Journal articles: 'MTOB'

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ROCH, Anne-Marie, Gerard QUASH, Yvonne MICHAL, Jacqueline CHANTEPIE, Bernard CHANTEGREL, Christian DESHAYES, Alain DOUTHEAU, and Jacqueline MARVEL. "Altered methional homoeostasis is associated with decreased apoptosis in BAF3 bcl2 murine lymphoid cells." Biochemical Journal 313, no. 3 (February 1, 1996): 973–81. http://dx.doi.org/10.1042/bj3130973.

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Methional is a potent inducer of apoptosis in an interleukin 3-dependent murine lymphoid cell line BAF3 b0 when it is added to the culture medium. In these cells transfected with the bcl2 gene, BAF3 bcl2, the apoptotic-inducing activity of methional is dramatically reduced. The addition of disulfiram (an inhibitor of aldehyde dehydrogenase) in order to reduce methional oxidation brought about an increase in apoptosis in BAF3 b0 but not in BAF3 bcl2 cells. In contrast, the addition of quercetin (an inhibitor of aldehyde reductase) in an attempt to diminish methional reduction increased apoptosis in both BAF3 b0 and BAF3 bcl2 cells. The extent of DNA fragmentation in BAF3 bcl2 cells approached that in BAF3 b0 cells in the presence of quercetin and exogenous methional, suggesting a defect in methional biosynthesis in BAF3 bcl2 cells. Direct evidence for this was obtained by measuring labelled methional in cells incubated with the sodium salt of [U-14C]4-methylthio-2-oxobutanoic acid (MTOB), the precursor of methional. The 80% decrease in labelled methional in BAF3 bcl2 compared with BAF3 b0 cells was accompanied by a concomitant rise in the transamination of [14C]MTOB to [14C]methionine in BAF3 bcl2 cells. Inhibition of the transaminase, however, by a synthetic transition-state-type compound, pyridoxal-L-methionine ethyl ester, induced apoptosis in BAF3 b0 but not in BAF3 bcl2 cells, confirming that the defect in BAF3 bcl2 cells was not in the transaminase itself but rather in the oxidative decarboxylation step MTOB →methional. In addition, no evidence was obtained for the synthesis of [14C]malondialdehyde from [14C]methional in BAF3 bcl2 cells. As these cells show no deficiency in their content of reactive oxygen species compared with that of BAF3 b0 cells, they may possess some other defect in the β-hydroxylase enzyme system itself.

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Zhu, Lin, Jing Wu, and Hong Liu. "Downregulation of HERC5 E3 ligase attenuates the ubiquitination of CtBP1 to inhibit apoptosis in colorectal cancer cells." Carcinogenesis 42, no. 8 (June 19, 2021): 1119–30. http://dx.doi.org/10.1093/carcin/bgab053.

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Abstract The homologous to E6AP C-terminus (HECT) domain and RCC1-like domain-containing (HERC) proteins can function as tumour suppressors and as oncogenes, depending on the cancer type. However, the expression patterns of HERCs in colorectal cancer (CRC) cells are unclear. Here, we show that only HERC1 and HERC5 are downregulated in CRC tumours, and we focus our study on revealing HERC5-mediating signalling because the change in downregulation is much more obvious for HERC5 than for HERC1. We demonstrate that HERC5 recruits an adaptor protein, CREB-binding protein, to ubiquitinate C-terminal binding protein 1 (CtBP1) in non-cancerous colon cells. The downregulation of HERC5 in CRC cells attenuates the ubiquitination of CtBP1, which then accumulates and assembles into a transcriptional complex with histone deacetylase 1 and a transcription factor c-MYC. This transcriptional complex binds to the promoters of three proapoptotic genes, Bcl2 associated X (BAX), Bcl2 interacting killer (BIK) and p53upregulated modulator of apoptosis (PUMA), and inhibits their expression, thereby suppressing apoptotic signalling and promoting tumourigenesis. Overexpression of HERC5, downregulation of CtBP1 or blocking of the CtBP1 function with its inhibitors (NSC95397 and 4-methylthio-2-oxobutyric acid [MTOB]) significantly prevents CRC cell proliferation in vitro and tumour growth in vivo. Combining NSC95397 (or MTOB) with chemotherapeutic drugs (oxaliplatin or capecitabine) gives a much stronger inhibition of cell proliferation and tumour growth compared with their single treatments. Collectively, our results reveal that downregulation of HERC5 E3 ligase attenuates the ubiquitination of CtBP1 to inhibit apoptosis. Therefore, CtBP1 may be a promising target in CRC chemotherapy.

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Hilbert, Brendan J., Steven R. Grossman, Celia A. Schiffer, and William E. Royer. "Crystal structures of human CtBP in complex with substrate MTOB reveal active site features useful for inhibitor design." FEBS Letters 588, no. 9 (March 19, 2014): 1743–48. http://dx.doi.org/10.1016/j.febslet.2014.03.026.

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Reyes-Hernández, Blanca Jazmín, Svetlana Shishkova, Rachel Amir, Aranza Xhaly Quintana-Armas, Selene Napsucialy-Mendivil, Rocio Guadalupe Cervantes-Gamez, Héctor Hugo Torres-Martínez, Jesús Montiel, Christopher D. Wood, and Joseph G. Dubrovsky. "Root stem cell niche maintenance and apical meristem activity critically depend on THREONINE SYNTHASE1." Journal of Experimental Botany 70, no. 15 (April 11, 2019): 3835–49. http://dx.doi.org/10.1093/jxb/erz165.

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AbstractIndeterminate root growth depends on the stem cell niche (SCN) and root apical meristem (RAM) maintenance whose regulation permits plasticity in root system formation. Using a forward genetics approach, we isolated the moots koom1 (‘short root’ in Mayan) mutant that shows complete primary RAM exhaustion and abolished SCN activity. We identified that this phenotype is caused by a point mutation in the METHIONINE OVERACCUMULATOR2 (MTO2) gene that encodes THREONINE SYNTHASE1 and renamed the mutant as mto2-2. The amino acid profile showed drastic changes, most notorious of which was accumulation of methionine. In non-allelic mto1-1 (Arabidopsis thaliana cystathionine gamma-synthetase1) and mto3-1 (S-adenosylmethionine synthetase) mutants, both with an increased methionine level, the RAM size was similar to that of the wild type, suggesting that methionine overaccumulation itself did not cause RAM exhaustion in mto2 mutants. When mto2-2 RAM is not yet completely exhausted, exogenous threonine induced de novo SCN establishment and root growth recovery. The threonine-dependent RAM re-establishment in mto2-2 suggests that threonine is a limiting factor for RAM maintenance. In the root, MTO2 was predominantly expressed in the RAM. The essential role of threonine in mouse embryonic stem cells and in RAM maintenance suggests that common regulatory mechanisms may operate in plant and animal SCN maintenance.

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Cerni, Stephen, Dylan Shafer, Kimberly To, and Vishwanath Venketaraman. "Investigating the Role of Everolimus in mTOR Inhibition and Autophagy Promotion as a Potential Host-Directed Therapeutic Target in Mycobacterium tuberculosis Infection." Journal of Clinical Medicine 8, no. 2 (February 11, 2019): 232. http://dx.doi.org/10.3390/jcm8020232.

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Tuberculosis (TB) is a serious infectious disease caused by the pathogen Mycobacterium tuberculosis (Mtb). The current therapy consists of a combination of antibiotics over the course of four months. Current treatment protocols run into problems due to the growing antibiotic resistance of Mtb and poor compliance to the multi-drug-resistant TB treatment protocol. New treatments are being investigated that target host intracellular processes that could be effective in fighting Mtb infections. Autophagy is an intracellular process that is involved in eliminating cellular debris, as well as intracellular pathogens. Mammalian target of rapamycin (mTOR) is an enzyme involved in inhibiting this pathway. Modulation of mTOR and the autophagy cellular machinery are being investigated as potential therapeutic targets for novel Mtb treatments. In this review, we discuss the background of Mtb pathogenesis, including its interaction with the innate and adaptive immune systems, the mTOR and autophagy pathways, the interaction of Mtb with these pathways, and finally, the drug everolimus, which targets these pathways and is a potential novel therapy for TB treatment.

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Yang, Yi, Yingfei Sun, Jinrui Xu, Kangda Bao, Meihui Luo, Xiaoming Liu, and Yujiong Wang. "Epithelial Cells Attenuate Toll-Like Receptor-Mediated Inflammatory Responses in Monocyte-Derived Macrophage-Like Cells to Mycobacterium tuberculosis by Modulating the PI3K/Akt/mTOR Signaling Pathway." Mediators of Inflammation 2018 (September 26, 2018): 1–19. http://dx.doi.org/10.1155/2018/3685948.

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Both alveolar macrophages (AMs) and alveolar epithelial cells (AECs) are main targets of Mycobacterium tuberculosis (M. tuberculosis (Mtb)). Intercellular communications between mucosal AECs and AMs have important implications in cellular responses to exogenous insults. However, molecular mechanisms underpinning interactions responding to Mtb remain largely unknown. In this study, impacts of AECs on Toll-like receptor- (TLR-) mediated inflammatory responses of AMs to Mtb virulent strain H37Rv were interrogated using an air-liquid interface (ALI) coculture model of epithelial A549 cells and U937 monocyte-derived macrophage-like cells. Results showed that Mtb-activated TLR-mediated inflammatory responses in U937 cells were significantly alleviated when A549 cells were coinfected with H37Rv, in comparison with the infection of U937 cells alone. Mechanistically, PI3K/Akt/mTOR signaling was involved in the epithelial cell-modulated Mtb-activated TLR signaling. The epithelial cell-attenuated TLR signaling in U937s could be reversed by PI3K inhibitor LY294002 and mTOR inhibitor rapamycin, but not glycogen synthase kinase 3β inhibitor LiCl, suggesting that the epithelially modulated-TLR signaling in macrophages was in part caused by inhibiting the TLR-triggered PI3K/Akt/mTOR signaling pathway. Together, this study demonstrates that mucosal AEC-derived signals play an important role in modulating inflammatory responses of AMs to Mtb, which thus also offers an insight into cellular communications between AECs and AMs to Mtb infections.

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Kountz, Duncan J., Edward J. Behrman, Liwen Zhang, and Joseph A. Krzycki. "MtcB, a member of the MttB superfamily from the human gut acetogen Eubacterium limosum, is a cobalamin-dependent carnitine demethylase." Journal of Biological Chemistry 295, no. 34 (June 22, 2020): 11971–81. http://dx.doi.org/10.1074/jbc.ra120.012934.

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The trimethylamine methyltransferase MttB is the first described member of a superfamily comprising thousands of microbial proteins. Most members of the MttB superfamily are encoded by genes that lack the codon for pyrrolysine characteristic of trimethylamine methyltransferases, raising questions about the activities of these proteins. The superfamily member MtcB is found in the human intestinal isolate Eubacterium limosum ATCC 8486, an acetogen that can grow by demethylation of l-carnitine. Here, we demonstrate that MtcB catalyzes l-carnitine demethylation. When growing on l-carnitine, E. limosum excreted the unusual biological product norcarnitine as well as acetate, butyrate, and caproate. Cellular extracts of E. limosum grown on l-carnitine, but not lactate, methylated cob-(I)alamin or tetrahydrofolate using l-carnitine as methyl donor. MtcB, along with the corrinoid protein MtqC and the methylcorrinoid:tetrahydrofolate methyltransferase MtqA, were much more abundant in E. limosum cells grown on l-carnitine than on lactate. Recombinant MtcB methylates either cob(I)alamin or Co(I)-MtqC in the presence of l-carnitine and, to a much lesser extent, γ-butyrobetaine. Other quaternary amines were not substrates. Recombinant MtcB, MtqC, and MtqA methylated tetrahydrofolate via l-carnitine, forming a key intermediate in the acetogenic Wood–Ljungdahl pathway. To our knowledge, MtcB methylation of cobalamin or Co(I)-MtqC represents the first described mechanism of biological l-carnitine demethylation. The conversion of l-carnitine and its derivative γ-butyrobetaine to trimethylamine by the gut microbiome has been linked to cardiovascular disease. The activities of MtcB and related proteins in E. limosum might demethylate proatherogenic quaternary amines and contribute to the perceived health benefits of this human gut symbiont.

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Dundon, Samantha E. R., and Thomas D. Pollard. "Microtubule nucleation promoters Mto1 and Mto2 regulate cytokinesis in fission yeast." Molecular Biology of the Cell 31, no. 17 (August 1, 2020): 1846–56. http://dx.doi.org/10.1091/mbc.e19-12-0686.

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Dundon and Pollard show that compromising the Mto1 or Mto2 regulators of the fission yeast γ-tubulin complex reduces or eliminates astral microtubules, exaggerates the effects of a D277N substitution in β-glucan synthase 1 (Cps1/Bgs1) on the rate of cytokinetic furrow formation, and increases Rho1-GTP at the cleavage site.

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Cronin, David. "Are Member States’ Budgetary Policies Adhering to the EU Fiscal Rules?" Applied Economics Quarterly: Volume 66, Issue 1 66, no. 1 (January 1, 2020): 47–64. http://dx.doi.org/10.3790/aeq.66.1.47.

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Harmonised data from the 2013 to 2018 Stability and Convergence Programmes (SCPs) are used to assess whether member states are acting to meet EU fiscal requirements and, in particular, their medium-term objectives (MTOs). EU AMECO data are employed to check whether planned fiscal policy, set out in the SCPs, materialises ex-post. The main finding is that planned changes in the fiscal stance aim towards meeting the MTO when that target has not yet been attained but less effort occurs in practice. Member states who have already met their MTO loosen their fiscal stance. The policy message is that, in general, the enhanced, post-crisis EU fiscal framework is delivering budgetary policy that contributes to avoiding excessive deficit and debt positions. The fiscal consolidation actually undertaken, however, is less than planned and the upside of the economic cycle does not see greater effort towards meeting MTOs. Moreover, those member states with prior excessive deficits do not make, nor plan, any additional fiscal effort over other member states also striving to meet their MTO. The policy reaction to the economic cycle is pro-cyclical in nature.

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LIN, XUE, MENGMENG WEI, FUYANG SONG, DI XUE, and YUJIONG WANG. "N-acetylcysteine (NAC) Attenuating Apoptosis and Autophagy in RAW264.7 Cells in Response to Incubation with Mycolic Acid from Bovine Mycobacterium tuberculosis Complex." Polish Journal of Microbiology 69, no. 2 (June 2020): 223–29. http://dx.doi.org/10.33073/pjm-2020-026.

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Bovine tuberculosis is an airborne infectious disease caused by organisms of the Mycobacterium tuberculosis (MTB) complex. Mycolic acid (MA) is the main lipid component of the cell membrane of MTB. It is non-enzymatically reduced by NAD(P)H and further produces reactive oxygen species (ROS), which can cause oxidative stress in human cells. N-acetylcysteine (NAC) is a synthetic precursor of glutathione (GSH) and exhibits anti-ROS activity. However, the underlying mechanisms of its protective properties remain uncertain. Herein, after pre-incubation of RAW264.7 cells with NAC, the factors associated with apoptosis and autophagy were measured. Mechanistically, NAC could reduce MA-induced expression of pro-apoptotic and pro-autophagy proteins. At the mRNA level, NAC can inhibit AMPK and activate mTOR expression. The results indicate that NAC might regulate autophagy in RAW264.7 cells through the AMPK/mTOR pathway. To further prove the effect of NAC on MA, ICR mice were used to evaluate the lung injury. Hematoxylin-eosin (HE) staining was performed on the lung. The results show that NAC could reduce cell injury induced by MA. In conclusion, our research showed that NAC attenuates apoptosis and autophagy in response to incubation with mycolic acid.

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Zhang, Qingwen, Jinxia Sun, Yan Fu, Weigang He, Yinhong Li, Hongsheng Tan, Hongxi Xu, and Xin Jiang. "Guttiferone K Exerts the Anti-inflammatory Effect on Mycobacterium Tuberculosis- (H37Ra-) Infected Macrophages by Targeting the TLR/IRAK-1 Mediated Akt and NF-κB Pathway." Mediators of Inflammation 2020 (October 10, 2020): 1–16. http://dx.doi.org/10.1155/2020/8528901.

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Mycobacterium tuberculosis (Mtb) remains a great threat to global health, killing more people than any other single infectious agent and causing uncontrollable inflammation in the host. Poorly controlled inflammatory processes can be deleterious and result in immune exhaustion. The current tuberculosis (TB) control is facing the challenge of drugs deficiency, especially in the context of increasingly multidrug resistant (MDR) TB. Under this circumstance, alternative host-directed therapy (HDT) emerges timely which can be exploited to improve the efficacy of TB treatment and disease prognosis by targeting the host. Here, we established the in vitro infection model of Mtb macrophages with H37Ra strain to seek effective anti-TB active agent. The present study showed that Guttiferone K, isolated from Garcinia yunnanensis, could significantly inhibit Mtb-induced inflammation in RAW264.7 and primary peritoneal macrophages. It was evidenced by the decreased production of inflammatory mediators, including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). Further studies with immunoblotting and immunofluorescence revealed that Guttiferone K obviously inhibits the nuclear factor-kappa B (NF-κB) both in RAW264.7 and primary peritoneal macrophages relying on the TLR/IRAK-1 pathway. Guttiferone K could also suppress the NLRP3 inflammasome activity and induce autophagy by inhibiting the protein kinase B (p-Akt) and mammalian target of rapamycin (mTOR) phosphorylation at Ser473 and Ser2448 in both cell lines. Thus, Guttiferone K possesses significant anti-inflammatory effect, alleviating Mtb-induced inflammation with an underlying mechanism that targeting on the TLR/IRAK-1 pathway and inhibiting the downstream NF-κB and Akt/mTOR signaling pathways. Together, Guttiferone K can be an anti-inflammatory agent candidate for the design of new adjunct HDT drugs fighting against tuberculosis.

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Rieke, Damian Tobias, Mario Lamping, Serge Leyvraz, Theo Daniel Kim, Lutz Brinkmann, Antje Tessmer, Lars Fischer, et al. "Precision oncology for the treatment of salivary gland tumors." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e17577-e17577. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e17577.

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e17577 Background: Salivary gland tumors (SGT) represent a rare and heterogeneous group of malignancies. No standard treatment exists in the advanced situation and the prognosis is poor. We here report characteristics and clinical outcomes of patients with SGT discussed at the Charité molecular tumor board (MTB). Methods: Patients with advanced cancer and no curative treatment option were discussed at the Charité MTB. Eligible patients underwent fresh tissue sampling and subsequent whole exome (WES) and RNA sequencing (RNA-seq) and immunohistochemical analyses (EGFR, HER2, AR as well as validation tests) or panel sequencing. Results from molecular testing were discussed at the MTB and patients were followed-up after recommendations were made. Results: 24 patients (median age 56 years, 13 male, 11 female) with advanced SGT were presented at the MTB between 2016 and 2019 (9 adenoidcystic carcinomas, 5 adenocarcinomas, 3 mucoepidermoid, 2 carcinosarcoma, 5 miscellaneous). WES/RNA sequencing was performed on tumor tissue from 16 patients. 2 patients were not included in the sequencing program and WES/RNA-Seq was ongoing for another 4 patients at the time of analysis. For another 2 patients, panel sequencing and IHC analysis, respectively was done. Results from analyses were discussed and a median of 2 recommendations, ranked by priority according to prespecified evidence levels, were made for 17 patients, each. Most commonly proposed treatment options by the MTB were FGFR inhibitors in 6 patients, mTOR or PARP inhibitors in 5 each, EGFR, HDAC inhibitors or antiandrogen therapy in 4, each. Treatments following MTB recommendations were initiated in 8 patients, 1 of which received a second recommended therapy after progression (antiandrogen therapy in 4, EGFR inhibitor in 2, a PDGFR, mTOR and PARP inhibitor in 1, each). A clinical benefit (CR = 1; Mixed Response = 1, SD = 3) was achieved in 5 patients, including a complete response in a patient with a metastatic adenocarcinoma of the parotid gland, treated with antiandrogen therapy. Conclusions: Precision oncology represents a feasible treatment strategy in patients with advanced SGT and shows early evidence of activity in a subset of patients. These results suggest further exploration of personalized therapy in these hard-to-treat tumors.

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Sachdeva, Kuldeep, Manisha Goel, Malvika Sudhakar, Mansi Mehta, Rajmani Raju, Karthik Raman, Amit Singh, and Varadharajan Sundaramurthy. "Mycobacterium tuberculosis (Mtb) lipid mediated lysosomal rewiring in infected macrophages modulates intracellular Mtb trafficking and survival." Journal of Biological Chemistry 295, no. 27 (May 18, 2020): 9192–210. http://dx.doi.org/10.1074/jbc.ra120.012809.

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Intracellular pathogens commonly manipulate the host lysosomal system for their survival. However, whether this pathogen-induced alteration affects the organization and functioning of the lysosomal system itself is not known. Here, using in vitro and in vivo infections and quantitative image analysis, we show that the lysosomal content and activity are globally elevated in Mycobacterium tuberculosis (Mtb)-infected macrophages. We observed that this enhanced lysosomal state is sustained over time and defines an adaptive homeostasis in the infected macrophage. Lysosomal alterations are caused by mycobacterial surface components, notably the cell wall-associated lipid sulfolipid-1 (SL-1), which functions through the mTOR complex 1 (mTORC1)–transcription factor EB (TFEB) axis in the host cells. An Mtb mutant lacking SL-1, MtbΔpks2, shows attenuated lysosomal rewiring compared with the WT Mtb in both in vitro and in vivo infections. Exposing macrophages to purified SL-1 enhanced the trafficking of phagocytic cargo to lysosomes. Correspondingly, MtbΔpks2 exhibited a further reduction in lysosomal delivery compared with the WT. Reduced trafficking of this mutant Mtb strain to lysosomes correlated with enhanced intracellular bacterial survival. Our results reveal that global alteration of the host lysosomal system is a defining feature of Mtb-infected macrophages and suggest that this altered lysosomal state protects host cell integrity and contributes to the containment of the pathogen.

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Gümüş, Zeynep Zehra, Zeki Soypaçacı, and Servet Akar. "mTOR pathway and its role in rheumatologic diseases." Ulusal Romatoloji Dergisi 11, no. 2 (December 1, 2019): 132–56. http://dx.doi.org/10.2399/raed.19.85530.

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Picking, Jonathan W., Edward J. Behrman, Liwen Zhang, and Joseph A. Krzycki. "MtpB, a member of the MttB superfamily from the human intestinal acetogen Eubacterium limosum, catalyzes proline betaine demethylation." Journal of Biological Chemistry 294, no. 37 (July 24, 2019): 13697–707. http://dx.doi.org/10.1074/jbc.ra119.009886.

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Choi, Kyoungcheol, Seongho Lee, Miji Kwon, Seyoung Hong, Hee Ho Park, and Kwang Suk Lim. "Development of Anticancer Chemotherapy: Inhibitors of Topoisomerase, HSP90, mTOR and Tyrosine Kinase." KSBB Journal 36, no. 2 (June 30, 2021): 99–117. http://dx.doi.org/10.7841/ksbbj.2021.36.2.99.

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Marin, Philippe, Julie Meffre, and Joël Bockaert. "mTOR." médecine/sciences 29, no. 1 (January 2013): 28–30. http://dx.doi.org/10.1051/medsci/2013291009.

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Bestul, Andrew J., Zulin Yu, Jay R. Unruh, and Sue L. Jaspersen. "Molecular model of fission yeast centrosome assembly determined by superresolution imaging." Journal of Cell Biology 216, no. 8 (June 15, 2017): 2409–24. http://dx.doi.org/10.1083/jcb.201701041.

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Microtubule-organizing centers (MTOCs), known as centrosomes in animals and spindle pole bodies (SPBs) in fungi, are important for the faithful distribution of chromosomes between daughter cells during mitosis as well as for other cellular functions. The cytoplasmic duplication cycle and regulation of the Schizosaccharomyces pombe SPB is analogous to centrosomes, making it an ideal model to study MTOC assembly. Here, we use superresolution structured illumination microscopy with single-particle averaging to localize 14 S. pombe SPB components and regulators, determining both the relationship of proteins to each other within the SPB and how each protein is assembled into a new structure during SPB duplication. These data enabled us to build the first comprehensive molecular model of the S. pombe SPB, resulting in structural and functional insights not ascertained through investigations of individual subunits, including functional similarities between Ppc89 and the budding yeast SPB scaffold Spc42, distribution of Sad1 to a ring-like structure and multiple modes of Mto1 recruitment.

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Pupyshev, A. B., M. V. Tenditnik, M. V. Ovsyukova, A. A. Akopyan, N. I. Dubrovina, and M. A. Tikhonova. "Restoration of Parkinson’s disease-like deficits by activating autophagy through mTOR-dependent and mTOR-independent mechanisms in pharmacological and transgenic models of Parkinson’s disease in mice." Bulletin of Experimental Biology and Medicine 171, no. 4 (2021): 429–35. http://dx.doi.org/10.47056/0365-9615-2021-171-4-429-435.

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Kang, Seung-Woo, and Young-Jae Kim. "Analysis of Relationship between Modified Planned Behavior Theory (MTPB) and Serious Leisure by Leisure Type." Korean Journal of Sports Science 28, no. 2 (April 30, 2019): 187–99. http://dx.doi.org/10.35159/kjss.2019.04.28.2.187.

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Kilic, Banu, Meryem Temiz-Resitoglu, and Seyhan Sahan Firat. "Targeting mTOR: up-to-date mTOR inhibitors." Biorganic and Medicinal Chemistry Reports 2, no. 1-2 (December 26, 2019): 1–14. http://dx.doi.org/10.25135/bmcr.16.19.09.1417.

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Елистратова, И. В., А. В. Гречко, Е. А. Горелова, С. В. Потапова, and С. Г. Морозов. "Measurement of the kinase mTOR expression in blood cell of patients with atopic dermatitis." Nauchno-prakticheskii zhurnal «Patogenez», no. 3() (September 29, 2018): 142–46. http://dx.doi.org/10.25557/2310-0435.2018.03.142-146.

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В клетках крови больных атопическим дерматитом (АД) исследовали экспрессию белка mTOR методом проточной цитометрии. Установлено, что общий пул белка mTOR в лимфоцитах повышен при АД по сравнению с донорами. Экспрессия белка mTOR в CD4+ и CD8+ Т-лимфоцитах крови в период обострения АД выше, чем у доноров и больных в периоде ремиссии. Оба комплекса киназы mTOR (mTORC1 и mTORC2) участвуют в изменениях субпопуляций лимфоцитов при АД. Активация белков Raptor и Rictor (mTORC1 vs mTORC2) достоверно выше в лимфоцитах больных АД легкой и средней степени тяжести (по индексу SCORAD), чем у доноров. The kinase mTOR expression was studied in blood cells of patients with atopic dermatitis (AD) using flow cytometry. The total level of lymphocyte mTOR protein was increased in AD patients compared with healthy donors. The mTOR protein expression in CD4+ and CD8+ T cells was higher in patients with AD in a relapse than in donors and patients in a remission. Both mTORC1 and mTORC2 complexes formed by mTOR kinase were found to participate in lymphocyte disruption during AD. Activation of Raptor and Rictor proteins (from mTORC1 and mTORC2, respectively) was significantly increased in lymphocytes of patients with mild and moderate AD (according to the SCORAD index).

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Kim, Eun Ji, Guen Tae Kim, Bo Min Kim, Eun Gyeong Lim, Sung Ho Ha, Sang-Yong Kim, and Young Min Kim. "Apoptotic Effect of Extract from Artemisia annua Linné by Akt/mTOR/GSK-3β Signal Pathway in Hep3B Human Hepatoma Cells." Journal of Life Science 26, no. 7 (July 30, 2016): 764–71. http://dx.doi.org/10.5352/jls.2016.26.7.764.

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Liu, Cang-Li. "A Study on the Behavioral Intention of Chinese Rural Tourists : Using Modified Theory of Planned Behavior(MTPB)." Journal of Tourism Enhancement 9, no. 2 (May 31, 2021): 39–61. http://dx.doi.org/10.35498/kotes.2021.9.2.039.

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Laplante, M., and D. M. Sabatini. "mTOR Signaling." Cold Spring Harbor Perspectives in Biology 4, no. 2 (November 30, 2011): a011593. http://dx.doi.org/10.1101/cshperspect.a011593.

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Gohlisch, Christopher. "mTOR-Inhibition." Dialyse aktuell 20, no. 08 (October 10, 2016): 389–92. http://dx.doi.org/10.1055/s-0042-116347.

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Haas, Michael J. "mTOR caveats." Science-Business eXchange 1, no. 6 (March 2008): 132. http://dx.doi.org/10.1038/scibx.2008.132.

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Ernstoff, Marc S. "mTOR Pathway and mTOR Inhibitors in Cancer Therapy." British Journal of Clinical Pharmacology 71, no. 6 (May 12, 2011): 970. http://dx.doi.org/10.1111/j.1365-2125.2011.03919.x.

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Hwang, Jong Sun. "The Effect of MTB Participating Motivation as Sports for All on the Intention to Continue Exercise." Journal of Sport and Leisure Studies 32 (May 31, 2008): 595–601. http://dx.doi.org/10.51979/kssls.2008.05.32.595.

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Li, Na, Jie Chen, Qiang Liu, Hongyi Qu, Xiaoqing Yang, Peng Gao, Yao Wang, Huayu Gao, Hong Wang, and Zuohui Zhao. "Prognostic significance and tumor-immune infiltration of mTOR in clear cell renal cell carcinoma." PeerJ 9 (August 17, 2021): e11901. http://dx.doi.org/10.7717/peerj.11901.

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Mammalian target of rapamycin (mTOR), a serine/threonine kinase involved in cell proliferation, survival, metabolism and immunity, was reportedly activated in various cancers. However, the clinical role of mTOR in renal cell carcinoma (RCC) is controversial. Here we detected the expression and prognosis of total mTOR and phosphorylated mTOR (p-mTOR) in clear cell RCC (ccRCC) patients, and explored the interactions between mTOR and immune infiltrates in ccRCC. The protein level of mTOR and p-mTOR was determined by western blotting (WB), and their expression was evaluated in 145 ccRCC and 13 non-tumor specimens by immunohistochemistry (IHC). The relationship to immune infiltration of mTOR was further investigated using TIMER and TISIDB databases, respectively. WB demonstrated the ratio of p-mTOR to mTOR was higher in ccRCC than adjacent specimens (n = 3), and IHC analysis elucidated that p-mTOR expression was positively correlated with tumor size, stage and metastasis status, and negatively correlated with cancer-specific survival (CSS). In univariate analysis, high grade, large tumor, advanced stage, metastasis, and high p-mTOR expression were recognized as prognostic factors of poorer CSS, and multivariate survival analysis elucidated that tumor stage, p-mTOR and metastasis were of prognostic value for CSS in ccRCC patients. Further TIMER and TISIDB analyses uncovered that mTOR gene expression was significantly associated with numerous immune cells and immunoinhibitors in patients with ccRCC. Collectively, these findings revealed p-mTOR was identified as an independent predictor of poor survival, and mTOR was associated with tumor immune infiltrates in ccRCC patients, which validated mTOR could be implicated in the initiation and progression of ccRCC.

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Qian, Jiayi, Siyuan Su, and Pengda Liu. "Experimental Approaches in Delineating mTOR Signaling." Genes 11, no. 7 (July 2, 2020): 738. http://dx.doi.org/10.3390/genes11070738.

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The mTOR signaling controls essential biological functions including proliferation, growth, metabolism, autophagy, ageing, and others. Hyperactivation of mTOR signaling leads to a plethora of human disorders; thus, mTOR is an attractive drug target. The discovery of mTOR signaling started from isolation of rapamycin in 1975 and cloning of TOR genes in 1993. In the past 27 years, numerous research groups have contributed significantly to advancing our understanding of mTOR signaling and mTOR biology. Notably, a variety of experimental approaches have been employed in these studies to identify key mTOR pathway members that shape up the mTOR signaling we know today. Technique development drives mTOR research, while canonical biochemical and yeast genetics lay the foundation for mTOR studies. Here in this review, we summarize major experimental approaches used in the past in delineating mTOR signaling, including biochemical immunoprecipitation approaches, genetic approaches, immunofluorescence microscopic approaches, hypothesis-driven studies, protein sequence or motif search driven approaches, and bioinformatic approaches. We hope that revisiting these distinct types of experimental approaches will provide a blueprint for major techniques driving mTOR research. More importantly, we hope that thinking and reasonings behind these experimental designs will inspire future mTOR research as well as studies of other protein kinases beyond mTOR.

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Song, Xiaoxiao, Yoichiro Kusakari, Chun-Yang Xiao, Stuart D. Kinsella, Michael A. Rosenberg, Marielle Scherrer-Crosbie, Kenta Hara, Anthony Rosenzweig, and Takashi Matsui. "mTOR attenuates the inflammatory response in cardiomyocytes and prevents cardiac dysfunction in pathological hypertrophy." American Journal of Physiology-Cell Physiology 299, no. 6 (December 2010): C1256—C1266. http://dx.doi.org/10.1152/ajpcell.00338.2010.

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Previous studies have suggested that inhibition of the mammalian target of rapamycin (mTOR) by rapamycin suppresses myocardial hypertrophy. However, the role of mTOR in the progression of cardiac dysfunction in pathological hypertrophy has not been fully defined. Interestingly, recent reports indicate that the inflammatory response, which plays an important role in the development of heart failure, is enhanced by rapamycin under certain conditions. Our aim in this study was to determine the influence of mTOR on pathological hypertrophy and to assess whether cardiac mTOR regulates the inflammatory response. We generated transgenic mice with cardiac-specific overexpression of wild-type mTOR (mTOR-Tg). mTOR-Tg mice were protected against cardiac dysfunction following left ventricular pressure overload induced by transverse aortic constriction (TAC) ( P < 0.01) and had significantly less interstitial fibrosis compared with littermate controls (WT) at 4 wk post-TAC ( P < 0.01). In contrast, TAC caused cardiac dysfunction in WT. At 1 wk post-TAC, the proinflammatory cytokines interleukin (IL)-1β and IL-6 were significantly increased in WT mice but not in mTOR-Tg mice. To further characterize the effects of mTOR activation, we exposed HL-1 cardiomyocytes transfected with mTOR to lipopolysaccharide (LPS). mTOR overexpression suppressed LPS-induced secretion of IL-6 ( P < 0.001), and the mTOR inhibitors rapamycin and PP242 abolished this inhibitory effect of mTOR. In addition, mTOR overexpression reduced NF-κB-regulated transcription in HL-1 cells. These data suggest that mTOR mitigates adverse outcomes of pressure overload and that this cardioprotective effect of mTOR is mediated by regulation of the inflammatory reaction.

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Avruch, Joseph, Xiaomeng Long, Yenshou Lin, Sara Ortiz-Vega, Joseph Rapley, Angela Papageorgiou, Noriko Oshiro, and Ushio Kikkawa. "Activation of mTORC1 in two steps: Rheb-GTP activation of catalytic function and increased binding of substrates to raptor1." Biochemical Society Transactions 37, no. 1 (January 20, 2009): 223–26. http://dx.doi.org/10.1042/bst0370223.

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The signalling function of mTOR complex 1 is activated by Rheb-GTP, which controls the catalytic competence of the mTOR (mammalian target of rapamycin) kinase domain by an incompletely understood mechanism. Rheb can bind directly to the mTOR kinase domain, and association with inactive nucleotide-deficient Rheb mutants traps mTOR in a catalytically inactive state. Nevertheless, Rheb-GTP targets other than mTOR, such as FKBP38 (FK506-binding protein 38) and/or PLD1 (phospholipase D1), may also contribute to mTOR activation. Once activated, the mTOR catalytic domain phosphorylates substrates only when they are bound to raptor (regulatory associated protein of mTOR), a separate polypeptide within the complex. The mechanism of insulin/nutrient stimulation of mTOR complex 1 signalling, in addition to Rheb-GTP activation of the mTOR catalytic function, also involves a stable modification of the configuration of mTORC1 (mTOR complex 1) that increases access of substrates to their binding site on the raptor polypeptide. The mechanism underlying this second step in the activation of mTORC1 is unknown.

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Xu, Song, Li Li, Min Li, Mengli Zhang, Mei Ju, Xu Chen, and Heng Gu. "Impact on Autophagy and Ultraviolet B Induced Responses of Treatment with the MTOR Inhibitors Rapamycin, Everolimus, Torin 1, and pp242 in Human Keratinocytes." Oxidative Medicine and Cellular Longevity 2017 (2017): 1–21. http://dx.doi.org/10.1155/2017/5930639.

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The mechanistic target of Rapamycin (MTOR) protein is a crucial signaling regulator in mammalian cells that is extensively involved in cellular biology. The function of MTOR signaling in keratinocytes remains unclear. In this study, we detected the MTOR signaling and autophagy response in the human keratinocyte cell line HaCaT and human epidermal keratinocytes treated with MTOR inhibitors. Moreover, we detected the impact of MTOR inhibitors on keratinocytes exposed to the common carcinogenic stressors ultraviolet B (UVB) and UVA radiation. As a result, keratinocytes were sensitive to the MTOR inhibitors Rapamycin, everolimus, Torin 1, and pp242, but the regulation of MTOR downstream signaling was distinct. Next, autophagy induction only was observed in HaCaT cells treated with Rapamycin. Furthermore, we found that MTOR signaling was insensitive to UVB but sensitive to UVA radiation. UVB treatment also had no impact on the inhibition of MTOR signaling by MTOR inhibitors. Finally, MTOR inhibition by Rapamycin, everolimus, or pp242 did not affect the series of biological events in keratinocytes exposed to UVB, including the downregulation of BiP and PERK, activation of Histone H2A and JNK, and cleavage of caspase-3 and PARP. Our study demonstrated that MTOR inhibition in keratinocytes cannot always induce autophagy, and the MTOR pathway does not play a central role in the UVB triggered cellular response.

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Dowling, Ryan J. O., Ivan Topisirovic, Bruno D. Fonseca, and Nahum Sonenberg. "Dissecting the role of mTOR: Lessons from mTOR inhibitors." Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics 1804, no. 3 (March 2010): 433–39. http://dx.doi.org/10.1016/j.bbapap.2009.12.001.

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Gomez-Pinillos, Alejandro, and Anna C. Ferrari. "mTOR Signaling Pathway and mTOR Inhibitors in Cancer Therapy." Hematology/Oncology Clinics of North America 26, no. 3 (June 2012): 483–505. http://dx.doi.org/10.1016/j.hoc.2012.02.014.

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Patel, Raina A., Imran Ahmad, Christine E. Sheehan, Jeffrey S. Ross, George D. Wilner, Alida Hayner-Buchan, and Tipu Nazeer. "Expression of Phosphorylated mTOR (p-mTOR) Correlates with Advanced Stage in Diffuse Large B-Cell Lymphomas." Blood 110, no. 11 (November 16, 2007): 1573. http://dx.doi.org/10.1182/blood.v110.11.1573.1573.

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Abstract Background: The mammalian target of rapamycin (mTOR), plays a major role in regulating cell growth. The activated form of mTOR (phosphorylated mTOR) mediates its effects through mitogen and nutrient dependant signal transduction that regulates mRNA translation. Levels of phosphorylated mTOR (p-mTOR) have been shown to correlate with cell proliferation and inhibition of the mTOR pathway has shown therapeutic promise in some tumors. Information on the role of p-mTOR in hematopoietic malignancies is limited. The aim of the current study is to evaluate the expression of p-mTOR in diffuse large B-cell lymphomas. Design: Formalin-fixed paraffin-embedded tissue sections from 45 DLBCLs were immunostained by an automated method (Ventana Medical Systems, Inc., Tucson, AZ) using p-mTOR rabbit monoclonal antibody (IHC specific Ser2448/49F9; Cell Signaling Technology, Inc., Danvers, MA). Immunoreactivity (cytoplasmic with membranous accentuation) was semiquantitatively assessed based on p-mTOR stain intensity (none, weak, moderate, intense) and distribution (none, focal<10%, regional 11–50%, diffuse>50%). Staining was correlated with histologic and prognostic factors. Results: Membranous/cytoplasmic p-mTOR immunoreactivity was present in 88% of DLBCLs and correlated with advanced tumor stage, with 100% advanced stage versus 73% low stage tumors expressing membranous/cytoplasmic p-mTOR protein (p=0.002). One hundred percent of cases with complete absence of p-mTOR immunoreactivity were low stage DLBCLs. Conclusion: Membranous/cytoplasmic protein expression of p-mTOR correlates with advanced stage in DLBCL. Activated mTOR may play an important role in disease progression and provide a target for therapy in DLBCL. Further studies of the m-TOR pathway in hematopoietic malignancies appear warranted.

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Goodman, Craig A., Man Hing Miu, John W. Frey, Danielle M. Mabrey, Hannah C. Lincoln, Yejing Ge, Jie Chen, and Troy A. Hornberger. "A Phosphatidylinositol 3-Kinase/Protein Kinase B-independent Activation of Mammalian Target of Rapamycin Signaling Is Sufficient to Induce Skeletal Muscle Hypertrophy." Molecular Biology of the Cell 21, no. 18 (September 15, 2010): 3258–68. http://dx.doi.org/10.1091/mbc.e10-05-0454.

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It has been widely proposed that signaling by mammalian target of rapamycin (mTOR) is both necessary and sufficient for the induction of skeletal muscle hypertrophy. Evidence for this hypothesis is largely based on studies that used stimuli that activate mTOR via a phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB)-dependent mechanism. However, the stimulation of signaling by PI3K/PKB also can activate several mTOR-independent growth-promoting events; thus, it is not clear whether signaling by mTOR is permissive, or sufficient, for the induction of hypertrophy. Furthermore, the presumed role of mTOR in hypertrophy is derived from studies that used rapamycin to inhibit mTOR; yet, there is very little direct evidence that mTOR is the rapamycin-sensitive element that confers the hypertrophic response. In this study, we determined that, in skeletal muscle, overexpression of Rheb stimulates a PI3K/PKB-independent activation of mTOR signaling, and this is sufficient for the induction of a rapamycin-sensitive hypertrophic response. Transgenic mice with muscle specific expression of various mTOR mutants also were used to demonstrate that mTOR is the rapamycin-sensitive element that conferred the hypertrophic response and that the kinase activity of mTOR is necessary for this event. Combined, these results provide direct genetic evidence that a PI3K/PKB-independent activation of mTOR signaling is sufficient to induce hypertrophy. In summary, overexpression of Rheb activates mTOR signaling via a PI3K/PKB-independent mechanism and is sufficient to induce skeletal muscle hypertrophy. The hypertrophic effects of Rheb are driven through a rapamycin-sensitive (RS) mechanism, mTOR is the RS element that confers the hypertrophy, and the kinase activity of mTOR is necessary for this event.

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Wang, Xuerong, Ping Yue, Chi-Bun Chan, Keqiang Ye, Takeshi Ueda, Rie Watanabe-Fukunaga, Rikiro Fukunaga, Haian Fu, Fadlo R. Khuri, and Shi-Yong Sun. "Inhibition of Mammalian Target of Rapamycin Induces Phosphatidylinositol 3-Kinase-Dependent and Mnk-Mediated Eukaryotic Translation Initiation Factor 4E Phosphorylation." Molecular and Cellular Biology 27, no. 21 (August 27, 2007): 7405–13. http://dx.doi.org/10.1128/mcb.00760-07.

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ABSTRACT The initiation factor eukaryotic translation initiation factor 4E (eIF4E) plays a critical role in initiating translation of mRNAs, including those encoding oncogenic proteins. Therefore, eIF4E is considered a survival protein involved in cell cycle progression, cell transformation, and apoptotic resistance. Phosphorylation of eIF4E (usually at Ser209) increases its binding affinity for the cap of mRNA and may also favor its entry into initiation complexes. Mammalian target of rapamycin (mTOR) inhibitors suppress cap-dependent translation through inhibition of the phosphorylation of eIF4E-binding protein 1. Paradoxically, we have shown that inhibition of mTOR signaling increases eIF4E phosphorylation in human cancer cells. In this study, we focused on revealing the mechanism by which mTOR inhibition increases eIF4E phosphorylation. Silencing of either mTOR or raptor could mimic mTOR inhibitors’ effects to increase eIF4E phosphorylation. Moreover, knockdown of mTOR, but not rictor or p70S6K, abrogated rapamycin's ability to increase eIF4E phosphorylation. These results indicate that mTOR inhibitor-induced eIF4E phosphorylation is secondary to mTOR/raptor inhibition and independent of p70S6K. Importantly, mTOR inhibitors lost their ability to increase eIF4E phosphorylation only in cells where both Mnk1 and Mnk2 were knocked out, indicating that mTOR inhibitors increase eIF4E phosphorylation through a Mnk-dependent mechanism. Given that mTOR inhibitors failed to increase Mnk and eIF4E phosphorylation in phosphatidylinositol 3-kinase (PI3K)-deficient cells, we conclude that mTOR inhibition increases eIF4E phosphorylation through a PI3K-dependent and Mnk-mediated mechanism. In addition, we also suggest an effective therapeutic strategy for enhancing mTOR-targeted cancer therapy by cotargeting mTOR signaling and Mnk/eIF4E phosphorylation.

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Machado, Luis Eduardo, Arthur William Alvarenga, Fernanda Ferreira da Silva, Martín Roffé, Maria Dirlei Begnami, Luís Fernando Bleggi Torres, Isabela Werneck da Cunha, Vilma Regina Martins, and Glaucia Noeli Maroso Hajj. "Overexpression of mTOR and p(240–244)S6 in IDH1 Wild-Type Human Glioblastomas Is Predictive of Low Survival." Journal of Histochemistry & Cytochemistry 66, no. 6 (January 12, 2018): 403–14. http://dx.doi.org/10.1369/0022155417750838.

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Summary PI3K/Akt/mTOR pathway activation is a hallmark of high-grade gliomas, which prompted clinical trials for the use of PI3K and mTOR inhibitors. However, the poor results in the original trials suggested that better patient profiling was needed for such drugs. Thus, accurate and reproducible monitoring of mTOR complexes can lead to improved therapeutic strategies. In this work, we evaluated the expression and phosphorylation of mTOR, RAPTOR, and rpS6 in 195 human astrocytomas and 30 normal brain tissue samples. The expression of mTOR increased in glioblastomas, whereas mTOR phosphorylation, expression of RAPTOR, and expression and phosphorylation of rpS6 were similar between grades. Interestingly, the overexpression of total and phosphorylated mTOR as well as phosphorylated rpS6 (residues 240–244) were associated with wild-type IDH1 only glioblastomas. The expression and phosphorylation of mTOR and phosphorylation of rpS6 at residues 240–244 were associated with a worse prognosis in glioblastomas. Our results suggest that mTOR and rpS6 could be used as markers of overactivation of the PI3K-mTOR pathway and are predictive factors for overall survival in glioblastomas. Our study thus suggests that patients who harbor IDH1 wild-type glioblastomas might have increased benefit from targeted therapy against mTOR.

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Guglielmelli, Tommasina, Emilia Giugliano, Vanessa Brunetto, Sokol Rrodhe, and Giuseppe Saglio. "Cytoplasmic-Nuclear Shuttling of mTOR Protein in Multiple Myeloma Cell Lines and Primary Myeloma Cells: A New Mechanism Regulated by Pomalidomide." Blood 120, no. 21 (November 16, 2012): 4019. http://dx.doi.org/10.1182/blood.v120.21.4019.4019.

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Abstract Abstract 4019 Introduction. mTOR is a serine-threonine protein kinase that plays a central role in regulating critical cellular processes. Consistent with its primary target being the translation machinery, mTOR is predominantly localized in the cytoplasm. However, a nuclear localization of mTOR has been found in rhabdomyosarcomas and HCT8 colon carcinoma cells. Furthermore, mTOR becomes nuclear in HEK293 cells treated with leptomycin B, a specific inhibitor of nuclear export receptor Crm1, suggesting that mTOR may be a cytoplasmic-nuclear shuttling protein. Aims of this study is to evaluate cellular localization of mTOR in multiple myeloma (MM) cell lines and primary MM cells and to evaluate the role of pomalidomide (CC-4047) in regulating the mTOR pathway. Methods. We used OPM-2 and RPMI-8226 MM cell lines and primary MM cells. For primary myeloma specimens, plasmacell population was positively selected by the immunomagnetic method using CD138+ microbeads. Proliferation was evaluated by MTT assay on OPM-2 and RPMI-8226 cells following incubation with pomalidomide at concentrations ranging from 0.01 to 10 μM. Apoptosis was assessed by flow cytometry for the detection of annexin V-positive cells in both MM cell lines and in plasmacells from 3 MM patients. Cellular localization of mTOR protein was also evaluated using a confocal scanning microscopy in RPMI-8226 and OPM-2 cells and in plasmacells from 4 MM patients in basal conditions and after pomalidomide treatment. Immunohistochemistry with antibody against phospho-mTOR was performed on bone marrow sections of 92 MM patients. Furthermore, RPMI-8226 and OPM-2 cells untreated or treated with the drug, were fractionated and both cytoplasmic and nuclear fractions were analysed by Western blotting with specific antibodies for mTOR and pospho-mTOR. Results. MTT assay performed on MM cell lines demonstrated that pomalidomide has a dose-dependent activity. Pomalidomide 1 μM at 48 hours inhibited proliferation of OPM-2 and RPMI-8226 cells with 50% and 40% decrease in cell numbers, respectively. Only minor increase of apoptosis could be detected in RPMI-8226 and OPM-2 cells incubated with pomalidomide at varying concentrations for 24, 48 and 72 hours. Pomalidomide 1 μM was effective in plasmacells from 3 MM patients at 24 hours with 23%, 33% and 26% annexin-V positive cells (versus 11%,18% and 3% of annexin-V positive cells cultured with media alone, respectively). Immunofluorescence assays with mTOR antibody, demonstrated that mTOR protein is distributed throughout the cytoplasm and the nucleus at baseline in both MM cell lines and in plasmacells of 3 out 4 MM patients. A clearly increase of the nuclear mTOR protein was detected after pomalidomide treatment in RPMI-8226 and OPM-2 cells (10 μM at 48 hours) and in plasmacells from 3 MM patients (1 μM at 24 hours) (2 with nuclear mTOR localization at baseline and 1 without it). Immunohistochemistry performed on bone marrow sections evidenced that 41 out 92 MM samples (44.4%) stained positive for cytoplasmic phospho-mTOR. A nuclear phospho-mTOR staining was also demonstrated in 11 cases (12%). All patients but one showed both nuclear and cytoplasmic phospho-mTOR staining. Cytoplasmic and nuclear distribution of mTOR and pospho-mTOR was also evidenced by Western blotting in RPMI-8226 and OPM-2 cells. As expected, the mTOR and phospho-mTOR protein levels were significantly higher in the cytoplasm when compared to the nucleus. Treatment with pomalidomide 10 μM at 48 hours increased the nuclear mTOR and phospho-mTOR expression levels in the nucleus with a concomitant decrease of the cytoplasmic phospho-mTOR protein amount. Conclusions. In RPMI-8226 and OPM-2 cell lines and in a fraction of primary MM cells, mTOR is distributed throughout the cell cytoplasm and in some nucleus. The anti-myeloma activity of pomalidomide may be mediated by the downregulation of the mTOR pathway with a nuclear shuttling of mTOR protein and a reduction of the cytoplasmic phospho-mTOR. Further studies are needed to establish the mechanism of mTOR shuttling, to evaluate the role of pomalidomide in regulating the mTOR pathway and to assess the potential synergism between pomalidomide and mTOR inhibitors. Disclosures: Guglielmelli: Celgene: This study was sponsored by Celgene Other, Honoraria, Research Funding.

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Shen, Juan, Tianpeng Li, Xiaojia Niu, Wenyue Liu, Shengnan Zheng, Jing Wang, Fengsong Wang, et al. "The J-domain cochaperone Rsp1 interacts with Mto1 to organize noncentrosomal microtubule assembly." Molecular Biology of the Cell 30, no. 2 (January 15, 2019): 256–67. http://dx.doi.org/10.1091/mbc.e18-05-0279.

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Microtubule biogenesis initiates at various intracellular sites, including the centrosome, the Golgi apparatus, the nuclear envelope, and preexisting microtubules. Similarly, in the fission yeast Schizosaccharomyces pombe, interphase microtubules are nucleated at the spindle pole body (SPB), the nuclear envelope, and preexisting microtubules, depending on Mto1 activity. Despite the essential role of Mto1 in promoting microtubule nucleation, how distribution of Mto1 in different sites is regulated has remained elusive. Here, we show that the J-domain cochaperone Rsp1 interacts with Mto1 and specifies the localization of Mto1 to non-SPB nucleation sites. The absence of Rsp1 abolishes the localization of Mto1 to non-SPB nucleation sites, with concomitant enrichment of Mto1 to the SPB and the nuclear envelope. In contrast, Rsp1 overexpression impairs the localization of Mto1 to all microtubule organization sites. These findings delineate a previously uncharacterized mechanism in which Rsp1-Mto1 interaction orchestrates non-SPB microtubule formation.

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Eng, Edward W., Adam Bettio, John Ibrahim, and Rene E. Harrison. "MTOC Reorientation Occurs during FcγR-mediated Phagocytosis in Macrophages." Molecular Biology of the Cell 18, no. 7 (July 2007): 2389–99. http://dx.doi.org/10.1091/mbc.e06-12-1128.

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Cell polarization is essential for targeting signaling elements and organelles to active plasma membrane regions. In a few specialized cell types, cell polarity is enhanced by reorientation of the MTOC and associated organelles toward dynamic membrane sites. Phagocytosis is a highly polarized process whereby particles >0.5 μm are internalized at stimulated regions on the cell surface of macrophages. Here we provide detailed evidence that the MTOC reorients toward the site of particle internalization during phagocytosis. We visualized MTOC proximity to IgG-sRBCs in fixed RAW264.7 cells, during live cell imaging using fluorescent chimeras to label the MTOC and using frustrated phagocytosis assays. MTOC reorientation in macrophages is initiated by FcγR ligation and is complete within 1 h. Polarization of the MTOC toward the phagosome requires the MT cytoskeleton and dynein motor activity. cdc42, PI3K, and mPAR-6 are all important signaling molecules for MTOC reorientation during phagocytosis. MTOC reorientation was not essential for particle internalization or phagolysosome formation. However Golgi reorientation in concert with MTOC reorientation during phagocytosis implicates MTOC reorientation in antigen processing events in macrophages.

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Che, Xiangyu, Xiaochen Qi, Yingkun Xu, Qifei Wang, and Guangzhen Wu. "Genomic and Transcriptome Analysis to Identify the Role of the mTOR Pathway in Kidney Renal Clear Cell Carcinoma and Its Potential Therapeutic Significance." Oxidative Medicine and Cellular Longevity 2021 (June 7, 2021): 1–28. http://dx.doi.org/10.1155/2021/6613151.

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The mTOR pathway, a major signaling pathway, regulates cell growth and protein synthesis by activating itself in response to upstream signals. Overactivation of the mTOR pathway may affect the occurrence and development of cancer, but no specific treatment has been proposed for targeting the mTOR pathway. In this study, we explored the expression of mTOR pathway genes in a variety of cancers and the potential compounds that target the mTOR pathway and focused on an abnormal type of cancer, kidney renal clear cell carcinoma (KIRC). Based on the mRNA expression of the mTOR pathway gene, we divided KIRC patient samples into three clusters. We explored possible therapeutic targets of the mTOR pathway in KIRC. We predicted the IC50 of some classical targeted drugs to analyze their correlation with the mTOR pathway. Subsequently, we investigated the correlation of the mTOR pathway with histone modification and immune infiltration, as well as the response to anti-PD-1 and anti-CTLA-4 therapy. Finally, we used a LASSO regression analysis to construct a model to predict the survival of patients with KIRC. This study shows that mTOR scores can be used as tools to study various treatments targeting the mTOR pathway and that we can predict the recovery of KIRC patients through the expression of mTOR pathway genes. These research results can provide a reference for future research on KIRC patient treatment strategies.

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Aoyagi, Toshinori, Yoichiro Kusakari, Chun-Yang Xiao, Brendan T. Inouye, Masaya Takahashi, Marielle Scherrer-Crosbie, Anthony Rosenzweig, Kenta Hara, and Takashi Matsui. "Cardiac mTOR protects the heart against ischemia-reperfusion injury." American Journal of Physiology-Heart and Circulatory Physiology 303, no. 1 (July 1, 2012): H75—H85. http://dx.doi.org/10.1152/ajpheart.00241.2012.

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Cardiac mammalian target of rapamycin (mTOR) is necessary and sufficient to prevent cardiac dysfunction in pathological hypertrophy. However, the role of cardiac mTOR in heart failure after ischemic injury remains undefined. To address this question, we used transgenic (Tg) mice with cardiac-specific overexpression of mTOR (mTOR-Tg mice) to study ischemia-reperfusion (I/R) injury in two animal models: 1) in vivo I/R injury with transient coronary artery ligation and 2) ex vivo I/R injury in Langendorff-perfused hearts with transient global ischemia. At 28 days after I/R, mortality was lower in mTOR-Tg mice than littermate control mice [wild-type (WT) mice]. Echocardiography and MRI demonstrated that global cardiac function in mTOR-Tg mice was preserved, whereas WT mice exhibited significant cardiac dysfunction. Masson's trichrome staining showed that 28 days after I/R, the area of interstitial fibrosis was smaller in mTOR-Tg mice compared with WT mice, suggesting that adverse left ventricular remodeling is inhibited in mTOR-Tg mice. In the ex vivo I/R model, mTOR-Tg hearts demonstrated improved functional recovery compared with WT hearts. Perfusion with Evans blue after ex vivo I/R yielded less staining in mTOR-Tg hearts than WT hearts, indicating that mTOR overexpression inhibited necrosis during I/R injury. Expression of proinflammatory cytokines, including IL-6 and TNF-α, in mTOR-Tg hearts was lower than in WT hearts. Consistent with this, IL-6 in the effluent post-I/R injury was lower in mTOR-Tg hearts than in WT hearts. These findings suggest that cardiac mTOR overexpression in the heart is sufficient to provide substantial cardioprotection against I/R injury and suppress the inflammatory response.

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Fan, Cuiqing, Xiongwei Cai, Feng Zhang, Cindy Hochstetler, Xiaoyi Chen, Fukun Guo, Weidong Tian, and Yi Zheng. "Precision Assessment of on- and Off-Target Effects of mTOR Kinase Inhibitors in a Mouse Model." Blood 132, Supplement 1 (November 29, 2018): 2632. http://dx.doi.org/10.1182/blood-2018-99-115225.

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Abstract mTOR plays a critical role in controlling cell growth, survival and metabolism and is an important anti-cancer target. There are over 2,000 clinical trials involving mTOR inhibitors as single or combo-agent. The first gen mTOR inhibitors, i.e. rapamycin and rapalogs, are only effective towards mTORC1 and have shown limited efficacy in multiple clinical settings. The second gen mTOR inhibitors target mTOR kinase domain with significantly stronger antineoplastic potency, and over 30 clinical trials of various mTOR kinase inhibitors including AZD2014 are under way. While the new mTOR inhibitors are promising in effectiveness to suppress both mTORC1 and mTORC2 signaling mediated through the mTOR kinase activity, their safety and toxicity features remain a major concern. To precisely determine the on-/off-target effects of mTOR kinase inhibitors, we have generated the conditional Mx1-Cre;mTORflox/flox and Mx1-Cre;mTORflox/knockin D2338Amice that can inducibly yield the mTOR-/- (KO) and the mTOR kinase-activity deficient D2338A mutant knockin (KI) blood genotypes, respectively, upon poly I:C induction. Our previous studies have shown that mTOR KO in blood cells causes hematopoietic failure, with a remarkable reduction in bone marrow cellularity and a transient expansion but long-term exhaustion of hematopoietic stem cells (HSCs). mTOR KO HSCs displayed a loss of quiescence and increased proliferation but normal survival activity. In the current study, we found that the mTOR kinase-deficient D2338A KI mice show several similar phenotypes as mTOR KO, including a drastic inhibition of the mTORC1/mTORC2 downstream effectors p-S6K, p-4E-BP1 and p-AKT (S473) and transient increase in HSC number and proliferation. mTOR kinase deficiency leads to defective engraftment of HSCs in transplantation and failure of colony-formation by progenitors. RNA-seq analysis of the HSC (Lin-Sca-1+c-Kit+CD135-) population reveals that loss of mTOR and loss of mTOR kinase activity share similar changes in over a thousand genes which are enriched in functional clusters including ribosome biogenesis, cell cycle, MAPK pathway, PI3K-Akt pathway, Jak-Stat pathway, and NFkB pathway. Upon mTOR knockout or knockin, several key compensatory genes involved in cell proliferation and survival, including c-myc, Ccnd1, Fos, Jun, and Dusp1 are upregulated. RT-PCR and Western blot further validated that mTOR KO or KI leads to elevated mRNA and protein expression of these compensatory genes. Our RNA-seq analysis also identified ~1000 upregulated genes (such as Ocln, Itgal, and Dlg5) and ~700 downregulated genes (such as Lipg, Cndp2, and Ndst2) in KI vs. KO HSCs: the upregulated genes were enriched in several pathways such as cell adhesion, tight junction, TNF and Ras pathways, while the metabolic pathways were significantly enriched among the downregulated genes. These differential gene expressions underlie the difference in survival between mTOR KI and KO mice, with the median survival for KI mice at 29 days compared to 14 days for KO mice. These results indicate that while the mTOR kinase activity mediates a majority of mTOR regulator pathways, mTOR also confers kinase-independent roles. We next examined gene expression changes of mTOR WT and mTOR KI in response to 200 nM AZD2014. Further examination of differentially expressed (DE) genes between WT+AZD2014 and WT found around 200 DE genes, in which 150 genes (75% changes) overlapped with those DE genes between KI and WT. These overlapped 150 genes shared between WT HSCs treated with AZD2014 and mTOR KI are enriched in a number of important GO and Pathways, such as signal transduction, metabolic pathway, and PI3K-Akt pathway, and they represent on-target effects by the kinase inhibitor AZD2014. On the other hand, less than 40 DE genes between KI+AZD2014 and KI were detected, including Lilrb4, Nptx1 and Ahnak2, which represent off-target genes induced by AZD2014 treatment. Interestingly, the off-target gene set is not enriched in any GO or Pathway. Taken together, our inducible mTOR D2338A KI mouse presents an excellent model for precisely assessing mTOR kinase inhibitor efficacy and specificity. Our studies provide valuable information for the on- and off-target effects by the AZD2014 class of mTOR kinase inhibitors at a therapeutic dose, and reveal several potential biomarkers that can be useful in predicting the off-target effect of mTOR targeted therapies. Disclosures No relevant conflicts of interest to declare.

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47

Gilley, Rebecca, Kathryn Balmanno, Claire L. Cope, and Simon J. Cook. "Adaptation to chronic mTOR inhibition in cancer and in aging." Biochemical Society Transactions 41, no. 4 (July 18, 2013): 956–61. http://dx.doi.org/10.1042/bst20130080.

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The mTOR [mammalian (or mechanistic) target of rapamycin] protein kinase co-ordinates catabolic and anabolic processes in response to growth factors and nutrients and is a validated anticancer drug target. Rapamycin and related allosteric inhibitors of mTORC1 (mTOR complex 1) have had some success in specific tumour types, but have not exhibited broad anticancer activity, prompting the development of new ATP-competitive mTOR kinase inhibitors that inhibit both mTORC1 and mTORC2. In common with other targeted kinase inhibitors, tumours are likely to adapt and acquire resistance to mTOR inhibitors. In the present article, we review studies that describe how tumour cells adapt to become resistant to mTOR inhibitors. mTOR is a central signalling hub which responds to an array of signalling inputs and activates a range of downstream effector pathways. Understanding how this signalling network is remodelled and which pathways are invoked to sustain survival and proliferation in the presence of mTOR inhibitors can provide new insights into the importance of the various mTOR effector pathways and may suggest targets for intervention to combine with mTOR inhibitors. Finally, since chronic mTOR inhibition by rapamycin can increase lifespan and healthspan in nematodes, fruitflies and mice, we contrast these studies with tumour cell responses to mTOR inhibition.

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Hou, Guiqin, Shuai Yang, Yuanyuan Zhou, Cong Wang, Wen Zhao, and Zhaoming Lu. "Targeted Inhibition of mTOR Signaling Improves Sensitivity of Esophageal Squamous Cell Carcinoma Cells to Cisplatin." Journal of Immunology Research 2014 (2014): 1–9. http://dx.doi.org/10.1155/2014/845763.

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mTOR is an evolutionarily conserved serine-threonine kinase with a central role in cell growth, invasion, and metastasis of tumors, and is activated in many cancers. The aims of this study were to investigate the expression of mTOR in ESCC tissues and its relationship with progression of ESCC and measure the changes of sensitivity of ESCC cells to cisplatin after cells were treated with mTOR siRNA by WST-8 assays, TUNEL, RT-PCR, and western blots in vitro and in vivo. The results showed that the expression of mTOR was higher in ESCC specimens than that in normal esophageal tissues and its expression was closely correlated with the TNM stage of ESCC. mTOR siRNA significantly increased the sensitivity of the EC9706 cells to cisplatin at proliferation in vitro and in vivo. The growth of ESCC xenografts was significantly inhibited by mTOR siRNA or cisplatin, and the cell number of apoptosis was obviously increased after xenografts were treated with mTOR siRNA or cisplatin alone, especially when mTOR siRNA combined with cisplatin. The present study demonstrates that the expression of mTOR has important clinical significance and inhibition of mTOR pathway by mTOR siRNA can improve the sensitivity of ESCC cells to cisplatin.

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Ge, Yejing, Ai-Luen Wu, Christine Warnes, Jianming Liu, Chongben Zhang, Hideki Kawasome, Naohiro Terada, Marni D. Boppart, Christopher J. Schoenherr, and Jie Chen. "mTOR regulates skeletal muscle regeneration in vivo through kinase-dependent and kinase-independent mechanisms." American Journal of Physiology-Cell Physiology 297, no. 6 (December 2009): C1434—C1444. http://dx.doi.org/10.1152/ajpcell.00248.2009.

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Rapamycin-sensitive signaling is required for skeletal muscle differentiation and remodeling. In cultured myoblasts, the mammalian target of rapamycin (mTOR) has been reported to regulate differentiation at different stages through distinct mechanisms, including one that is independent of mTOR kinase activity. However, the kinase-independent function of mTOR remains controversial, and no in vivo studies have examined those mTOR myogenic mechanisms previously identified in vitro. In this study, we find that rapamycin impairs injury-induced muscle regeneration. To validate the role of mTOR with genetic evidence and to probe the mechanism of mTOR function, we have generated and characterized transgenic mice expressing two mutants of mTOR under the control of human skeletal actin (HSA) promoter: rapamycin-resistant (RR) and RR/kinase-inactive (RR/KI). Our results show that muscle regeneration in rapamycin-administered mice is restored by RR-mTOR expression. In the RR/KI-mTOR mice, nascent myofiber formation during the early phase of regeneration proceeds in the presence of rapamycin, but growth of the regenerating myofibers is blocked by rapamycin. Igf2 mRNA levels increase drastically during early regeneration, which is sensitive to rapamycin in wild-type muscles but partially resistant to rapamycin in both RR- and RR/KI-mTOR muscles, consistent with mTOR regulation of Igf2 expression in a kinase-independent manner. Furthermore, systemic ablation of S6K1, a target of mTOR kinase, results in impaired muscle growth but normal nascent myofiber formation during regeneration. Therefore, mTOR regulates muscle regeneration through kinase-independent and kinase-dependent mechanisms at the stages of nascent myofiber formation and myofiber growth, respectively.

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Gangloff, Yann-Gaël, Matthias Mueller, Stephen G. Dann, Petr Svoboda, Melanie Sticker, Jean-Francois Spetz, Sung Hee Um, et al. "Disruption of the Mouse mTOR Gene Leads to Early Postimplantation Lethality and Prohibits Embryonic Stem Cell Development." Molecular and Cellular Biology 24, no. 21 (November 1, 2004): 9508–16. http://dx.doi.org/10.1128/mcb.24.21.9508-9516.2004.

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ABSTRACT The mammalian target of rapamycin (mTOR) is a key component of a signaling pathway which integrates inputs from nutrients and growth factors to regulate cell growth. Recent studies demonstrated that mice harboring an ethylnitrosourea-induced mutation in the gene encoding mTOR die at embryonic day 12.5 (E12.5). However, others have shown that the treatment of E4.5 blastocysts with rapamycin blocks trophoblast outgrowth, suggesting that the absence of mTOR should lead to embryonic lethality at an earlier stage. To resolve this discrepancy, we set out to disrupt the mTOR gene and analyze the outcome in both heterozygous and homozygous settings. Heterozygous mTOR (mTOR +/ −) mice do not display any overt phenotype, although mouse embryonic fibroblasts derived from these mice show a 50% reduction in mTOR protein levels and phosphorylation of S6 kinase 1 T389, a site whose phosphorylation is directly mediated by mTOR. However, S6 phosphorylation, raptor levels, cell size, and cell cycle transit times are not diminished in these cells. In contrast to the situation in mTOR +/ − mice, embryonic development of homozygous mTOR − / − mice appears to be arrested at E5.5; such embryos are severely runted and display an aberrant developmental phenotype. The ability of these embryos to implant corresponds to a limited level of trophoblast outgrowth in vitro, reflecting a maternal mRNA contribution, which has been shown to persist during preimplantation development. Moreover, mTOR − / − embryos display a lesion in inner cell mass proliferation, consistent with the inability to establish embryonic stem cells from mTOR − / − embryos.

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Journal articles on the topic 'MTOB'

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