The initiation of protein synthesis consists in the recruitment of a ribosome·initiator tRNA complex to the initiation codon of a messenger RNA. In eukaryotes, this process is facilitated by eukaryotic translation initiation factor 4E (eIF4E), which recognizes the cap structure present at the 5' end of all nuclear-transcribed mRNAs. The eIF4E-binding proteins (4E-BPs) inhibit cap-dependent translation by binding to eIF4E, and preventing ribosomal recruitment to the mRNA. The interaction of 4E-BPs with eIF4E is reversible, and it is regulated by the 4E-BPs phosphorylation state. Here I report the isolation of a third member of the 4E-BP family, 4E-BP3, and I demonstrate that it shares all the basic structural and functional characteristics of 4E-BP1 and 4E-BP2. I also analyzed the genomic locus for human 4E-BP3 (EIF4EBP3). I established that EIF4EBP3 can be fused with the gene located immediately upstream, and which encodes the human homologue of Drosophila MASK (Multiple Ankyrin Repeats Single KH domain). Interestingly, the open reading frame of the MASK-BP3 fusion transcript is different from that of 4E-BP3, indicating that the EIF4EBP3 locus encodes two different proteins. Finally, I investigated the biological function of 4E-BP1 by disrupting its gene (Eif4ebp1) in the mouse. Eif4ebp1-/- mice are remarkably lean, and the males' white adipose tissue contains cells exhibiting the distinctive multilocular appearance of brown adipocytes, and it expresses the uncoupling protein 1. Consistent with these observations, translation of the peroxisome proliferator-activated receptor-gamma co-activator 1 (PGC1) is increased in white adipose tissue from Eif4ebp1-/- mice. PGC1 is a transcriptional co-activator implicated in mitochondrial biogenesis and adaptive thermogenesis. These findings demonstrate that 4E-BP1 is a novel regulator of metabolism in mammals.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.84416 |
| Date | January 2003 |
| Creators | Poulin, Francis |
| Contributors | Sonenberg, Nahum (advisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Department of Biochemistry.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001975676, proquestno: AAINQ88559, Theses scanned by UMI/ProQuest. |
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