tailieunhanh - Báo cáo Y học: Phosphorylation of initiation factor-2a is required for activation of internal translation initiation during cell differentiation

The long uORF-burdened 5¢UTRs of many genes encoding regulatory proteins involved in cell growth and differentiation contain internal ribosomal entry site (IRES) elements. In a previous study we showed that utilization of the weak IRES of platelet-derived growth factor (PDGF2) is activated during megakaryocytic differentiation. The establishment of permissive conditions for IRES-mediated translation during differentiation has been confirmed by our demonstration of the enhanced activity of vascular endothelial growth factor, c-Myc and encephalomyocarditis virus IRES elements under these conditions, although their mRNAs are not naturally expressed in differentiated K562 cells | Eur. J. Biochem. 269 2810-2819 2002 FEBS 2002 doi Phosphorylation of initiation factor-2a is required for activation of internal translation initiation during cell differentiation Gabi Gerlitz1 Rosemary Jagus2 and Orna Elroy-Stein1 1Cell Research and Immunology George S. Wise Faculty of Life Sciences Tel Aviv University Israel 2Center of Marine Biotechnology University of Maryland Biotechnology Institute Baltimore USA The long uORF-burdened 5 UTRs of many genes encoding regulatory proteins involved in cell growth and differentiation contain internal ribosomal entry site IRES elements. In a previous study we showed that utilization of the weak IRES of platelet-derived growth factor PDGF2 is activated during megakaryocytic differentiation. The establishment of permissive conditions for IRES-mediated translation during differentiation has been confirmed by our demonstration of the enhanced activity of vascular endothelial growth factor c-Myc and encephalomyocarditis virus IRES elements under these conditions although their mRNAs are not naturally expressed in differentiated K562 cells. In contrast with the enhancement of IRES-mediated protein synthesis during differentiation global protein synthesis is reduced as judged by polysomal profiles and radiolabelled amino acid incorporation rate. The reduction in protein synthesis rate correlates with increased phosphorylation of the translation initiation factor eIF2a. Furthermore IRES use is decreased by over-expression of the dominant-negative form of the eIF2a kinase PKR the vaccinia virus K3L gene or the eIF2a-S51A variant which result in decreased eIF2a phosphorylation. These data demonstrate a connection between eIF2a phosphorylation and activation of cellular IRES elements. It suggests that phosphorylation of eIF2a known to be important for cap-dependent transaltional control serves to fine-tune the translation efficiency of different mRNA subsets during the course of differentiation