The regulation of protein synthesis ultimately determines most cell fate decisions. Cells undergoing any form of differentiation control both the rate of global synthesis and the types of new proteins made. The role of mRNA translational control is becoming increasingly apparent in gametogenesis, embryogenesis and oncogenesis. Intriguingly, early embryonic development displays many functional parallels to oncogenesis, among them are mRNA translational control and cell proliferation. Like a cleaving embryo, cancer cells upregulate protein synthesis and cell cycle progression relative to normal somatic cells. The focus of our studies is the protein synthesis apparatus itself (i.e. translation initiation factors), which controls the utilization of mRNAs in cells undergoing rapid growth, differentiation or even cell death (apoptosis). Translation initiation factors 4E and 4G (eIF4E and eIF4G) alter the mode of translation initiation in a way that discriminates for or against particular mRNAs. Disruption of this complex causes preferential translation of mRNAs that promote apoptosis. Protein synthesis mechanism therefore represents a novel point of intervention for cancer therapies and developmental defects. Using biochemical methods, microinjection, transgenesis, genetics and genomics in the model organism, C. elegans, we are attempting to artificially modulate eIF4E and eIF4G isoforms in vivo as a means to inhibit cell proliferation or alter differentiation pathways.
Song A., Labella S., Korneeva N.L., Keiper B.D., Aamodt E.J., Zetka M. and Rhoads R.E. (2010) A C.elegans eIF4E-family member upregulates translational at elevated temperatures of mRNAs encoding MSH-5 and other meiotic crossover proteins. J. Cell Sci. 123(Pt 13): 2228-2237. (link to article)
Henderson, M.A., Cronland, E., Dunkelbarger, S., Contreras, V., Strome, S., andKeiper, B.D. (2009) A germ line-specific isoform of eIF4E (IFE-1) is required for efficient translation of stored mRNAs and maturation of both oocytes and sperm. J. Cell Sci. 122: 1529-1539. (link to article)
Contreras, V., Richardson, M.A., Hao, E. and Keiper, B.D. (2008). Depletion of the cap-associated isoform of translation factor eIF4G induces germline apoptosis in C. elegans. Cell Death Differ. 15: 1232-1242. (link to abstract)
Dinkova, T.D., Keiper, B.D., Korneeva, N.L., Aamodt, E.J. and Rhoads, R.E. (2005) Translation of a small subset of Caenorhabditis elegans mRNAs is dependent on a specific eukaryotic translation initiation factor 4E isoform. Mol. Cell. Biol. 25(1): 100-113.
Miyoshi, H., Dwyer, D., Keiper, B.D., Jankowska, M., Darzynkiewicz, E. and R.E. Rhoads (2002) Discrimination between mono- and trimethylated cap structures by two isoforms of Caenorhabditis elegans eIF4E. EMBO J. 21(17): 4680-4690.
Amiri, A., Keiper, B.D., Kawasaki, I., Fan, Y., Kohara, Y., Rhoads, R.E., and S. Strome (2001) An Isoform of eIF4E is a Component of Germ Granules and is Required for Spermatogenesis in C. elegans. Development 128 (20): 3899-3912.
Keiper, B.D., Lamphear, B.J., Deshpande, A.M., Jankowska-Anyszka, M., Aamodt, E.J., Blumenthal, T., and R.E. Rhoads (2000) Functional Characterization of Five eIF4E Isoforms in Caenorhabditis elegans. J. Biol. Chem. 275 (14): 10590-10596. (link to article)
Keiper, B.D. and R.E. Rhoads (1999b) Translational Recruitment of XenopusMaternal mRNAs in Response to Poly(A) Elongation Requires Initiation Factor eIF4G-1. Dev. Biol. 206 (1): 1-14.
Keiper, B.D. and R.E. Rhoads (1997) Cap-Independent Translation Initiation inXenopus Oocytes, Nucleic Acids Res. 25 (2): 395-403.
Spevak, W., Keiper, B.D., Stratowa, C., and M.J. Castanon (1993) Saccharomyces cerevisiae cdc15 Mutants Arrested at a Late Stage in Anaphase are Rescued byXenopus cDNAs Encoding N-ras or a Protein with ß-Transducin Repeats (ßTrCP).Mol. Cell. Biol. 13 (8), 4953-4966.
Keiper, B.D. (2003) Translation of mRNAs in Xenopus Oocytes. In: Encyclopedia of Life Sciences. (Online Reviews) London: Nature Publishing Group. (http://www.els.net/)
Keiper, B.D., Gan, W., and R.E. Rhoads (1999a) Molecules in Focus: Protein Synthesis Initiation Factor 4G, Int. J. Biochem. Cell Biol. 31(1): 37-41. (link to article)
|National Science Foundation|
|Title: “Translational control of growth & apoptosis in C. elegans development by initiation factors”|
|National Science Foundation|
|Title: “Function of Tissue-specific eIF4E Isoforms in Caenorhabditis elegans”|
|ECU Division of Research & Graduate Studies|
|Research Development Grant (ECU)||2008-2009|
|Title: “Translational control of growth and apoptosis in the C. elegans ovary”|
|Leo Jenkins Cancer Center (Dr. Mary A Farwell, co-PI)|
|Seed Grant (ECU)||2006|
|Title: “Targeted depletion of N-terminally extended eIF4G-1 isoforms in breast cancer cell lines to reduce proliferation and/or increase susceptibility to apoptosis”|
|North Carolina Biotechnology Center (Dr. Jim McCubrey, co-PI)|
|2004-IDG 1002, Institutional Development Grant||2005-2006|
|Title: “Phosphor-Imaging and Fluorescence-Imaging Core Facility at ECU Brody School of Medicine”|
Associate Professor of Biochemistry & Molecular Biology
Graduate Program Committee Chairman
The Brody School of Medicine at East Carolina University
Greenville, NC 27834