IRES-mediated translation of cellular messenger RNA operates in eIF2?- independent manner during stress.

ABSTRACT: Physiological and pathophysiological stress attenuates global translation via phosphorylation of eIF2?. This in turn leads to the reprogramming of gene expression that is required for adaptive stress response. One class of cellular messenger RNAs whose translation was reported to be insensitive to eIF2? phosphorylation-mediated repression of translation is that harboring an Internal Ribosome Entry Site (IRES). IRES-mediated translation of several apoptosis-regulating genes increases in response to hypoxia, serum deprivation or gamma irradiation and promotes tumor cell survival and chemoresistance. However, the molecular mechanism that allows IRES-mediated translation to continue in an eIF2?-independent manner is not known. Here we have used the X-chromosome linked Inhibitor of Apoptosis, XIAP, IRES to address this question. Using toeprinting assay, western blot analysis and polysomal profiling we show that the XIAP IRES supports cap-independent translation when eIF2? is phosphorylated both in vitro and in vivo. During normal growth condition eIF2?-dependent translation on the IRES is preferred. However, IRES-mediated translation switches to eIF5B-dependent mode when eIF2? is phosphorylated as a consequence of cellular stress.

SUBMITTER: Thakor N 

PROVIDER: S-EPMC3258125 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature