Repressed eIF2B‐epsilon expression delays tumor growth in transformed mouse embryonic fibroblasts (TMEF)

Abstract

eIF2B is an essential translation initiation factor that mediates both global and specific regulation of mRNA translation. One mechanism for increasing eIF2B activity is upregulated expression of the catalytic ε-subunit of the protein. In this regard, in many transformed cells, expression of eIF2Bε, but not the other four subunits of the protein, is increased. Furthermore, eIF2Bε mRNA expression is elevated in 80% of tumors examined. In the present study, the hypothesis that increased eIF2B activity due to elevated expression of eIF2Bε leads to cellular transformation and tumor progression was examined using spontaneously transformed MEF's. A lentiviral shRNA system was generated that repressed eIF2Bε protein expression by 60% with no change in expression of any of the other four eIF2B subunits. Repression of eIF2Bε expression in TMEFs resulted in a ~30% reduction in eIF2B activity and global rates of protein synthesis, and a marked reduction in growth rate. Repression of eIF2Bε expression also attenuated the transformed phenotype as assessed both by markedly decreased colony formation in soft agar and dramatically delayed tumor appearance and progression in nude mice. The studies help solidify the role of eIF2B, and specifically eIF2Bε, as an important regulator of overall cell growth and proliferation, and may highlight a novel cancer drug target. (Supported by NIH grant DK-15658)