The cap-binding protein eIF4E is the rate-limiting factor in translation initiation. eIF4E activity is regulated by phosphorylation, with its phosphorylation corresponding to increased translation initiation and cell growth. eIF4E overexpression contributes to cellular transformation and tumor formation in nude mice, indicating that loss of eIF4E regulation may play a role in cancer. Thus, the long-term goal of this research is to understand the mechanism(s) of regulation of eIF4E. The eIF4E-binding proteins, 4E-BPs, inhibit eIF4E activity by associating with eIF4E and preventing its phosphorylation and interaction with other initiation factors. In this capacity as translational repressors, the 4E-BPs are expected to be regulators of cell growth, and their activity should require regulation as well. Consistent with this, growth factors induce phosphorylation of 4E-BP1 which prevents its association with eIF4E. The specific goals of this research, therefore, are to characterize the effects of 4E-BP on cellular translation and growth, and to elucidate the 4E-BP kinase activity. 4E-BP inactivation will be studied in 4E-BP knockout mice and primary cell lines established from these mice, and translation and growth properties will be examined. 4E-BP kinase studies will involve an assay for inhibition of 4E-BP1-eIF4E binding and co-transfections with 4E-BP1 and potential kinase pathway mediators. Collectively, these studies will provide insight into the potential anti-tumor properties of the 4E-BPs.
| Banko, Jessica L; Poulin, Francis; Hou, Lingfei et al. (2005) The translation repressor 4E-BP2 is critical for eIF4F complex formation, synaptic plasticity, and memory in the hippocampus. J Neurosci 25:9581-90 |
| Khaleghpour, K; Svitkin, Y V; Craig, A W et al. (2001) Translational repression by a novel partner of human poly(A) binding protein, Paip2. Mol Cell 7:205-16 |
