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eIF4GI links nutrient sensing by mTOR to cell proliferation and inhibition of autophagy.

Ramírez-Valle F, Braunstein S, Zavadil J, Formenti SC, Schneider RJ - J. Cell Biol. (2008)

Bottom Line: Depletion or overexpression of other eIF4G family members did not recapitulate these results.The majority of mRNAs that were translationally impaired with eIF4GI depletion were excluded from polyribosomes due to the presence of multiple upstream open reading frames and low mRNA abundance.These results suggest that the high levels of eIF4GI observed in many breast cancers might act to specifically increase proliferation, prevent autophagy, and release tumor cells from control by nutrient sensing.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA.

ABSTRACT
Translation initiation factors have complex functions in cells that are not yet understood. We show that depletion of initiation factor eIF4GI only modestly reduces overall protein synthesis in cells, but phenocopies nutrient starvation or inhibition of protein kinase mTOR, a key nutrient sensor. eIF4GI depletion impairs cell proliferation, bioenergetics, and mitochondrial activity, thereby promoting autophagy. Translation of mRNAs involved in cell growth, proliferation, and bioenergetics were selectively inhibited by reduction of eIF4GI, as was the mRNA encoding Skp2 that inhibits p27, whereas catabolic pathway factors were increased. Depletion or overexpression of other eIF4G family members did not recapitulate these results. The majority of mRNAs that were translationally impaired with eIF4GI depletion were excluded from polyribosomes due to the presence of multiple upstream open reading frames and low mRNA abundance. These results suggest that the high levels of eIF4GI observed in many breast cancers might act to specifically increase proliferation, prevent autophagy, and release tumor cells from control by nutrient sensing.

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Related in: MedlinePlus

eIF4GI in the context of mTORC1 and other eIF4G family members. mTORC1 signaling regulates cellular growth at various levels, including increasing anabolic processes (ribosome biogenesis and increased protein synthesis), and preventing catabolic processes such as autophagy and fatty acid oxidation. mTORC1 controls translation through the well-known factors 4E-BPs and S6K. eIF4GI total and phosphorylated levels increase in response to mTORC1 activity. eIF4GI modulates translation of low abundance, uORF-containing mRNAs such as Skp2, promoting decreased levels of p27 and therefore proliferation, as well as preventing autophagy. DAP5 and eIF4GI are both required to maintain overall protein synthesis rates, and silencing results in autophagy. Whether DAP5 is also controlled by mTOR is not known. Both DAP5 and eIF4GI are thought to participate in cap-independent translation during apoptosis. eIF4GII silencing does not alter global translation rates, and it may instead participate in translational reprogramming during differentiation.
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fig7: eIF4GI in the context of mTORC1 and other eIF4G family members. mTORC1 signaling regulates cellular growth at various levels, including increasing anabolic processes (ribosome biogenesis and increased protein synthesis), and preventing catabolic processes such as autophagy and fatty acid oxidation. mTORC1 controls translation through the well-known factors 4E-BPs and S6K. eIF4GI total and phosphorylated levels increase in response to mTORC1 activity. eIF4GI modulates translation of low abundance, uORF-containing mRNAs such as Skp2, promoting decreased levels of p27 and therefore proliferation, as well as preventing autophagy. DAP5 and eIF4GI are both required to maintain overall protein synthesis rates, and silencing results in autophagy. Whether DAP5 is also controlled by mTOR is not known. Both DAP5 and eIF4GI are thought to participate in cap-independent translation during apoptosis. eIF4GII silencing does not alter global translation rates, and it may instead participate in translational reprogramming during differentiation.

Mentions: Fig. 7 outlines the control of translation by the mTOR signaling network and places our results in the context of known and potential regulatory components of the eIF4G family. In summary, the phenotypic similarities of eIF4GI silencing and mTORC1 inhibition described here indicate that eIF4GI is an essential factor of the nutrient-sensing pathway. These data also suggest that the function of overexpressed eIF4GI in tumors may involve suppression of autophagy-mediated cell death.


eIF4GI links nutrient sensing by mTOR to cell proliferation and inhibition of autophagy.

Ramírez-Valle F, Braunstein S, Zavadil J, Formenti SC, Schneider RJ - J. Cell Biol. (2008)

eIF4GI in the context of mTORC1 and other eIF4G family members. mTORC1 signaling regulates cellular growth at various levels, including increasing anabolic processes (ribosome biogenesis and increased protein synthesis), and preventing catabolic processes such as autophagy and fatty acid oxidation. mTORC1 controls translation through the well-known factors 4E-BPs and S6K. eIF4GI total and phosphorylated levels increase in response to mTORC1 activity. eIF4GI modulates translation of low abundance, uORF-containing mRNAs such as Skp2, promoting decreased levels of p27 and therefore proliferation, as well as preventing autophagy. DAP5 and eIF4GI are both required to maintain overall protein synthesis rates, and silencing results in autophagy. Whether DAP5 is also controlled by mTOR is not known. Both DAP5 and eIF4GI are thought to participate in cap-independent translation during apoptosis. eIF4GII silencing does not alter global translation rates, and it may instead participate in translational reprogramming during differentiation.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2315676&req=5

fig7: eIF4GI in the context of mTORC1 and other eIF4G family members. mTORC1 signaling regulates cellular growth at various levels, including increasing anabolic processes (ribosome biogenesis and increased protein synthesis), and preventing catabolic processes such as autophagy and fatty acid oxidation. mTORC1 controls translation through the well-known factors 4E-BPs and S6K. eIF4GI total and phosphorylated levels increase in response to mTORC1 activity. eIF4GI modulates translation of low abundance, uORF-containing mRNAs such as Skp2, promoting decreased levels of p27 and therefore proliferation, as well as preventing autophagy. DAP5 and eIF4GI are both required to maintain overall protein synthesis rates, and silencing results in autophagy. Whether DAP5 is also controlled by mTOR is not known. Both DAP5 and eIF4GI are thought to participate in cap-independent translation during apoptosis. eIF4GII silencing does not alter global translation rates, and it may instead participate in translational reprogramming during differentiation.
Mentions: Fig. 7 outlines the control of translation by the mTOR signaling network and places our results in the context of known and potential regulatory components of the eIF4G family. In summary, the phenotypic similarities of eIF4GI silencing and mTORC1 inhibition described here indicate that eIF4GI is an essential factor of the nutrient-sensing pathway. These data also suggest that the function of overexpressed eIF4GI in tumors may involve suppression of autophagy-mediated cell death.

Bottom Line: Depletion or overexpression of other eIF4G family members did not recapitulate these results.The majority of mRNAs that were translationally impaired with eIF4GI depletion were excluded from polyribosomes due to the presence of multiple upstream open reading frames and low mRNA abundance.These results suggest that the high levels of eIF4GI observed in many breast cancers might act to specifically increase proliferation, prevent autophagy, and release tumor cells from control by nutrient sensing.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA.

ABSTRACT
Translation initiation factors have complex functions in cells that are not yet understood. We show that depletion of initiation factor eIF4GI only modestly reduces overall protein synthesis in cells, but phenocopies nutrient starvation or inhibition of protein kinase mTOR, a key nutrient sensor. eIF4GI depletion impairs cell proliferation, bioenergetics, and mitochondrial activity, thereby promoting autophagy. Translation of mRNAs involved in cell growth, proliferation, and bioenergetics were selectively inhibited by reduction of eIF4GI, as was the mRNA encoding Skp2 that inhibits p27, whereas catabolic pathway factors were increased. Depletion or overexpression of other eIF4G family members did not recapitulate these results. The majority of mRNAs that were translationally impaired with eIF4GI depletion were excluded from polyribosomes due to the presence of multiple upstream open reading frames and low mRNA abundance. These results suggest that the high levels of eIF4GI observed in many breast cancers might act to specifically increase proliferation, prevent autophagy, and release tumor cells from control by nutrient sensing.

Show MeSH
Related in: MedlinePlus