Figure 8

Regulation of proteins translation in Jurkat cells. Schema shows signaling pathway regulating cap-dependent translation in non-irradiated (left) and irradiated (right) cells. In non-irradiated Jurkat cells, the Akt signaling pathway is constitutively activated. Active Akt, indicated by two phosphorylation sites, phosphorylates and activates the kinase mTOR which in turn upregulates the ribosomal translation through phosphorylation of S6K. In addition, phosphorylation of 4EBP1 prevents the protein from binding to the initiation factor eIF4E and allows eIF4E to recruit eIF4G, eIF4A and the eIF3 complex containing the eIF3A subunit to the cap structure at the 5’ end of the mRNA. Thus assembled, the complex is able to initiate protein translation. eIF4B supports eIF4A thereby positively regulating protein translation. IR had no effect on Akt activity. Therefore, Akt and mTOR as well as S6K remain phosphorylated and activated 24 h after irradiation. In contrast, 4EBP1 is dephosphorylated in response to IR, probably due to an enhanced phosphatase activity. Hypophosphorylated 4EBP1 associates with eIF4E and prevents the recruitment of eIF4G to the cap structure. Furthermore, eIF4G, eIF3A, and eIF4B are cleaved downstream of caspase activation (indicated by the white line). As a consequence, the pre-initiation complex is disassembled and cap-dependent translation averted. In addition to eIF4G, eIF4A and the eIF3A complex associate with DAP5 in non-irradiated Jurkat cells suggesting a cap-independent protein translation through an alternative initiation site. In response to IR, DAP5 is cleaved in a caspase-dependent manner. The cleavage coincides with a disassembly of the DAP5-dependent initiation complex, probably resulting in reduced DAP5-dependent translation.