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mTOR Signaling: Recent Progress
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mTOR Signaling: Recent Progress

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (30 May 2024) | Viewed by 14119

Special Issue Editor

Dr. Antonios N. Gargalionis

E-Mail Website
Guest Editor
Assistant Professor of Clinical Biochemistry and Medical Chemistry, Department of Clinical Biochemistry, School of Medicine, National and Kapodistrian University of Athens, 115 28 Athens, Greece
Interests: signal transduction; mechanobiology; tumorigenesis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The Mechanistic Target of Rapamycin (mTOR), previously known as the mammalian target of rapamycin, is a central protein kinase that mediates the dynamic crosstalk of notable signal transduction pathways in physiology and disease. The mTOR-associated signaling cascades have been extensively investigated in the past two decades. Their fundamental role has been highlighted in several physiological processes, including cell growth and protein synthesis, metabolism and homeostasis of macromolecules, autophagy, immune, and brain function. Furthermore, deregulation of mTOR signaling networks has been well-documented in molecular mechanisms which drive carcinogenesis, diabetes, and aging. Recent findings also demonstrate that aberrant mTOR signaling is implicated in disorders of the central nervous system, including autism and Alzheimer's disease, as well as in systemic autoimmune diseases. Novel insights further suggest that mTOR regulates alterations in gut microbiota but also mediates viral survival and replication, and therefore, it plays a substantial role in regulating the host metabolic and immune functions. Regarding therapy, the mTOR inhibitors are a class of drugs that has been established as major immunosuppressants against transplant rejection, and they have been extensively tested as anticancer agents in the past with limited clinical activity. However, second-generation agents hold promise for potential efficacy in various disease entities.

In this Special Issue, we invite investigators to submit original research or review articles on the many facets in the regulation of mTOR signaling.

Dr. Antonios N. Gargalionis
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • mTOR signaling in cancer
  • mTOR inhibitors
  • mTOR signaling in metabolism
  • Alzheimer’s disease and mTOR signaling
  • mTOR and autophagy
  • mTOR and gut microbiota
  • mTOR and viral pathogenesis
  • mTOR and autoimmune diseases

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Published Papers (7 papers)

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Editorial

Jump to: Research, Review

4 pages, 177 KiB  
Editorial
mTOR Signaling: Recent Progress
by Antonios N. Gargalionis, Kostas A. Papavassiliou and Athanasios G. Papavassiliou
Int. J. Mol. Sci. 2024, 25(5), 2587; https://doi.org/10.3390/ijms25052587 - 23 Feb 2024
Cited by 2 | Viewed by 1114
Abstract
In the intricate landscape of human biology, the mechanistic target of rapamycin (mTOR) emerges as a key regulator, orchestrating a vast array of processes in health and disease [...] Full article
(This article belongs to the Special Issue mTOR Signaling: Recent Progress)

Research

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10 pages, 1693 KiB  
Article
Maternal Diet High in Linoleic Acid Alters Renal Branching Morphogenesis and mTOR/AKT Signalling Genes in Rat Fetal Kidneys
by Connie McClelland, Olivia J. Holland, Nirajan Shrestha, Claire L. Jukes, Anna E. Brandon, James S. M. Cuffe, Anthony V. Perkins, Andrew J. McAinch and Deanne H. Hryciw
Int. J. Mol. Sci. 2024, 25(9), 4688; https://doi.org/10.3390/ijms25094688 - 25 Apr 2024
Viewed by 878
Abstract
Linoleic acid (LA), an n-6 polyunsaturated fatty acid (PUFA), is obtained from the maternal diet during pregnancy, and is essential for normal fetal growth and development. A maternal high-LA (HLA) diet alters maternal and offspring fatty acids, maternal leptin and male/female ratio at [...] Read more.
Linoleic acid (LA), an n-6 polyunsaturated fatty acid (PUFA), is obtained from the maternal diet during pregnancy, and is essential for normal fetal growth and development. A maternal high-LA (HLA) diet alters maternal and offspring fatty acids, maternal leptin and male/female ratio at embryonic (E) day 20 (E20). We investigated the effects of an HLA diet on embryonic offspring renal branching morphogenesis, leptin signalling, megalin signalling and angiogenesis gene expression. Female Wistar Kyoto rats were fed low-LA (LLA; 1.44% energy from LA) or high-LA (HLA; 6.21% energy from LA) diets during pregnancy and gestation/lactation. Offspring were sacrificed and mRNA from kidneys was analysed by real-time PCR. Maternal HLA decreased the targets involved in branching morphogenesis Ret and Gdnf in offspring, independent of sex. Furthermore, downstream targets of megalin, namely mTOR, Akt3 and Prkab2, were reduced in offspring from mothers consuming an HLA diet, independent of sex. There was a trend of an increase in the branching morphogenesis target Gfra1 in females (p = 0.0517). These findings suggest that an HLA diet during pregnancy may lead to altered renal function in offspring. Future research should investigate the effects an HLA diet has on offspring kidney function in adolescence and adulthood. Full article
(This article belongs to the Special Issue mTOR Signaling: Recent Progress)
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20 pages, 5499 KiB  
Article
Selective Eradication of Colon Cancer Cells Harboring PI3K and/or MAPK Pathway Mutations in 3D Culture by Combined PI3K/AKT/mTOR Pathway and MEK Inhibition
by Velina S. Atanasova, Angelika Riedl, Marcus Strobl, Julia Flandorfer, Daniela Unterleuthner, Claudia Weindorfer, Patrick Neuhold, Simone Stang, Markus Hengstschläger, Michael Bergmann and Helmut Dolznig
Int. J. Mol. Sci. 2023, 24(2), 1668; https://doi.org/10.3390/ijms24021668 - 14 Jan 2023
Cited by 9 | Viewed by 3482
Abstract
Colorectal cancer (CRC) is the second deadliest cancer in the world. Besides APC and p53 alterations, the PI3K/AKT/MTOR and MAPK pathway are most commonly mutated in CRC. So far, no treatment options targeting these pathways are available in routine clinics for CRC patients. [...] Read more.
Colorectal cancer (CRC) is the second deadliest cancer in the world. Besides APC and p53 alterations, the PI3K/AKT/MTOR and MAPK pathway are most commonly mutated in CRC. So far, no treatment options targeting these pathways are available in routine clinics for CRC patients. We systematically analyzed the response of CRC cells to the combination of small molecular inhibitors targeting the PI3K and MAPK pathways. We used CRC cells in 2D, 3D spheroid, collagen gel cultures and freshly isolated organoids for drug response studies. Readout for drug response was spheroid or organoid growth, spheroid outgrowth, metabolic activity, Western blotting and immunofluorescence. We found profound tumor cell destruction under treatment with a combination of Torin 1 (inhibiting mTOR), MK2206 (targeting AKT) and selumetinib (inhibiting MEK) in 3D but not in 2D. Induction of cell death was due to apoptosis. Western blot analysis revealed efficient drug action. Gedatolisib, a dual PI3K/mTOR inhibitor, could replace Torin1/MK2206 with similar efficiency. The presence of PI3K and/or RAS-RAF-MAPK pathway mutations accounted for treatment responsiveness. Here, we identified a novel, efficient therapy, which induced proliferation stop and tumor cell destruction in vitro based on the genetic background. These preclinical findings show promise to further test this combi-treatment in vivo in mice and to potentially develop a mutation specific targeted therapy for CRC patients. Full article
(This article belongs to the Special Issue mTOR Signaling: Recent Progress)
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14 pages, 3755 KiB  
Article
Nuclear S6K1 Enhances Oncogenic Wnt Signaling by Inducing Wnt/β-Catenin Transcriptional Complex Formation
by Min Gyu Lee, Hwamok Oh, Jong Woo Park, Jueng Soo You and Jeung-Whan Han
Int. J. Mol. Sci. 2022, 23(24), 16143; https://doi.org/10.3390/ijms232416143 - 18 Dec 2022
Cited by 3 | Viewed by 1990
Abstract
Ribosomal protein S6 kinase 1 (S6K1), a key downstream effector of the mammalian target of rapamycin (mTOR), regulates diverse functions, such as cell proliferation, cell growth, and protein synthesis. Because S6K1 was previously known to be localized in the cytoplasm, its function has [...] Read more.
Ribosomal protein S6 kinase 1 (S6K1), a key downstream effector of the mammalian target of rapamycin (mTOR), regulates diverse functions, such as cell proliferation, cell growth, and protein synthesis. Because S6K1 was previously known to be localized in the cytoplasm, its function has been mainly studied in the cytoplasm. However, the nuclear localization and function of S6K1 have recently been elucidated and other nuclear functions are expected to exist but remain elusive. Here, we show a novel nuclear role of S6K1 in regulating the expression of the Wnt target genes. Upon activation of the Wnt signaling, S6K1 translocated from the cytosol into the nucleus and subsequently bound to β-catenin and the cofactors of the Wnt/β-catenin transcriptional complex, leading to the upregulation of the Wnt target genes. The depletion or repression of S6K1 downregulated the Wnt target gene expression by inhibiting the formation of the Wnt/β-catenin transcriptional complex. The S6K1-depleted colon cancer cell lines showed lower transcription levels of the Wnt/β-catenin target genes and a decrease in the cell proliferation and invasion compared to the control cell lines. Taken together, these results indicate that nuclear S6K1 positively regulates the expression of the Wnt target genes by inducing the reciprocal interaction of the subunits of the transcriptional complex. Full article
(This article belongs to the Special Issue mTOR Signaling: Recent Progress)
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9 pages, 1591 KiB  
Article
Quetiapine Shortens the Lifespan of Caenorhabditis elegans through DOP-2, DAF-2 and RSKS-1
by Yizhou Jiang, Uma Gaur, Zhibai Cao, Sheng-Tao Hou and Wenhua Zheng
Int. J. Mol. Sci. 2022, 23(21), 12927; https://doi.org/10.3390/ijms232112927 - 26 Oct 2022
Cited by 1 | Viewed by 1693
Abstract
Recent studies implicate a key role of dopamine signaling in lifespan regulation. Our previous study found that quetiapine, an atypical antipsychotic drug that has antagonistic activity on dopamine D2-like receptors (D2Rs), shortened the lifespan of Caenorhabditis elegans (C. elegans). However, the [...] Read more.
Recent studies implicate a key role of dopamine signaling in lifespan regulation. Our previous study found that quetiapine, an atypical antipsychotic drug that has antagonistic activity on dopamine D2-like receptors (D2Rs), shortened the lifespan of Caenorhabditis elegans (C. elegans). However, the detailed mechanism of this effect was not clear. In the present study, we evaluate the effect of quetiapine on aging and explore its underlying molecular mechanism. The results show that quetiapine shortened healthspan in C. elegans. The lifespan-shortening effect is dependent on DOP-2, a D2R expressed in worms. Quetiapine shortens lifespan through the C. elegans insulin and IGF-1 receptor DAF-2, but not the downstream Akt pathway. Quetiapine-induced lifespan reduction is dependent on RSKS-1, a key protein kinase that functions in mTOR signaling. In addition, the quetiapine effect is also related to mitochondrial function. These findings further support the key role of dopamine signaling in lifespan regulation and promote our insight into the mechanism of action of antipsychotic drugs. Full article
(This article belongs to the Special Issue mTOR Signaling: Recent Progress)
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Review

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18 pages, 342 KiB  
Review
The Role of mTOR in B Cell Lymphoid Malignancies: Biologic and Therapeutic Aspects
by Eleni A. Karatrasoglou, Maria Dimou, Alexia Piperidou, Eleftheria Lakiotaki, Penelope Korkolopoulou and Theodoros P. Vassilakopoulos
Int. J. Mol. Sci. 2023, 24(18), 14110; https://doi.org/10.3390/ijms241814110 - 14 Sep 2023
Cited by 1 | Viewed by 1125
Abstract
Non-Hodgkin lymphoma’s (NHL) incidence is rising over time, and B cell lymphomas comprise the majority of lymphomas. The phosphoinositide 3-kinase (PI3K)/v-akt murine thymoma viral oncogene homologue 1 (Akt)/mammalian target of the rapamycin (mTOR) signaling pathway plays a critical role in a variety of [...] Read more.
Non-Hodgkin lymphoma’s (NHL) incidence is rising over time, and B cell lymphomas comprise the majority of lymphomas. The phosphoinositide 3-kinase (PI3K)/v-akt murine thymoma viral oncogene homologue 1 (Akt)/mammalian target of the rapamycin (mTOR) signaling pathway plays a critical role in a variety of cellular processes, such as cell proliferation and survival. Its role in lymphomagenesis is confirmed in many different types of B cell lymphomas. This review is mainly focused on the PI3K/v-akt/mTOR pathway-related oncogenic mechanisms in B cell NHLs with an emphasis on common B cell lymphoma types [diffuse large B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL)]. Furthermore, it summarizes the literature regarding the clinical applications of the mTOR inhibitors temsirolimus and everolimus in B cell NHLs, which have been tested in a range of clinical trials enrolling patients with B cell malignancies, either as monotherapy or in combination with other agents or regimens. Full article
(This article belongs to the Special Issue mTOR Signaling: Recent Progress)
23 pages, 1647 KiB  
Review
mTOR Signaling Pathway and Gut Microbiota in Various Disorders: Mechanisms and Potential Drugs in Pharmacotherapy
by Yuan Gao and Tian Tian
Int. J. Mol. Sci. 2023, 24(14), 11811; https://doi.org/10.3390/ijms241411811 - 22 Jul 2023
Cited by 5 | Viewed by 2763
Abstract
The mammalian or mechanistic target of rapamycin (mTOR) integrates multiple intracellular and extracellular upstream signals involved in the regulation of anabolic and catabolic processes in cells and plays a key regulatory role in cell growth and metabolism. The activation of the mTOR signaling [...] Read more.
The mammalian or mechanistic target of rapamycin (mTOR) integrates multiple intracellular and extracellular upstream signals involved in the regulation of anabolic and catabolic processes in cells and plays a key regulatory role in cell growth and metabolism. The activation of the mTOR signaling pathway has been reported to be associated with a wide range of human diseases. A growing number of in vivo and in vitro studies have demonstrated that gut microbes and their complex metabolites can regulate host metabolic and immune responses through the mTOR pathway and result in disorders of host physiological functions. In this review, we summarize the regulatory mechanisms of gut microbes and mTOR in different diseases and discuss the crosstalk between gut microbes and their metabolites and mTOR in disorders in the gastrointestinal tract, liver, heart, and other organs. We also discuss the promising application of multiple potential drugs that can adjust the gut microbiota and mTOR signaling pathways. Despite the limited findings between gut microbes and mTOR, elucidating their relationship may provide new clues for the prevention and treatment of various diseases. Full article
(This article belongs to the Special Issue mTOR Signaling: Recent Progress)
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