Dietary and Pharmacological Interventions That Inhibit Mammalian Target of Rapamycin Activity Alter the Brain Expression Levels of Neurogenic and Glial Markers in an Age-and Treatment-Dependent Manner

Cell can integrate the caspase family and mammalian target of rapamycin (mTOR) signaling in response to cellular stress triggered by environment. It is necessary here to elucidate the direct response and interaction mechanism between the two signaling pathways in regulating cell survival and determining cell fate under cellular stress. Members of the caspase family are crucial regulators of inflammation, endoplasmic reticulum stress response and apoptosis. mTOR signaling is known to mediate cell growth, nutrition and metabolism. For instance, over-nutrition can cause the hyperactivation of mTOR signaling, which is associated with diabetes. Nutrition deprivation can inhibit mTOR signaling via SH3 domain-binding protein 4. It is striking that Ras GTPase-activating protein 1 is found to mediate cell survival in a caspase-dependent manner against increasing cellular stress, which describes a new model of apoptosis. The components of mTOR signaling-raptor can be cleaved by caspases to control cell growth. In addition, mTOR is identified to coordinate the defense process of the immune system by suppressing the vitality of caspase-1 or regulating other interferon regulatory factors. The present review discusses the roles of the caspase family or mTOR pathway against cellular stress and generalizes their interplay mechanism in cell fate determination.

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T-2 Toxin Exposure Induces Apoptosis in TM3 Cells by Inhibiting Mammalian Target of Rapamycin/Serine/Threonine Protein Kinase(mTORC2/AKT) to Promote Ca2+Production

International Journal of Molecular Sciences ◽

10.3390/ijms19113360 ◽

2018 ◽

Vol 19 (11) ◽

pp. 3360 ◽

Cited By ~ 4

Author(s):

Ji Wang ◽

Chenglin Yang ◽

Zhihang Yuan ◽

Jine Yi ◽

Jing Wu

Keyword(s):

Cell Injury ◽

Mammalian Target Of Rapamycin ◽

Annexin V ◽

Target Of Rapamycin ◽

Dependent Manner ◽

Toxin Exposure ◽

Concentration Changes ◽

Vitro Model ◽

Induced Apoptosis

Although mTOR (the mammalian target of rapamycin) can regulate intracellular free Ca2+concentration in normal cultured podocytes, it remains elusive as to how mTORC2/AKT-mediated Ca2+participates in the process of T-2 toxin-induced apoptosis. The potential signaling responsible for intracellular Ca2+ concentration changes was investigated using immunoblot assays in an in vitro model of TM3 cell injury induced by T-2 toxin. Changes in Ca2+ were assessed using the Ca2+-sensitive fluorescent indictor dye Fura 2-AM. The cytotoxicity of TM3 cells was assessed with an MTT bioassay, and apoptosis was measured using Annexin V-FITC staining. Following T-2 toxin treatment, the growth of cells, phospho-mTORSer2481, phospho-mTORSer2448, and phospho-AktSer473 were significantly decreased in a time-dependent manner, whereas Ca2+ and apoptosis were increased. T-2 toxin-induced apoptosis was prevented by BAPTA-AM (a Ca2+chelator) and MHY1485 (an mTOR activator), and the application of mTOR activator MHY1485 also prevented the increase of intracellular free Ca2+concentration in TM3 cells. Our results strongly suggest that T-2 toxin exposure induces apoptosis in TM3 cells by inhibiting mTORC2/AKT to promote Ca2+ production.

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The mammalian target of rapamycin (mTOR) kinase mediates haloperidol-induced cataleptic behavior

Translational Psychiatry ◽

10.1038/s41398-020-01014-x ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Uri Nimrod Ramírez-Jarquín ◽

Neelam Shahani ◽

William Pryor ◽

Alessandro Usiello ◽

Srinivasa Subramaniam

Keyword(s):

Side Effects ◽

Mammalian Target Of Rapamycin ◽

Target Of Rapamycin ◽

Typical Antipsychotic ◽

Dependent Manner ◽

Serine Threonine Kinase ◽

Therapeutic Benefits ◽

Dopamine 2 Receptor ◽

Pharmacological Method ◽

Extrapyramidal Motor

Abstract The mammalian target of rapamycin (mTOR) is a ubiquitously expressed serine/threonine kinase protein complex (mTORC1 or mTORC2) that orchestrates diverse functions ranging from embryonic development to aging. However, its brain tissue-specific roles remain less explored. Here, we have identified that the depletion of the mTOR gene in the mice striatum completely prevented the extrapyramidal motor side effects (catalepsy) induced by the dopamine 2 receptor (D2R) antagonist haloperidol, which is the most widely used typical antipsychotic drug. Conversely, a lack of striatal mTOR in mice did not affect catalepsy triggered by the dopamine 1 receptor (D1R) antagonist SCH23390. Along with the lack of cataleptic effects, the administration of haloperidol in mTOR mutants failed to increase striatal phosphorylation levels of ribosomal protein pS6 (S235/236) as seen in control animals. To confirm the observations of the genetic approach, we used a pharmacological method and determined that the mTORC1 inhibitor rapamycin has a profound influence upon post-synaptic D2R-dependent functions. We consistently found that pretreatment with rapamycin entirely prevented (in a time-dependent manner) the haloperidol-induced catalepsy, and pS6K (T389) and pS6 (S235/236) signaling upregulation, in wild-type mice. Collectively, our data indicate that striatal mTORC1 blockade may offer therapeutic benefits with regard to the prevention of D2R-dependent extrapyramidal motor side effects of haloperidol in psychiatric illness.

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Mammalian Target of Rapamycin Complex 2 Controls CD8 T Cell Memory Differentiation in a Foxo1-Dependent Manner

Cell Reports ◽

10.1016/j.celrep.2015.12.095 ◽

2016 ◽

Vol 14 (5) ◽

pp. 1206-1217 ◽

Cited By ~ 63

Author(s):

Lianjun Zhang ◽

Benjamin O. Tschumi ◽

Isabel C. Lopez-Mejia ◽

Susanne G. Oberle ◽

Marten Meyer ◽

...

Keyword(s):

T Cell ◽

Mammalian Target Of Rapamycin ◽

Cd8 T Cell ◽

Target Of Rapamycin ◽

T Cell Memory ◽

Dependent Manner ◽

Cell Memory ◽

Memory Differentiation ◽

Cd8 T Cell Memory

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Interferon α Induces Nucleus-independent Apoptosis by Activating Extracellular Signal-regulated Kinase 1/2 and c-Jun NH2-Terminal Kinase Downstream of Phosphatidylinositol 3-Kinase and Mammalian Target of Rapamycin

Molecular Biology of the Cell ◽

10.1091/mbc.e07-04-0358 ◽

2008 ◽

Vol 19 (1) ◽

pp. 41-50 ◽

Cited By ~ 33

Author(s):

Theocharis Panaretakis ◽

Linn Hjortsberg ◽

Katja Pokrovskaja Tamm ◽

Ann-Charlotte Björklund ◽

Bertrand Joseph ◽

...

Keyword(s):

Apoptotic Cell ◽

Mammalian Target Of Rapamycin ◽

Target Of Rapamycin ◽

Interferon Α ◽

Dependent Manner ◽

Phosphatidylinositol 3 Kinase ◽

Extracellular Signal Regulated Kinase ◽

Extracellular Signal ◽

Induced Apoptosis ◽

Phosphatidylinositol 3

Interferon (IFN)α induces apoptosis via Bak and Bax and the mitochondrial pathway. Here, we investigated the role of known IFNα-induced signaling cascades upstream of Bak activation. By pharmacological and genetic inhibition of the kinases protein kinase C (PKC)δ, extracellular signal-regulated kinase (ERK), and c-Jun NH2-terminal kinase (JNK) in U266-1984 and RHEK-1 cells, we could demonstrate that all three enzymes are critical for the apoptosis-associated mitochondrial events and apoptotic cell death induced by IFNα, at a step downstream of phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR). Furthermore, the activation of JNK was found to occur in a PKCδ/ERK-dependent manner. Inhibition of these kinases did not affect the canonical IFNα-stimulated Janus tyrosine kinase-signal transducer and activator of transcription signaling or expression of IFN-responsive genes. Therefore, enucleated cells (cytoplasts) were examined for IFNα-induced apoptosis, to test directly whether this process depends on gene transcription. Cytoplasts were found to undergo apoptosis after IFNα treatment, as analyzed by several apoptosis markers by using flow cytometry, live cell imaging, and biochemical analysis of flow-sorted cytoplasts. Furthermore, inhibition of mTOR, ERK, and JNK blocked IFNα-induced apoptosis in cytoplasts. In conclusion, IFNα-induced apoptosis requires activation of ERK1/2, PKCδ, and JNK downstream of PI3K and mTOR, and it can occur in a nucleus-independent manner, thus demonstrating for the first time that IFNα induces apoptosis in the absence of de novo transcription.

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Resistance Exercise Increases Muscle Protein Synthesis and Translation of Eukaryotic Initiation Factor 2Bϵ mRNA in a Mammalian Target of Rapamycin-dependent Manner

Journal of Biological Chemistry ◽

10.1074/jbc.m413732200 ◽

2004 ◽

Vol 280 (9) ◽

pp. 7570-7580 ◽

Cited By ~ 150

Author(s):

Neil Kubica ◽

Douglas R. Bolster ◽

Peter A. Farrell ◽

Scot R. Kimball ◽

Leonard S. Jefferson

Keyword(s):

Protein Synthesis ◽

Resistance Exercise ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Mammalian Target Of Rapamycin ◽

Initiation Factor ◽

Target Of Rapamycin ◽

Dependent Manner ◽

Eukaryotic Initiation Factor

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The Mammalian Target of Rapamycin (mTOR) Kinase Mediates Haloperidol-Induced Cataleptic Behavior

10.1101/2020.06.18.160416 ◽

2020 ◽

Author(s):

Uri Nimrod Ramírez-Jarquín ◽

Neelam Shahani ◽

William Pryor ◽

Alessandro Usiello ◽

Srinivasa Subramaniam

Keyword(s):

Side Effects ◽

Mammalian Target Of Rapamycin ◽

Target Of Rapamycin ◽

Typical Antipsychotic ◽

Dependent Manner ◽

Serine Threonine Kinase ◽

Therapeutic Benefits ◽

Dopamine 2 Receptor ◽

Pharmacological Method ◽

Extrapyramidal Motor

ABSTRACTThe mammalian target of rapamycin (mTOR) is a ubiquitously expressed serine/threonine kinase protein complex (mTORC1 or mTORC2) that orchestrates diverse functions ranging from embryonic development to aging. However, its brain tissue-specific roles remain less explored. Here, we have identified that the depletion of the mTOR gene in the mice striatum completely prevented the extrapyramidal motor side-effects (catalepsy) induced by the dopamine 2 receptor (D2R) antagonist haloperidol, which is the most widely used typical antipsychotic drug. Conversely, a lack of striatal mTOR in mice did not affect catalepsy triggered by the dopamine 1 receptor (D1R) antagonist SCH23390. Along with the lack of cataleptic effects, the administration of haloperidol in mTOR mutants failed to increase striatal phosphorylation levels of ribosomal protein pS6 (S235/236) as seen in control animals. To confirm the observations of the genetic approach, we used a pharmacological method and determined that the mTORC1 inhibitor rapamycin has a profound influence upon post-synaptic D2R-dependent functions. We consistently found that pretreatment with rapamycin entirely prevented (in a time-dependent manner) the haloperidol-induced catalepsy in wild-type mice. Collectively, our data indicate that striatal mTORC1 blockade may offer therapeutic benefits with regard to the prevention of D2R-dependent extrapyramidal motor side-effects of haloperidol in psychiatric illness.

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(R,S)-Ketamine Metabolites (R,S)-norketamine and (2S,6S)-hydroxynorketamine Increase the Mammalian Target of Rapamycin Function

Anesthesiology ◽

10.1097/aln.0000000000000285 ◽

2014 ◽

Vol 121 (1) ◽

pp. 149-159 ◽

Cited By ~ 76

Author(s):

Rajib K. Paul ◽

Nagendra S. Singh ◽

Mohammed Khadeer ◽

Ruin Moaddel ◽

Mitesh Sanghvi ◽

...

Keyword(s):

Parent Compound ◽

Mammalian Target Of Rapamycin ◽

Mtor Pathway ◽

Target Of Rapamycin ◽

Dependent Manner ◽

Α7 Nicotinic Acetylcholine Receptor ◽

Concentration Dependent Manner ◽

Pheochromocytoma Cells ◽

The Impact

Abstract Background: Subanesthetic doses of (R,S)-ketamine are used in the treatment of neuropathic pain and depression. In the rat, the antidepressant effects of (R,S)-ketamine are associated with increased activity and function of mammalian target of rapamycin (mTOR); however, (R,S)-ketamine is extensively metabolized and the contribution of its metabolites to increased mTOR signaling is unknown. Methods: Rats (n = 3 per time point) were given (R,S)-ketamine, (R,S)-norketamine, and (2S,6S)-hydroxynorketamine and their effect on the mTOR pathway determined after 20, 30, and 60 min. PC-12 pheochromocytoma cells (n = 3 per experiment) were treated with escalating concentrations of each compound and the impact on the mTOR pathway was determined. Results: The phosphorylation of mTOR and its downstream targets was significantly increased in rat prefrontal cortex tissue by more than ~2.5-, ~25-, and ~2-fold, respectively, in response to a 60-min postadministration of (R,S)-ketamine, (R,S)-norketamine, and (2S,6S)-hydroxynorketamine (P < 0.05, ANOVA analysis). In PC-12 pheochromocytoma cells, the test compounds activated the mTOR pathway in a concentration-dependent manner, which resulted in a significantly higher expression of serine racemase with ~2-fold increases at 0.05 nM (2S,6S)-hydroxynorketamine, 10 nM (R,S)-norketamine, and 1,000 nM (R,S)-ketamine. The potency of the effect reflected antagonistic activity of the test compounds at the α7-nicotinic acetylcholine receptor. Conclusions: The data demonstrate that (R,S)-norketamine and (2S,6S)-hydroxynorketamine have potent pharmacological activity both in vitro and in vivo and contribute to the molecular effects produced by subanesthetic doses of (R,S)-ketamine. The results suggest that the determination of the mechanisms underlying the antidepressant and analgesic effects of (R,S)-ketamine requires a full study of the parent compound and its metabolites.

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Prolactin activates mammalian target-of-rapamycin through phosphatidylinositol 3-kinase and stimulates phosphorylation of p70S6K and 4E-binding protein-1 in lymphoma cells

Journal of Endocrinology ◽

10.1677/joe.1.06368 ◽

2006 ◽

Vol 190 (2) ◽

pp. 307-312 ◽

Cited By ~ 24

Author(s):

Jessica D Bishop ◽

Wei Lun Nien ◽

Shauna M Dauphinee ◽

Catherine K L Too

Keyword(s):

Binding Protein ◽

Mammalian Target Of Rapamycin ◽

Mtor Pathway ◽

Target Of Rapamycin ◽

Dependent Manner ◽

Phosphatidylinositol 3 Kinase ◽

Lymphoma Cells ◽

Nb2 Cells ◽

Initiation Of Translation ◽

Phosphatidylinositol 3

Mitogens activate the mammalian target-of-rapamycin (mTOR) pathway through phosphatidylinositol 3-kinase (PI3K). The activated mTOR kinase phosphorylates/ activates ribosomal protein S6 kinase (p70S6K) and phosphorylates/inactivates eukaryotic initiation factor 4E-binding protein-1 (4E-BP1), resulting in the initiation of translation and cell-cycle progression. The prolactin receptor signaling cascade has been implicated in crosstalk with the mTOR pathway, but whether prolactin (PRL) directly activates mTOR is not known. This study showed that PRL stimulated the phosphorylation of mTOR, p70S6K, Akt, and Jak2 kinases in a dose- and time-dependent manner in PRL-dependent rat Nb2 lymphoma cells. PRL-stimulated phosphorylation of mTOR was detected as early as 10 min, closely following the phosphorylation of Akt (upstream of mTOR), but preceding that of the downstream p70S6K. PRL activation of mTOR was inhibited by rapamycin (mTOR inhibitor), LY249002, and wortmannin (P13K inhibitors), but not by AG490 (Jak2 inhibitor), indicating that it was mediated by the P13K/Akt, but not Jak2, pathway. PRL also stimulated phosphorylation of 4E-BP1 in Nb2 cells. PRL-induced phosphorylation of p70S6K and 4E-BP1 was inhibited by rapamycin, but not by okadaic acid (inhibitor of protein phosphatase, PP2A). PRL induced a transient interaction between p70S6K and the catalytic subunit of PP2A (PP2Ac) in 1 and 2 h, whereas a PP2Ac–4E-BP1 complex was constitutively present in quiescent and PRL-treated Nb2 cells. These results suggested that p70S6K and 4E-BP1 were substrates of PP2A and the inhibition of mTOR promoted their dephosphorylation by PP2A. In summary, PRL-stimulated phosphorylation of mTOR is mediated by PI3K. PRL-activated mTOR may phosphorylate p70S6K and 4E-BP1 by restraining PP2A.

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