When translation meets transformation: the mTOR story

Avérous, Julien; Proud, Christopher G.

doi:10.1038/sj.onc.1209887

Cited by 176 publications

(155 citation statements)

References 128 publications

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“…EGFR is suggested to activate Akt, PI3K and mTOR, which have important roles in protein synthesis and metabolism, ribosome biogenesis, transcription, cell proliferation and migration. 22,35,36 Akt, PI3K and mTOR are also associated with both oncogenesis and neurodegenerative diseases. 26 Our data show that Akt, PI3K and mTOR are involved in TNT development, suggesting that TNT development may have an important role in preventing cancer formation and neurodegeneration.…”

Section: Discussionmentioning

confidence: 99%

Tunneling-nanotube development in astrocytes depends on p53 activation

et al. 2010

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Tunneling nanotubes (TNTs) can be induced in rat hippocampal astrocytes and neurons with H 2 O 2 or serum depletion. Major cytoskeletal component of TNTs is F-actin. TNTs transfer endoplasmic reticulum, mitochondria, Golgi, endosome and intracellular as well as extracellular amyloid b. TNT development is a property of cells under stress. When two populations of cells are co-cultured, it is the stressed cells that always develop TNTs toward the unstressed cells. p53 is crucial for TNT development. When p53 function is deleted by either dominant negative construct or siRNAs, TNT development is inhibited. In addition, we find that among the genes activated by p53, epidermal growth factor receptor is also important to TNT development. Akt, phosphoinositide 3-kinase and mTOR are involved in TNT induction. Our data suggest that TNTs might be a mechanism for cells to respond to harmful signals and transfer cellular substances or energy to another cell under stress.

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Section: Discussionmentioning

confidence: 99%

Tunneling-nanotube development in astrocytes depends on p53 activation

et al. 2010

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“…Nonetheless, rapamycin strongly affects cell proliferation, cell growth and angiogenesis (Averous and Proud, 2006;Easton and Houghton, 2006;Mamane et al, 2006;Sabatini, 2006). One possible explanation is that mTORC1 only strongly regulates the translation of certain mRNAs.…”

Section: Introductionmentioning

confidence: 99%

Regulation of cyclin D1 expression by mTORC1 signaling requires eukaryotic initiation factor 4E-binding protein 1

2007

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There is currently substantial interest in the regulation of cell function by mammalian target of rapamycin (mTOR), especially effects linked to the rapamycin-sensitive mTOR complex 1 (mTORC1). Rapamycin induces G 1 arrest and blocks proliferation of many tumor cells, suggesting that the inhibition of mTORC1 signaling may be useful in cancer therapy. In MCF7 breast adenocarcinoma cells, rapamycin decreases levels of cyclin D1, without affecting cytoplasmic levels of its mRNA. In some cell-types, rapamycin does not affect cyclin D1 levels, whereas the starvation for leucine (which impairs mTORC1 signaling more profoundly than rapamycin) does. This pattern correlates with the behavior of eukaryotic initiation factor 4E-binding protein 1 (4E-BP1, an mTORC1 target that regulates translation initiation). siRNA-mediated knockdown of 4E-BP1 abrogates the effect of rapamycin on cyclin D1 expression and increases the polysomal association of the cyclin D1 mRNA. Our data identify 4E-BP1 as a key regulator of cyclin D1 expression, indicate that this effect is not mediated through the changes in cytoplasmic levels of cyclin D1 mRNA and suggest that, in some cell types, interfering with the amino acid input to mTORC1, rather than using rapamycin, may inhibit proliferation.

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“…The latter is also regulated by molecular players of the mTOR pathway (Averous and Proud, 2006;Mamane et al, 2006). In this respect, protein translation is a major example of collaboration between the MEK/ERK and the mTOR pathway, in which the cell synthesizes sufficient proteins for division.…”

Section: Phosphorylation and Degradation Of Dusp6 By The Mtor Pathwaymentioning

confidence: 99%

Post-translational regulation of the ERK phosphatase DUSP6/MKP3 by the mTOR pathway

et al. 2008

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MAP kinases phosphatases (MKPs) belong to the dualspecificity phosphatase family (DUSP) and dephosphorylate phosphothreonine and phosphotyrosine within MAP kinases. We had previously shown that DUSP6/MKP-3 was phosphorylated and degraded upon growth factor stimulation, in a MEK-dependent manner. Here we show that another pathway involved in growth factor signaling, the PI3K/mTOR signaling pathway, accounts for a part of the phosphorylation and degradation of DUSP6 induced by serum growth factors, as evidenced by experiments using pharmacological inhibitors of PI3 kinase and mammalian target of rapamycin (mTOR). Moreover, specific agonists of the mTOR pathway, such as amino acids or insulin/IGF-1, which do not activate extracellular signal regulated kinases (ERKs) in our cellular model, were also able to induce the phosphorylation and degradation of DUSP6. However, a basal activity of MEK was required for the mTOR pathwaymediated phosphorylation to occur. Mutagenesis studies identified serine 159 within DUSP6 as the target of the mTOR pathway. The ERK phosphatase DUSP6 may thus constitute a novel branch-point of the crosstalk between two major signaling pathways induced by growth factors, the MEK/ERK pathway and the PI3K/mTOR pathway.

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When translation meets transformation: the mTOR story

Cited by 176 publications

References 128 publications

Tunneling-nanotube development in astrocytes depends on p53 activation

Tunneling-nanotube development in astrocytes depends on p53 activation

Regulation of cyclin D1 expression by mTORC1 signaling requires eukaryotic initiation factor 4E-binding protein 1

Post-translational regulation of the ERK phosphatase DUSP6/MKP3 by the mTOR pathway

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