An activity-dependent switch to cap-independent translation triggered by eIF4E dephosphorylation

Dyer, John; Michel, Stephan; Lee, Wenjau; Castellucci, Vincent F.; Wayne, Nancy L.; Sossin, Wayne S.

doi:10.1038/nn1018

Cited by 59 publications

(73 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However, these findings do not negate the possibility of functional involvement of phosphorylation of eIF4E in specific physiologic situations (43). Dephosphorylation of eIF4E was correlated previously with stimulating the IRES activity of an egg-laying hormone in Aplysia neurons after an afterdischarge (44,45). Phosphorylation of eIF4E is generally thought to decrease its affinity for the cap; however, this has been interpreted to have positive and negative effects on overall protein translation (46)(47)(48)(49).…”

Section: Discussionmentioning

confidence: 86%

Ras Transformation of RIE-1 Cells Activates Cap-Independent Translation of Ornithine Decarboxylase: Regulation by the Raf/MEK/ERK and Phosphatidylinositol 3-Kinase Pathways

Origanti

Shantz

2007

Cancer Research

View full text Add to dashboard Cite

Ornithine decarboxylase (ODC) is the first and generally ratelimiting enzyme in polyamine biosynthesis. Deregulation of ODC is critical for oncogenic growth, and ODC is a target of Ras. These experiments examine translational regulation of ODC in RIE-1 cells, comparing untransformed cells with those transformed by an activated Ras12V mutant. Analysis of the ODC 5 ¶ untranslated region (5 ¶UTR) revealed four splice variants with the presence or absence of two intronic sequences. All four 5 ¶UTR species were found in both cell lines; however, variants containing intronic sequences were more abundant in Ras-transformed cells. All splice variants support internal ribosome entry site (IRES)-mediated translation, and IRES activity is markedly elevated in cells transformed by Ras. Inhibition of Ras effector targets indicated that the ODC IRES element is regulated by the phosphorylation status of the translation factor eIF4E. Dephosphorylation of eIF4E by inhibition of mitogen-activated protein/extracellular signalregulated kinase (ERK) kinase (MEK) or the eIF4E kinase Mnk1/2 increases ODC IRES activity in both cell lines. When both the Raf/MEK/ERK and phosphatidylinositol 3-kinase/ mammalian target of rapamycin pathways are inhibited in normal cells, ODC IRES activity is very low and cells arrest in G 1 . When these pathways are inhibited in Ras-transformed cells, cell cycle arrest does not occur and ODC IRES activity increases, helping to maintain high ODC activity. [Cancer Res 2007;67(10):4834-42]

show abstract

Section: Discussionmentioning

confidence: 86%

Ras Transformation of RIE-1 Cells Activates Cap-Independent Translation of Ornithine Decarboxylase: Regulation by the Raf/MEK/ERK and Phosphatidylinositol 3-Kinase Pathways

Origanti

Shantz

2007

Cancer Research

View full text Add to dashboard Cite

show abstract

“…However, at least two proteins (HIF1␣ and vascular endothelial growth factor) involved in cell survival are upregulated during hypoxia, presumably via their synthesis by IRES-dependent translation. It is also noteworthy that in neurons from the mollusk Aplysia californica the switch from cap-dependent to IRES-dependent translation is believed to be triggered by dephosphorylation of eIF4E (9). Knowing how selective translation allows cells to adapt to environmental and physiological stresses, such as hypoxia, heat shock, toxins, and drug exposure, is important for understanding many human disorders and may lead to the development of new therapeutic approaches for such conditions.…”

Section: Discussionmentioning

confidence: 99%

Eukaryotic Translation Initiation Factor 4E Availability Controls the Switch between Cap-Dependent andInternal Ribosomal Entry Site-Mediated Translation

Svitkin¹,

Herdy²,

Costa-Mattioli³

et al. 2005

Molecular and Cellular Biology

162

137

View full text Add to dashboard Cite

Translation of m 7 G-capped cellular mRNAs is initiated by recruitment of ribosomes to the 5 end of mRNAs via eukaryotic translation initiation factor 4F (eIF4F), a heterotrimeric complex comprised of a cap-binding subunit (eIF4E) and an RNA helicase (eIF4A) bridged by a scaffolding molecule (eIF4G). Internal translation initiation bypasses the requirement for the cap and eIF4E and occurs on viral and cellular mRNAs containing internal ribosomal entry sites (IRESs). Here we demonstrate that eIF4E availability plays a critical role in the switch from cap-dependent to IRES-mediated translation in picornavirus-infected cells. When both capped and IRES-containing mRNAs are present (as in intact cells or in vitro translation extracts), a decrease in the amount of eIF4E associated with the eIF4F complex elicits a striking increase in IRES-mediated viral mRNA translation. This effect is not observed in translation extracts depleted of capped mRNAs, indicating that capped mRNAs compete with IRES-containing mRNAs for translation. These data explain numerous reported observations where viral mRNAs are preferentially translated during infection.

show abstract

“…The changes of IRES activity along neuronal culture are the result of a concomitant but opposite regulation of IRES-and cap-dependent translation and are not linked to variations of bicistronic mRNA expression. This switch in mechanisms, previously described by Dyer et al (2003), may involve a coordinated regulation of factors specific for each mechanism and/or common factors with opposite effects on the two translational mechanisms. For instance, one of the specific factors could be hnRNP A1, which may be recruited for FGF-2 IRES activity (Bonnal et al 2005) and is highly expressed in brain, preferentially in neurons (Faura et al 1995;Kamma et al 1995).…”

Section: Discussionmentioning

confidence: 92%

“…For instance, one of the specific factors could be hnRNP A1, which may be recruited for FGF-2 IRES activity (Bonnal et al 2005) and is highly expressed in brain, preferentially in neurons (Faura et al 1995;Kamma et al 1995). On the other hand, events linked to cap-dependent translational inhibition such as eIF4E and eIF4E-binding protein (4E-BP) dephosphorylations, eIF2a phosphorylation, and 4E-BP overexpression have all been associated with IRES-mediated translation (Fernandez et al 2002;Dyer et al 2003). Whereas such a switch in translational mechanisms in mammalian cells has often been found associated with stress conditions (Fernandez et al 2002;Holcik and Sonenberg 2005), we show here that it can also exist under physiological conditions, namely, during neuronal maturation.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, NMDA receptor activation and, more generally, neuronal inputs may be one of the signals triggering IRES-dependent translation of a subset of mRNAs in neurons. Interestingly, several dendritically localized mRNAs contain an IRES in their 59 UTR (Pinkstaff et al 2001) and an electrical stimulus is involved in the IRES-dependent translation of the egg-laying hormone in Aplysia (Dyer et al 2003).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Potent activation of FGF-2 IRES-dependent mechanism of translation during brain development

Audigier¹,

Guiramand²,

Prado-Lourenço³

et al. 2008

RNA

View full text Add to dashboard Cite

Fibroblast growth factor-2 (FGF-2) plays a fundamental role in brain functions. This role may be partly achieved through the control of its expression at the translational level via an internal ribosome entry site (IRES)-dependent mechanism. Transgenic mice expressing a bicistronic mRNA allowed us to study in vivo and ex vivo where this translational mechanism operates. Along brain development, we identified a stringent spatiotemporal regulation of FGF-2 IRES activity showing a peak at post-natal day 7 in most brain regions, which is concomitant with neuronal maturation. At adult age, this activity remained relatively high in forebrain regions. By the enrichment of this activity in forebrain synaptoneurosomes and by the use of primary cultures of cortical neurons or cocultures with astrocytes, we showed that this activity is indeed localized in neurons, is dependent on their maturation, and correlates with endogenous FGF-2 protein expression. In addition, this activity was regulated by astrocyte factors, including FGF-2, and spontaneous electrical activity. Thus, neuronal IRES-driven translation of the FGF-2 mRNA may be involved in synapse formation and maturation.

show abstract

An activity-dependent switch to cap-independent translation triggered by eIF4E dephosphorylation

Cited by 59 publications

References 10 publications

Ras Transformation of RIE-1 Cells Activates Cap-Independent Translation of Ornithine Decarboxylase: Regulation by the Raf/MEK/ERK and Phosphatidylinositol 3-Kinase Pathways

Ras Transformation of RIE-1 Cells Activates Cap-Independent Translation of Ornithine Decarboxylase: Regulation by the Raf/MEK/ERK and Phosphatidylinositol 3-Kinase Pathways

Eukaryotic Translation Initiation Factor 4E Availability Controls the Switch between Cap-Dependent andInternal Ribosomal Entry Site-Mediated Translation

Potent activation of FGF-2 IRES-dependent mechanism of translation during brain development

Contact Info

Product

Resources

About