Nuclear export of messenger RNAs (mRNAs) and translation of mRNAs into protein are two of the most fundamental cellular processes. These processes, particularly translation, are manipulated by viruses and misregulated in cancer progression, which makes detailed knowledge of their mechanisms invaluable in designing therapeutics. This proposal is designed to elucidate links between export and translation by examining the role of Gle1 in translation regulation. Gle1 is an essential protein required for mRNA export in eukaryotes from yeast to humans. However, preliminary evidence indicates that Gle1 has a role in regulation of translation. The goal of aim I is to establish this role definitively through directed genetic screens, cell biology, and biochemical techniques primarily in the yeast S. cerevisiae.
In aim II the mechanism by which Gle1 is acting in translation will be further elucidated. This will be accomplished by first examining whether other known interactors impact its role in translation and by also determining the step of translation affected. This will require a range of different techniques, including biochemical purification and various reporter assays, done in yeast and mammalian cells.
Aim III will attempt to further broaden this research by identifying other factors that may regulate Gle1 in translation such as inositol hexakisphosphate (IP6), which is known to regulate Gle1 in export. The long-term goal is to demonstrate the interconnectedness of the critical activities of mRNA export and translation. ? ? Relevance: We propose to study links between two fundamental cellular activities. Viruses are known to hijack or manipulate these activities during infection, and these activities are also frequently not properly regulated in cancer progression. Therefore studying the mechanisms of these cellular processes may aid in designing future treatments as well as broadening our general understanding of cell biology. ? ? ?
| Bolger, Timothy A; Wente, Susan R (2011) Gle1 is a multifunctional DEAD-box protein regulator that modulates Ded1 in translation initiation. J Biol Chem 286:39750-9 |
| Alcázar-Román, Abel R; Bolger, Timothy A; Wente, Susan R (2010) Control of mRNA export and translation termination by inositol hexakisphosphate requires specific interaction with Gle1. J Biol Chem 285:16683-92 |
| Bolger, Timothy A; Folkmann, Andrew W; Tran, Elizabeth J et al. (2008) The mRNA export factor Gle1 and inositol hexakisphosphate regulate distinct stages of translation. Cell 134:624-33 |
