted therapies.

scholarly journals Targeting mTOR with MLN0128 Overcomes Rapamycin and Chemoresistant Primary Effusion Lymphoma

mBio ◽  
2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Carolina Caro-Vegas ◽  
Aubrey Bailey ◽  
Rachele Bigi ◽  
Blossom Damania ◽  
Dirk P. Dittmer
Keyword(s):  
Primary Effusion Lymphoma ◽  
Mammalian Target Of Rapamycin ◽  
Treated Group ◽  
Competitive Inhibitor ◽  
Mtor Pathway ◽  
Highly Active ◽  
Transcriptional Adaptation ◽  
Induced Apoptosis ◽  
Mtor Complex 1 ◽  
Vehicle Treated Group

ABSTRACT Primary effusion lymphoma (PEL) is caused by Kaposi’s sarcoma-associated herpesvirus (KSHV). PEL has a highly active mTOR pathway, which makes mTOR a potential therapeutic target. MLN0128 is an ATP-competitive inhibitor of mTOR that has entered clinical trials for solid tumors. Our results demonstrated that MLN0128 has a greater effect on inhibiting proliferation than the allosteric mTOR inhibitor rapamycin. MLN0128 has ∼30 nM 50% inhibitory concentration (IC50) across several PEL cell lines, including PEL that is resistant to conventional chemotherapy. MLN0128 induced apoptosis in PEL, whereas rapamycin induced G1 arrest, consistent with a different mechanism of action. MLN0128 inhibited phosphorylation of mTOR complex 1 and 2 targets, while rapamycin only partially inhibited mTOR complex 1 targets. PEL xenograft mouse models treated with MLN0128 showed reduced effusion volumes in comparison to the vehicle-treated group. Rapamycin-resistant (RR) clones with an IC50 for rapamycin 10 times higher than the parental IC50 emerged consistently after rapamycin exposure as a result of transcriptional adaptation. MLN0128 was nevertheless capable of inducing apoptosis in these RR clones. Our results suggest that MLN0128 might offer a new approach to the treatment of chemotherapy-resistant PEL. IMPORTANCE Primary effusion lymphoma (PEL) is an aggressive and incurable malignancy, which is usually characterized by lymphomatous effusions in body cavities without tumor masses. PEL has no established treatment and a poor prognosis, with a median survival time shorter than 6 months. PEL usually develops in the context of immunosuppression, such as HIV infection or post-organ transplantation. The optimal treatment for PEL has not been established, as PEL is generally resistant to traditional chemotherapy. The molecular drivers for PEL are still unknown; however, PEL displays a constitutively active mammalian target of rapamycin (mTOR) pathway, which is critical for metabolic and cell survival mechanisms. Therefore, the evaluation of novel agents targeting the mTOR pathway could be clinically relevant for the treatment of PEL.

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