Choo, A. Y. & Blenis, J. Not all substrates are treated equally: implications for mTOR, rapamycin-resistance and cancer therapy. Cell Cycle 8, 567-572

Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Cell cycle (Georgetown, Tex.) (Impact Factor: 4.57). 03/2009; 8(4):567-72. DOI: 10.4161/cc.8.4.7659
Source: PubMed


The mTORC1 signaling pathway is a critical regulator of cell growth and is hyper activated in many different cancers. Rapamycin, an allosteric inhibitor of mTORC1, has been approved for treatment against renal cell carcinomas and is being evaluated for other cancers. Mechanistically, mTORC1 controls cell growth in part through its two well-characterized substrates S6K1 and 4E-BP1. In this review, we discuss the implications of a recent finding that showed differential inhibition of S6K1 and 4E-BP1 by rapamycin, leading to cell-type-specific repression of cap-dependent translation. We discuss potential mechanisms for this effect, and propose that mTOR-specific kinase inhibitors, instead of rapamycin, should be considered for mTOR-targeted cancer therapy.

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Available from: John Blenis, Mar 19, 2014
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    • "New protein synthesis was required for cell death following exposure to everolimus, consistent with the activation of programmed cell death. This finding was perhaps surprising considering that inhibition of mTOR strongly suppresses CAP-dependent translation [41]. However CAP-independent (IRES-mediated) translation is activated in stressed cells and the proteins produced can modulate cell death [42]. "
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    ABSTRACT: Increasingly, anti-cancer medications are being reported to induce cell death mechanisms other than apoptosis. Activating alternate death mechanisms introduces the potential to kill cells that have defects in their apoptotic machinery, as is commonly observed in cancer cells, including in hematological malignancies. We, and others, have previously reported that the mTOR inhibitor everolimus has pre-clinical efficacy and induces caspase-independent cell death in acute lymphoblastic leukemia cells. Furthermore, everolimus is currently in clinical trial for acute lymphoblastic leukemia. Here we characterize the death mechanism activated by everolimus in acute lymphoblastic leukemia cells. We find that cell death is caspase-independent and lacks the morphology associated with apoptosis. Although mitochondrial depolarization is an early event, permeabilization of the outer mitochondrial membrane only occurs after cell death has occurred. While morphological and biochemical evidence shows that autophagy is clearly present it is not responsible for the observed cell death. There are a number of features consistent with paraptosis including morphology, caspase-independence, and the requirement for new protein synthesis. However in contrast to some reports of paraptosis, the activation of JNK signaling was not required for everolimus-induced cell death. Overall in acute lymphoblastic leukemia cells everolimus induces a cell death that resembles paraptosis.
    Full-text · Article · Jul 2014 · PLoS ONE
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    • "The work predicts that FKBP12-rapamycin complex bound FRB domain may come close to mLST8 thus reducing the access of the substrates to active site of mTOR. These structural properties of mTOR may contribute to the preferences of substrates and/or phosphorylation sites by rapamycin inhibition (Choo and Blenis, 2009; Kang et al., 2013). In case of mTORC2, its components may already be bound proximately to FRB domain thus inhibits FRB. "
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    ABSTRACT: Target of rapamycin (TOR) was first identified in yeast as a target molecule of rapamycin, an anti-fugal and immunosuppressant macrolide compound. In mammals, its orthologue is called mammalian TOR (mTOR). mTOR is a serine/threonine kinase that converges different extracellular stimuli, such as nutrients and growth factors, and diverges into several biochemical reactions, including translation, autophagy, transcription, and lipid synthesis among others. These biochemical reactions govern cell growth and cause cells to attain an anabolic state. Thus, the disruption of mTOR signaling is implicated in a wide array of diseases such as cancer, diabetes, and obesity. In the central nervous system, the mTOR signaling cascade is activated by nutrients, neurotrophic factors, and neurotransmitters that enhances protein (and possibly lipid) synthesis and suppresses autophagy. These processes contribute to normal neuronal growth by promoting their differentiation, neurite elongation and branching, and synaptic formation during development. Therefore, disruption of mTOR signaling may cause neuronal degeneration and abnormal neural development. While reduced mTOR signaling is associated with neurodegeneration, excess activation of mTOR signaling causes abnormal development of neurons and glia, leading to brain malformation. In this review, we first introduce the current state of molecular knowledge of mTOR complexes and signaling in general. We then describe mTOR activation in neurons, which leads to translational enhancement, and finally discuss the link between mTOR and normal/abnormal neuronal growth during development.
    Full-text · Article · Apr 2014 · Frontiers in Molecular Neuroscience
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    • "In the present study, we intended to inhibit 4E-BP1 phosphorylation during maturation of bovine oocytes, and we revealed its effects on meiotic progression. Rapamycin, however, was reported to block 4E-BP1 phosphorylation inefficiently (Choo and Blenis, 2009; Dowling et al., 2010; Livingstone and Bidinosti, 2012). Thus, we have used a member of a new class of mTor inhibitors, the so-called active-site inhibitor Torin2, for the first time in oocytes. "
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    ABSTRACT: The mammalian target of rapamycin (mTor), a Ser/Thr protein kinase, is implicated in the phosphorylation-triggered inactivation of translation repressors, the so called eukaryotic initiation factor 4E (eIF4E)-binding proteins (4E-BPs). Previous observations in porcine and bovine oocytes revealed an increasing phosphorylation of 4E-BP1 during meiotic maturation. The factor is hypophosphorylated in the germinal vesicle (GV) stage and highest phosphorylated in the metaphase II (M II). In the present approach we intended to block 4E-BP1 phosphorylation specifically to impair initiation of translation and elucidate effects on resumption of meiosis. Torin2, which acts as an active-site mTor inhibitor, reduces 4E-BP1 phosphorylation without any effect on eIF4E and arrests up to 60% of the oocytes in the M I stage. Effects of Torin2 treatment, analyzed by site-specific substrate phosphorylation, were also observed at protein kinase B (Akt, PKB) and cyclin dependent kinases (CDKs). However, if at all, only minor side effects were found at protein kinase A, C (PKA, PKC), ATM/ATR (Ataxia telangiectasia mutated/AT and Rad3-related protein) and the mitogen activated protein kinases (MAPK) ERK1, 2. The inhibition of 4E-BP1 phosphorylation by Torin2 is reversible when cultivating oocytes for additional 24 h in Torin2-free medium. However, even so, oocytes persist in the M I stage. This may indicate the necessity of spatiotemporally regulated translation during meiosis, which cannot be restored later. In conclusion, Torin2 enables an effective and specific inhibition of 4E-BP1 phosphorylation and such an approach may be valuable to investigate maturation specific protein synthesis in more detail. Mol. Reprod. Dev. © 2014 Wiley Periodicals, Inc.
    Full-text · Article · Apr 2014 · Molecular Reproduction and Development
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