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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Feoktistova, Kateryna Tuvshintogs, Enkhee Do, Angelie Fraser, Christopher S. |
| Description | Author Affiliation: Feoktistova K ( Department of Molecular and Cell Biology, College of Biological Sciences, University of California, Davis, CA 95616, USA.); |
| Abstract | Elevated eukaryotic initiation factor 4E (eIF4E) levels frequently occur in a variety of human cancers. Overexpression of eIF4E promotes cellular transformation by selectively increasing the translation of proliferative and prosurvival mRNAs. These mRNAs possess highly structured 5'-UTRs that impede ribosome recruitment and scanning, yet the mechanism for how eIF4E abundance elevates their translation is not easily explained by its cap-binding activity. Here, we show that eIF4E possesses an unexpected second function in translation initiation by strongly stimulating eukaryotic initiation factor 4A (eIF4A) helicase activity. Importantly, we demonstrate that this activity promotes mRNA restructuring in a manner that is independent of its cap-binding function. To explain these findings, we show that the eIF4E-binding site in eukaryotic initiation factor 4G (eIF4G) functions as an autoinhibitory domain to modulate its ability to stimulate eIF4A helicase activity. Binding of eIF4E counteracts this autoinhibition, enabling eIF4G to stimulate eIF4A helicase activity. Finally, we have successfully separated the two functions of eIF4E to show that its helicase promoting activity increases the rate of translation by a mechanism that is distinct from its cap-binding function. Based on our results, we propose that maintaining a connection between eIF4E and eIF4G throughout scanning provides a plausible mechanism to explain how eIF4E abundance selectively stimulates the translation of highly structured proliferation and tumor-promoting mRNAs. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 33 |
| Volume Number | 110 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2013-08-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Cell Transformation, Neoplastic Metabolism Enzyme Activation Physiology Eukaryotic Initiation Factor-4A Eukaryotic Initiation Factor-4E Eukaryotic Initiation Factor-4G RNA, Messenger Animals Chromatography, Gel Chromatography, Ion Exchange Oligonucleotides Genetics Sf9 Cells Spodoptera Research Support, N.I.H., Extramural Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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