mTOR, translation initiation and cancer

Mamane, Yaël; Petroulakis, Emmanuel; Bacquer, Olivier Le; Sonenberg, Nahum

doi:10.1038/sj.onc.1209888

Cited by 557 publications

(531 citation statements)

References 81 publications

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“…Furthermore, many cancers have been shown either clinically or experimentally to be responsive to mTOR inhibitors (summarized in Mamane et al 2006). Increased mTOR activity disrupts proper control of translation by inactivation of 4E-BP.…”

Section: How Is Translational Control Altered In Cancer?mentioning

confidence: 99%

Post-transcriptional regulation in cancer progression

Jewer

Findlay

Postovit

2012

J. Cell Commun. Signal.

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The microenvironment acts as a conduit for cellular communication, delivering signals that direct development and sustain tissue homeostasis. In pathologies such as cancer, this integral function of the microenvironment is hijacked to support tumor growth and progression. Cells sense the microenvironment via signal transduction pathways culminating in altered gene expression. In addition to induced transcriptional changes, the microenvironment exerts its effect on the cell through regulation of posttranscriptional processes including alternative splicing and translational control. Here we describe how alternative splicing and protein translation are controlled by microenvironmental parameters such as oxygen availability. We also emphasize how these pathways can be utilized to support processes that are hallmarks of cancer such as angiogenesis, proliferation, and cell migration. We stress that cancer cells respond to their microenvironment through an integrated regulation of gene expression at multiple levels that collectively contribute to disease progression.

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Section: How Is Translational Control Altered In Cancer?mentioning

confidence: 99%

Post-transcriptional regulation in cancer progression

Jewer

Findlay

Postovit

2012

J. Cell Commun. Signal.

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“…The role of mTORC1 in the control of cap-dependent translation has been extensively studied [29][30][31] . When mTORC1 is active, it phosphorylates (activates) p70S6 kinase (S6K) and the eIF4e binding protein (4E-BP) (FIG.…”

Section: Mtor Kinase Complexes and Their Activitiesmentioning

confidence: 99%

The TORrid affairs of viruses: effects of mammalian DNA viruses on the PI3K–Akt–mTOR signalling pathway

et al. 2008

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The successful replication of mammalian DNA viruses requires that they gain control of key cellular signalling pathways that affect broad aspects of cellular macromolecular synthesis, metabolism, growth and survival. The phosphatidylinositol 3′-kinase-Akt-mammalian target of rapamycin (PI3K-Akt-mTOR) pathway is one such pathway. Mammalian DNA viruses have evolved various mechanisms to activate this pathway to obtain the benefits of Akt activation, including the maintenance of translation through the activation of mTOR. In addition, viruses must overcome the inhibition of this pathway that results from the activation of cellular stress responses during viral infection. This Review will discuss the range of mechanisms that mammalian DNA viruses use to activate this pathway, as well as the multiple mechanisms these viruses have evolved to circumvent inhibitory stress signalling.The successful replication of mammalian DNA viruses, such as polyomaviruses (also called papovaviruses), adenoviruses, herpesviruses and poxviruses, requires viral adaptation of the host cell to establish an environment that can accommodate the increased demands for nutrients, energy and macromolecular synthesis that accompany viral infection. All DNA viruses must gain control of key cellular signalling pathways that affect broad aspects of cellular macromolecular synthesis, metabolism, growth and survival. The phosphatidylinositol 3′-kinase-Akt-mammalian target of rapamycin (PI3K-Akt-mTOR) pathway is one such pathway. Virtually all mammalian viruses, both DNA and RNA, must regulate this pathway, either by activating or inactivating some aspect of it 1 . In general, mammalian DNA viruses activate this pathway at some point in their life cycle to benefit from the growth, metabolic, anti-apoptotic and translational functions that the pathway controls. However, a viral mechanism for activating this pathway is not enough; to maintain control, viruses must also overcome the many controls that are used to inhibit this pathway when cellular stress responses are activated during viral infection.Correspondence to J.C.A., e-mail: alwine@mail.med.upenn.edu. * These authors contributed equally to this work. DATABASES NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptThe substantial alterations in cellular physiology that are induced by a viral lytic infectionas a result of nutrient depletion, energy depletion, hypoxia and endoplasmic reticulum stress -activate cellular stress responses that alert the cell to problems with metabolic and synthetic processes. The resulting stress signalling activates mechanisms that either alleviate the problems or, if this is not possible, induce apoptosis. Stress signalling has many effects that can be either beneficial or detrimental to viral growth. One example of a detrimental effect is inhibition of translation, which is among the most common consequences of cellular stress responses 2-6 . Although the inhibition of this energy-intensive process permits the cell to recover from stress,...

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“…The heightened interest in signaling through mammalian target of rapamycin (mTOR) reflects its role in many cellular functions and in human diseases including cancer (Easton and Houghton, 2006;Mamane et al, 2006;Sabatini 2006). This protein kinase occurs as two types of complex, that is, mTORC1 and mTORC2 (Wullschleger et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, eIF4E is expressed at high levels in many tumors (De Benedetti and Graff, 2004). Since enhanced expression of eIF4E increases eIF4F levels, eIF4E may transform cells by promoting the translation of specific mRNAs, for example, VEGF, cyclin D1 and cmyc (Mamane et al, 2006). This mechanism may explain the effect of mTOR inhibition on cell proliferation/ transformation, since blocking mTOR signaling should decrease eIF4F levels.…”

Section: Introductionmentioning

confidence: 99%

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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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mTOR, translation initiation and cancer

Cited by 557 publications

References 81 publications

Post-transcriptional regulation in cancer progression

Post-transcriptional regulation in cancer progression

The TORrid affairs of viruses: effects of mammalian DNA viruses on the PI3K–Akt–mTOR signalling pathway

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

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