Identification of mammalian target of rapamycin as a direct target of fenretinide both in vitro and in vivo

In mammals, feeding promotes protein accretion in skeletal muscle through a stimulation of the insulin- and amino acid- sensitive mammalian target of rapamycin (mTOR) signaling pathway, leading to the induction of mRNA translation. The purpose of the present study was to characterize both in vivo and in vitro the activation of several major kinases involved in the mTOR pathway in the muscle of the carnivorous rainbow trout. Our results showed that meal feeding enhanced the phosphorylation of the target of rapamycin (TOR), PKB, p70 S6 kinase, and eIF4E-binding protein-1, suggesting that the mechanisms involved in the regulation of mRNA translation are well conserved between lower and higher vertebrates. Our in vitro studies on primary culture of trout muscle cells indicate that insulin and amino acids regulate TOR signaling and thus may be involved in meal feeding effect in this species as in mammals. In conclusion, we report here for the first time in a fish species, the existence and the nutritional regulation of several major kinases involved in the TOR pathway, opening a new area of research on the molecular bases of amino acid utilization in teleosts.

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Effects of the Mammalian Target of Rapamycin Inhibitor Everolimus on Hepatitis C Virus Replication In Vitro and In Vivo

Transplantation Proceedings ◽

10.1016/j.transproceed.2017.04.012 ◽

2017 ◽

Vol 49 (8) ◽

pp. 1947-1955 ◽

Cited By ~ 3

Author(s):

A. Frey ◽

E.-M. Ecker ◽

K. Piras-Straub ◽

A. Walker ◽

T.G. Hofmann ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Virus Replication ◽

Mammalian Target Of Rapamycin ◽

Target Of Rapamycin

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Mammalian target of rapamycin is a direct target for protein kinase B: identification of a convergence point for opposing effects of insulin and amino-acid deficiency on protein translation

Biochemical Journal ◽

10.1042/bj3440427 ◽

1999 ◽

Vol 344 (2) ◽

pp. 427-431 ◽

Cited By ~ 419

Author(s):

Barbara T. NAVÉ ◽

D. Margriet OUWENS ◽

Dominic J. WITHERS ◽

Dario R. ALESSI ◽

Peter R. SHEPHERD

Keyword(s):

Amino Acid ◽

Protein Kinase ◽

Protein Kinase B ◽

Mammalian Target Of Rapamycin ◽

Protein Translation ◽

Target Of Rapamycin ◽

Direct Target ◽

Regulatory Effects ◽

Stimulation Of

Growth factor induced activation of phosphoinositide 3-kinase and protein kinase B (PKB) leads to increased activity of the mammalian target of rapamycin (mTOR). This subsequently leads to increased phosphorylation of eIF4E binding protein-1 (4EBP1) and activation of p70 ribosomal S6 protein kinase (p70S6K), both of which are important steps in the stimulation of protein translation. The stimulation of translation is attenuated in cells deprived of amino acids and this is associated with the attenuation of 4EBP1 phosphorylation and p70S6K activation. It has been suggested that PKB regulates mTOR function by phosphorylation although direct phosphorylation of mTOR by PKB has not been demonstrated previously. In the present work, we have found that PKB directly phosphorylates mTOR and, using phosphospecific antibodies, we have shown this phosphorylation occurs at Ser2448. Insulin also induces phosphorylation on Ser2448 and this effect is blocked by wortmannin but not rapamycin, consistent with the effect being mediated by PKB. Amino-acid starvation rapidly attenuated the reactivity of the Ser2448 phosphospecific antibody with mTOR and this could not be restored by either insulin stimulation of cells or incubation with PKB in vitro. Our findings demonstrate that mTOR is a direct target for PKB and support the conclusion that regulation of phosphorylation of Ser2448 is a point of convergence for the counteracting regulatory effects of growth factors and amino acid levels.

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Mammalian target of rapamycin regulates miRNA-1 and follistatin in skeletal myogenesis

The Journal of Cell Biology ◽

10.1083/jcb.200912093 ◽

2010 ◽

Vol 189 (7) ◽

pp. 1157-1169 ◽

Cited By ~ 116

Author(s):

Yuting Sun ◽

Yejing Ge ◽

Jenny Drnevich ◽

Yong Zhao ◽

Mark Band ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Development ◽

Mammalian Target Of Rapamycin ◽

Micro Rna ◽

Skeletal Muscle Regeneration ◽

Target Of Rapamycin ◽

Myoblast Differentiation ◽

Mirna Biogenesis

Mammalian target of rapamycin (mTOR) has emerged as a key regulator of skeletal muscle development by governing distinct stages of myogenesis, but the molecular pathways downstream of mTOR are not fully understood. In this study, we report that expression of the muscle-specific micro-RNA (miRNA) miR-1 is regulated by mTOR both in differentiating myoblasts and in mouse regenerating skeletal muscle. We have found that mTOR controls MyoD-dependent transcription of miR-1 through its upstream enhancer, most likely by regulating MyoD protein stability. Moreover, a functional pathway downstream of mTOR and miR-1 is delineated, in which miR-1 suppression of histone deacetylase 4 (HDAC4) results in production of follistatin and subsequent myocyte fusion. Collective evidence strongly suggests that follistatin is the long-sought mTOR-regulated fusion factor. In summary, our findings unravel for the first time a link between mTOR and miRNA biogenesis and identify an mTOR–miR-1–HDAC4–follistatin pathway that regulates myocyte fusion during myoblast differentiation in vitro and skeletal muscle regeneration in vivo.

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Mammalian target of rapamycin (mTOR) pathway signalling in lymphomas

Expert Reviews in Molecular Medicine ◽

10.1017/s1462399408000586 ◽

2008 ◽

Vol 10 ◽

Cited By ~ 24

Author(s):

Elias Drakos ◽

George Z. Rassidakis ◽

L. Jeffrey Medeiros

Keyword(s):

Mammalian Target Of Rapamycin ◽

Central Element ◽

Mtor Inhibitors ◽

Chemotherapeutic Agents ◽

Mtor Pathway ◽

Target Of Rapamycin ◽

In Vivo Studies ◽

Mtor Inhibition

AbstractThe mammalian target of rapamycin mTOR is a central element in an evolutionary conserved signalling pathway that regulates cell growth, survival and proliferation, orchestrating signals originating from growth factors, nutrients or particular stress stimuli. Two important modulators of mTOR activity are the AKT and ERK/MAPK signalling pathways. Many studies have shown that mTOR plays an important role in the biology of malignant cells, including deregulation of the cell cycle, inactivation of apoptotic machinery and resistance to chemotherapeutic agents. The development of several mTOR inhibitors, in addition to rapamycin, has facilitated studies of the role of mTOR in cancer, and verified the antitumour effect of mTOR inhibition in many types of neoplasms, including lymphomas. Clinical trials of rapamycin derivatives in lymphoma patients are already in development and there are encouraging preliminary results, such as the substantial response of a subset of mantle cell lymphoma patients to the rapamycin analogue temsirolimus. Based on results obtained from in vitro and in vivo studies of the mTOR pathway in lymphomas, it seems that better understanding of mTOR regulation will reveal aspects of lymphomagenesis and contribute to the development of more powerful, targeted therapies for lymphoma patients.

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AZD8055 Is a Potent, Selective, and Orally Bioavailable ATP-Competitive Mammalian Target of Rapamycin Kinase Inhibitor with In vitro and In vivo Antitumor Activity

Cancer Research ◽

10.1158/0008-5472.can-09-1751 ◽

2009 ◽

Vol 70 (1) ◽

pp. 288-298 ◽

Cited By ~ 513

Author(s):

Christine M. Chresta ◽

Barry R. Davies ◽

Ian Hickson ◽

Tom Harding ◽

Sabina Cosulich ◽

...

Keyword(s):

Antitumor Activity ◽

Kinase Inhibitor ◽

Mammalian Target Of Rapamycin ◽

Target Of Rapamycin ◽

In Vivo Antitumor Activity ◽

Orally Bioavailable

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Baicalin Induces Apoptotic Death of Human Chondrosarcoma Cells through Mitochondrial Dysfunction and Downregulation of the PI3K/Akt/mTOR Pathway

Planta Medica ◽

10.1055/a-0791-1049 ◽

2018 ◽

Vol 85 (05) ◽

pp. 360-369 ◽

Cited By ~ 4

Author(s):

Minyu Zhu ◽

Jinwei Ying ◽

Chaowei Lin ◽

Yu Wang ◽

Kelun Huang ◽

...

Keyword(s):

Protein Kinase ◽

Protein Kinase B ◽

Tumour Size ◽

Mammalian Target Of Rapamycin ◽

Target Of Rapamycin ◽

Human Chondrosarcoma ◽

Apoptotic Death ◽

Phosphoinositide 3 Kinase

AbstractThe aim of the present study was to investigate the cytotoxic and antitumour effects of baicalin in human chondrosarcoma both in vivo and in vitro. We examined the effects of baicalin on the growth and apoptosis of human chondrosarcoma cells. Baicalin inhibited the growth of SW1353 and CH2879 cells in a dose- and time-dependent manner, but did not inhibit the growth of normal chondrocytes. Baicalin reduced tumour growth and induced apoptotic death in SW1353-transplanted nude mice without reducing their body weight. Further studies showed that baicalin reduced the mitochondrial membrane potential, upregulated the expression of Bax and cytoplasmic cytochrome c, downregulated the expression of Bcl-2 and mitochondrial cytochromes, and activated caspase-3 and caspase-9. Baicalin inhibited the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin pathway by decreasing the expression of phosphorylated phosphoinositide 3-kinase, phosphorylated protein kinase B, and phosphorylated mammalian target of rapamycin both in vivo and in vitro. Moreover, the mice that received SC79 and baicalin exhibited a greater tumour size compared with the mice that received baicalin. The mice that received LY294002 and baicalin showed a smaller tumour size compared with the mice that received baicalin. In the in vitro study, SC79 and LY294002 affected the baicalin-induced cytotoxic effects on chondrosarcoma cells in the same manner. Our data suggest baicalin has therapeutic efficacy in human chondrosarcoma through the induction of apoptosis and inhibition of the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin pathway. Baicalin can be considered a potential therapeutic agent for treating chondrosarcomas.

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