Inhibition of Myc-dependent apoptosis by eukaryotic translation initiation factor 4E requires cyclin D1

Tan, Annie; Bitterman, Peter B.; Sonenberg, Nahum; Peterson, Mark S.; Polunovsky, Vitaly A.

doi:10.1038/sj.onc.1203446

Cited by 101 publications

(87 citation statements)

References 73 publications

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“…As might be expected, eIF4E rescue appears to be pleotropic; mediated by increasing the nuclear-cytoplasmic transport and ribosomal recruitment of numerous transcripts. For example, cells are rescued from oncogene-dependent apoptosis by interdiction of the apoptotic program at the mitochondrial checkpoint by cyclin D1 64 and Bcl-X L . 65 The relative importance of each transcript or repertoire of transcripts encoding candidate downstream effectors and the rules describing their integration into a biological response remains an active area of investigation.…”

Section: Translational Control Of Malignant Conversionmentioning

confidence: 99%

“…However, disrupting mTOR-mediated signaling with rapamycin does not restore apoptosis sensitivity to cancer cells harboring aberrantly activated eIF4F or suppress their tumorigenesis. 57,62,64 Direct approaches. Normalizing eIF4F function might be accomplished by disrupting association of monomeric components of the eIF4F heterotrimer or by antagonizing the interaction of the cap binding component of eIF4F, eIF4E, with the 7-methyl guanosine cap at the 5' end of the transcript.…”

Section: Approaches To Normalizing Deregulated Eif4f-mediated Translamentioning

confidence: 99%

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The Cap-Dependent Translation Apparatus Integrates and Amplifies Cancer Pathways

Polunovsky¹,

Bitterman²

2006

RNA Biology

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Section: Translational Control Of Malignant Conversionmentioning

confidence: 99%

Section: Approaches To Normalizing Deregulated Eif4f-mediated Translamentioning

confidence: 99%

The Cap-Dependent Translation Apparatus Integrates and Amplifies Cancer Pathways

Polunovsky¹,

Bitterman²

2006

RNA Biology

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“…The downstream effector proteins linking the cap-dependent translation initiation apparatus to the apoptotic machinery and the precise mechanisms regulating the translation of their cognate mRNAs are unknown. Prior studies have identified several candidate mRNAs encoding proteins subject to strong cap-dependent translational control that positively and negatively regulate cell viability including p53, Mdm-2, Fas/Apo-1, members of the Bcl-2 family, and cyclin D1 (33)(34)(35). Among these, we have recently shown that translational activation of cyclin D1 by eIF4E functions in the suppression of Myc-induced apoptosis (35).…”

Section: Activation Of Apoptosis By 4e-bp1 In Fibroblasts Expressingmentioning

confidence: 99%

Translational Control of the Antiapoptotic Function of Ras

Polunovsky

Gingras

Sonenberg

et al. 2000

Journal of Biological Chemistry

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104

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Activated Ras has been shown to provide powerful antiapoptotic signals to cells through well defined transcriptional and post-translational pathways, whereas translational control as a mechanism of Ras survival signaling remains unexplored. Here we show a direct relationship between assembly of the cap-dependent translation initiation apparatus and suppression of apoptosis by oncogenic Ras in vitro and in vivo. Decreasing protein synthesis with rapamycin, which is known to inhibit cap-dependent translation, increases the susceptibility of Ras-transformed fibroblasts to cytostatic drug-induced apoptosis. In contrast, suppressing global protein synthesis with equipotent concentrations of cycloheximide actually prevents apoptosis. Enforced expression of the cap-dependent translational repressor, the eukaryotic translation initiation factor (eIF) 4E-binding protein (4E-BPI), sensitizes fibroblasts to apoptosis in a manner strictly dependent on its ability to sequester eIF4E from a translationally active complex with eIF4GI and the co-expression of oncogenic Ras. Ectopic expression of 4E-BP1 also promotes apoptosis of Ras-transformed cells injected into immunodeficient mice and markedly diminishes their tumorigenicity. These results establish that eIF4E-dependent protein synthesis is essential for survival of fibroblasts bearing oncogenic Ras and support the concept that activation of cap-dependent translation by extracellular ligands or intrinsic survival signaling molecules suppresses apoptosis, whereas synthesis of proteins mediating apoptosis can occur independently of the cap.Extracellular survival factors suppress the intrinsic apoptotic apparatus through cognate receptor kinases at the cell surface, which activate the proto-oncogene ras and a number of pleiotropic transcriptional and post-translational effector pathways (1). A major effector of Ras survival signaling is the serine/threonine protein kinase, Akt (2, 3). Transcriptional control is exerted by Akt-mediated phosphorylation of the Forkhead1 family transcription factor FKHRL1(4) and the transcription factor nuclear factor-B (5), which alter expression of apoptosis-related genes. Akt-mediated phosphorylation of the Bcl-2 family member Bad (6) and the cell death protease caspase-9 (7) is implicated in post-translational suppression of the intrinsic apoptotic machinery. Akt also regulates the FK506 binding-protein 12 (FKBP12)-rapamycin-associated protein/mammalian target of rapamycin (FRAP/mTOR), 1 a kinase which functions in the control of translation by activating two components of the protein synthesis apparatus: (i) the initiation complex binding the 5Ј-mRNA cap and (ii) the 40 S ribosomal protein S6 kinase, p70 s6k (8 -11). However, data examining the importance of translational control in the mechanism of Ras survival signaling are lacking.Translational control is usually exerted at the initiation step. In eukaryotes, the 5Ј-mRNA cap is bound by the eukaryotic translation initiation complex eIF4F, which consists of a bidirectional RNA helicase eIF4...

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“…Translation of the Bcl-xL protein has been demonstrated to be cap dependent (Polunovsky et al, 1996;Tan et al, 2000;Li et al, 2003). Cap-dependent translation initiation is a process regulated by mTOR through phosphorylation of its known target, 4E-BP1.…”

Section: Discussionmentioning

confidence: 99%

Rapamycin induces apoptosis of JN-DSRCT-1 cells by increasing the Bax : Bcl-xL ratio through concurrent mechanisms dependent and independent of its mTOR inhibitory activity

2005

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Rapamycin, a complex macrolide and potent fungicide, immunosuppressant and anticancer agent, is a highly specific inhibitor of mammalian target of rapamycin (mTOR). Rapamycin has been shown to induce G1-phase cell cycle arrest in diverse tumor cell types, and its derivatives RAD001 and CCI-779 are currently in phase I and phase II clinical trials, respectively, as anticancer agents. In this study, we show that rapamycin induced the apoptotic death of JN-DSRCT-1 cells, the only available in vitro model for Desmoplastic Small Round Cell Tumors (DSRCT), while having only minor effects on their cell cycle. Rapamycin induced apoptosis by increasing the Bax : Bcl-xL ratio as a consequence of the concomitant downregulation of Bcl-xL and upregulation of Bax, both at the post-transcriptional level. Rapamycin also downregulated the levels of EWS/WT1, the fusion protein characteristic of DSRCT. Transient transfection studies using kinase-dead and rapamycin-resistant forms of mTOR demonstrated that only the downregulation of Bcl-xL was caused by the mTOR inhibitory action of rapamycin, which prevented cap-dependent translation initiation, whereas Bax upregulation was induced by rapamycin through a mechanism independent of its mTOR inhibitory activity. Moreover, rapamycin treatment downregulated the mRNA and protein levels of the 26S p44.5 proteasome subunit, suggesting the involvement of the proteasome complex in the mechanisms of rapamycin-induced apoptosis. Treatment of JN-DSRCT-1 cells with MG-132, a proteasome specific inhibitor, also resulted in the induction of apoptosis through a similar increase in the Bax : Bcl-xL ratio specifically caused by inhibiting Bax degradation and turnover. These results suggested that rapamycin induces apoptosis by preventing the degradation of the Bax protein by the proteasome, and that this process is independent of mTOR inhibition. Furthermore, these results strongly support the introduction of the use of rapamycin as a cytotoxic agent for the treatment of DSRCT.

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Inhibition of Myc-dependent apoptosis by eukaryotic translation initiation factor 4E requires cyclin D1

Cited by 101 publications

References 73 publications

The Cap-Dependent Translation Apparatus Integrates and Amplifies Cancer Pathways

The Cap-Dependent Translation Apparatus Integrates and Amplifies Cancer Pathways

Translational Control of the Antiapoptotic Function of Ras

Rapamycin induces apoptosis of JN-DSRCT-1 cells by increasing the Bax : Bcl-xL ratio through concurrent mechanisms dependent and independent of its mTOR inhibitory activity

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