Translation Regulation Meets Cell Survival and Transformation

Abstract

As a regulator of protein synthesis, eukaryotic translation initiation factor 4E (eIF4E) lies downstream in pathways that control cell growth and cell survival. eIF4E stimulates the translation of specific transcripts by promoting nucleocytoplasmic transport and delivering the transcripts to the ribosomes for translation. In the nucleus, eIF4E is associated with subnuclear structures called PML bodies (so-named because they also contain the protein product of the gene responsible for promyelocytic leukemia (PML). eIF4E is regulated by interaction with binding partners that are controlled through phosphorylation in response to growth factors (phosphorylation of these negative regulators inhibits their interaction with eIF4E allowing eIF4E to function) and by PML, which inhibits eIF4E activity in response to stress. Topisirovic et al . identified homeodomain proteins, traditionally considered to be transcriptional regulators, that may also functionally interact with eIF4E to inhibit its nuclear export function. Two homeodomain proteins out of the 199 homeodomain proteins that contain the eIF4E consensus binding motif were tested and interacted with eIF4E: proline-rich homeodomain (PRH) protein and Hox-11. Detailed analysis of the PRH-eIF4E interaction showed a direct interaction between the two proteins and overexpression of PRH inhibited eIF4E-mediated cyclin D1 nuclear export and inhibited cellular transformation associated with eIF4E overexpression. Overexpression of PRH also disrupted the PML bodies and caused redistribution of eIF4E and PML to the cytoplasm. Thus, transcriptional regulators, especially those important early in development, may also regulate protein production by influencing translational efficiency through interactions with eIF4E. In addition to having a role in cellular transformation, eIF4E is downstream of cell survival pathways and overexpression of the protein can inhibit apoptosis. Li et al . studied rescue from apoptosis of cells overexpressing Myc and subjected to the apoptosis-stimulating drug lovastatin. Cytochrome c was not released from the mitochondria of cells overexpressing eIF4E, nor was caspase 3 activated. The amount of the antiapoptotic factor Bcl-X L was increased in the eIF4E cells because increased mRNA abundance and increased recruitment of the transcripts to the polyribosomes. Thus, increasing Bcl-X L may be one mechanism by which translational regulation pathways intersect cell survival pathways. I. Topisirovic, B. Culjkovic, N. Cohen, J. M. Perez, L. Skrabanek, K. L. B. Borden, The proline-rich homeodomain protein, PRH, is a tissue-specific inhibitor of eIF4E-dependent cyclin D1 mRNA transport and growth. EMBO J. 22 , 689-703 (2003). [Abstract] [Full Text] S. Li, T. Takasu, D. M. Perlman, M. S. Peterson, D. Burrichter, S. Avdulov, P. B. Bitterman, V. A. Polunovsky, Translation factor eIF4E rescues cells from Myc-dependent apoptosis by inhibiting cytochrome c release. J. Biol. Chem. 278 , 3015-3022 (2003). [Abstract] [Full Text]