Phosphorylation of eIF4E attenuates its interaction with mRNA 5′ cap analogs by electrostatic repulsion: Intein-mediated protein ligation strategy to obtain phosphorylated protein

Zuberek, Joanna; Wysłouch‐Cieszyńska, Aleksandra; Niedzwiecka, Anna; Dadlez, Michał; Stępiński, Janusz; Augustyniak, W; Gingras, Anne‐Claude; Zhang, Zhibo; Burley, S.K.; Sonenberg, Nahum; Stolarski, Ryszard; Darżynkiewicz, Edward

doi:10.1261/rna.2133403

Cited by 119 publications

(108 citation statements)

References 40 publications

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“…Recent data suggest that phosphorylation of eIF4E weakens its binding to 7-methylguanosine triphosphate and to capped RNA Slepenkov et al, 2006). Detailed biophysical studies are The mTOR signalling J Averous and CG Proud consistent with the idea that electrostatic repulsion between the phosphoserine and negative charges on the capped RNA contribute to weakening cap-eIF4E binding (Zuberek et al, 2003(Zuberek et al, , 2004. One may speculate that this serves to allow additional ribosomal initiation complexes to bind the mRNA while the previous one is still engaged in scanning, or that it may permit eIF4E to be released from one mRNA in order to bind others, whose translation has been stimulated by other mechanisms .…”

Section: Control Of Eif4ementioning

confidence: 85%

When translation meets transformation: the mTOR story

2006

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Section: Control Of Eif4ementioning

confidence: 85%

When translation meets transformation: the mTOR story

2006

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“…Future work will be needed to identify the mechanisms that render the translation of these mRNAs more sensitive to eIF4E phosphorylation. Several studies have demonstrated that p-eIF4E binds with lower affinity to the cap structure (44)(45)(46). Although this finding is counterintuitive, it was proposed that the decreased affinity could stimulate translation by releasing eIF4E from the cap, akin to the mechanism of promoter clearing during transcription initiation (47).…”

Section: Discussionmentioning

confidence: 99%

eIF4E phosphorylation promotes tumorigenesis and is associated with prostate cancer progression

Furic

Liang

Larsson

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Translational regulation plays a critical role in the control of cell growth and proliferation. A key player in translational control is eIF4E, the mRNA 5′ cap-binding protein. Aberrant expression of eIF4E promotes tumorigenesis and has been implicated in cancer development and progression. The activity of eIF4E is dysregulated in cancer. Regulation of eIF4E is partly achieved through phosphorylation. However, the physiological significance of eIF4E phosphorylation in mammals is not clear. Here, we show that knock-in mice expressing a nonphosphorylatable form of eIF4E are resistant to tumorigenesis in a prostate cancer model. By using a genome-wide analysis of translated mRNAs, we show that the phosphorylation of eIF4E is required for translational up-regulation of several proteins implicated in tumorigenesis. Accordingly, increased phospho-eIF4E levels correlate with disease progression in patients with prostate cancer. Our findings establish eIF4E phosphorylation as a critical event in tumorigenesis. These findings raise the possibility that chemical compounds that prevent the phosphorylation of eIF4E could act as anticancer drugs. PTEN | translational controlA berrations in the control of mRNA translation initiation have been documented in many tumor types (1-4). Translation initiation is controlled in part by eIF4E, the mRNA 5′ cap-binding protein. eIF4E is a proto-oncogene, inasmuch as its overexpression in immortalized rodent fibroblasts or human epithelial cells causes transformation (5, 6), and in mouse models its overexpression engenders tumor formation (7,8). eIF4E is phosphorylated by the MNK1/2 serine/threonine kinases, which are activated in response to mitogenic and stress signaling downstream of ERK1/2 and p38 MAP kinase, respectively (9, 10). eIF4E phosphorylation at serine 209 by MNK1/2 promotes its transformation activity (11,12). To study the role of eIF4E phosphorylation in tumorigenesis in the whole organism, we generated a knock-in (KI) mouse in which eIF4E serine 209 was mutated to alanine. Here, we show that mouse embryonic fibroblasts (MEFs) isolated from eIF4E S209A/S209A embryos display a marked resistance to oncogene-induced transformation. Furthermore, the mutant mice are viable, but are resistant to development of Pten loss-induced prostate cancer, and this resistance is associated with a decrease in MMP3, CCL2, VEGFC, and BIRC2 proteins. Moreover, eIF4E is highly phosphorylated in hormone-refractory prostate cancer, which correlates with poor clinical outcome. These results demonstrate the importance of eIF4E phosphorylation in tumorigenesis and validate the eIF4E phosphorylation pathway as a potential therapeutic target for cancer. ResultsSer209 Is the Only Phosphorylation Site in eIF4E. To address the role of eIF4E phosphorylation in tumorigenesis, a knock-in (KI) mouse in which serine 209 was replaced by an alanine residue was generated. The strategy and targeting vector construction for the generation, selection, and genotyping of the S209A mice is shown in Fig. S1. The eIF4E S...

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“…11,12 Alternatively, it may reduce the affinity of eIF4E for capped mRNAs, thus suggesting that phosphorylation occurs only after the assembly of the initiation complex. 13,14 Whether eIF4E phosphorylation takes place before or after cap binding, or is absolutely required for translation initiation is still debated. 14,15 In Drosophila, amino acid residue Ser251 (corresponding to Ser209 in mammals) has been indicated as the major phosphorylation site within eIF4E, since it is necessary for the proper growth and development of the fly.…”

Section: Cup and The Phosphorylation Of Eif4ementioning

confidence: 99%