The translation factor eIF-4E promotes tumor formation and cooperates with c-Myc in lymphomagenesis

Ruggero, Davide; Montanaro, Lorenzo; Ma, Li; Xu, Wei; Londei, Paola; Cordon‐Cardo, Carlos; Pandolfi, Pier Paolo

doi:10.1038/nm1042

Cited by 545 publications

(474 citation statements)

References 12 publications

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“…This complex is probably especially critical for the translation of mRNAs with extensive secondary structure in their 5 0 -untranslated regions (5 0 -UTRs). Artificial overexpression of eIF4E leads to transformation in cell lines (Lazaris-Karatzas and Sonenberg, 1992) and in animal models (Ruggero et al, 2004). Interestingly, eIF4E is expressed at high levels in many tumors (De Benedetti and Graff, 2004).…”

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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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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“…The role of the initiation factor of translation eIF4E as a protooncogene and its sufficiency to promote metastatic progression has been demonstrated in tissue culture (Lazaris-Karatzas et al, 1990;Graff and Zimmer, 2003) and in vivo (Ruggero et al, 2004, Wendel et al, 2004. In addition to the components of translational machinery, RNA-binding proteins are also aberrantly expressed in tumors, including PTB (He et al, 2007), HuR (Lopez de Silanes et al, 2003), KH domain-containing protein, and hnRNPD among others (Gouble et al, 2002), with a direct correlation between abnormal expression of a particular RNA-binding protein and tumor formation (CRD-BP) in breast tissue (Tessier et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Akt phosphorylation of La regulates specific mRNA translation in glial progenitors

et al. 2008

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The Akt signaling pathway activity increases as normal tissue progresses to malignant transformation, and regulates the translation of specific messenger RNAs (mRNAs) through multiple mechanisms. We have identified one such mechanism of Akt-dependent translation control as involving the lupus autoantigen La. La is an RNA-associated protein that contains multiple trafficking elements to support the interaction with RNAs in different subcellular locations. We show here that the La protein is a direct target of the serine/threonine protein kinase Akt on threonine 301, and La nuclear export in mouse glial progenitors, as well as its association with polysomes is modulated by Akt activity. Using a functional approach to determine the network of genes affected by La in the cytoplasm by microarray analysis of polysome-bound mRNAs, we found that La binds 34% of the polysome bound mRNAs and regulates the expression of a specific pool of mRNAs under KRas/Akt activation. Therefore, La appears to be an important contributor to Aktmediated translational regulation of these transcripts in murine glial cells.

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“…Rapamycin has shown additive or synergistic activity when combined with other tyrosine kinase inhibitors such as Gleevec and PKC412 (Mohi et al, 2004). Rapamycin also enhances chemotherapy responses in breast cancer cell lines (Mondesire et al, 2004) and in Myc-driven murine lymphomas (Ruggero et al, 2004). Tumours with loss of PTEN, loss of p53 or amplification of GLI may be particularly sensitive to rapamycin (Hosoi et al, 1999;Louro et al, 1999;Neshat et al, 2001).…”

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confidence: 99%

“…Unphosphorylated 4E-BP1 binds and inhibits eIF4E. Overexpression of eIF4E can transform NIH 3T3 cells (Lazaris-Karatzas et al, 1990) and can cause rapamycin-sensitive murine lymphomas to become rapamycin-resistant (Ruggero et al, 2004). In contrast to inhibiting 4E-BP1 function, S6K is activated by mTOR which leads to the phosphorylation of ribosomal protein S6 (RPS6) and increased translation of mRNAs, particularly those encoding components of the translation machinery itself (e.g.…”

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confidence: 99%

Synergistic growth inhibition by Iressa and Rapamycin is modulated by VHL mutations in renal cell carcinoma

et al. 2005

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Epidermal growth factor receptor (EGFR) and tumour growth factor alpha (TGFa) are frequently overexpressed in renal cell carcinoma (RCC) yet responses to single-agent EGFR inhibitors are uncommon. Although von Hippel -Lindau (VHL) mutations are predominant, RCC also develops in individuals with tuberous sclerosis (TSC). Tuberous sclerosis mutations activate mammalian target of rapamycin (mTOR) and biochemically resemble VHL alterations. We found that RCC cell lines expressed EGFR mRNA in the near-absence of other ErbB family members. Combined EGFR and mTOR inhibition synergistically impaired growth in a VHLdependent manner. Iressa blocked ERK1/2 phosphorylation specifically in wt-VHL cells, whereas rapamycin inhibited phospho-RPS6 and 4E-BP1 irrespective of VHL. In contrast, phospho-AKT was resistant to these agents and MYC translation initiation (polysome binding) was similarly unaffected unless AKT was inhibited. Primary RCCs vs cell lines contained similar amounts of phospho-ERK1/2, much higher levels of ErbB-3, less phospho-AKT, and no evidence of phospho-RPS6, suggesting that mTOR activity was reduced. A subset of tumours and cell lines expressed elevated eIF4E in the absence of upstream activation. Despite similar amounts of EGFR mRNA, cell lines (vs tumours) overexpressed EGFR protein. In the paired cell lines, PRC3 and WT8, EGFR protein was elevated posttranscriptionally in the VHL mutant and EGF-stimulated phosphorylation was prolonged. We propose that combined EGFR and mTOR inhibitors may be useful in the subset of RCCs with wt-VHL. However, apparent differences between primary tumours and cell lines require further investigation.

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The translation factor eIF-4E promotes tumor formation and cooperates with c-Myc in lymphomagenesis

Cited by 545 publications

References 12 publications

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

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

Akt phosphorylation of La regulates specific mRNA translation in glial progenitors

Synergistic growth inhibition by Iressa and Rapamycin is modulated by VHL mutations in renal cell carcinoma

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