Translational control in stress and apoptosis

Abstract

Translation is the final step in the flow of the genetic information, and regulation at this level allows an immediate, rapid and reversible response to changes in physiological conditions. This type of regulation is especially advantageous during conditions of cellular stress. Translation is divided into three distinct phases: initiation, elongation and termination. Although all three phases are subject to regulatory mechanisms, under most circumstances the rate-limiting, regulated step is the initiation of translation. Most cellular mRNAs are translated by a cap-dependent mechanism that involves the interaction of the 5′ m⁷G-cap structure of the mRNA with the cap-binding protein, eukaryotic initiation factor-4E (eIF4E), and the translation-initiation machinery. Some viral and cellular mRNAs have evolved a cap-independent mechanism of translation initiation that uses the internal ribosome-entry site (IRES) sequence that is located in the 5′ untranslated regions of these mRNAs. IRESs recruit ribosomes directly to the vicinity of the initiation codon without the requirement for eIF4E. Global translation is reduced in response to most cellular stresses, both to conserve energy and to prevent the synthesis of unwanted proteins. Remarkably, the stress-induced attenuation of global translation is often accompanied by a switch to the selective translation of proteins that are required for cell survival under stress. Several genes that are involved in cell growth and proliferation, differentiation and the regulation of apoptosis use IRES-mediated translation. This mode of translation provides a means for escaping the global decline in protein synthesis, and allows the selective translation of specific mRNAs, which indicates that the selective regulation of IRES-mediated translation is crucial to the regulation of cell death and survival.