Internal ribosome entry segment-mediated initiation of c-Myc protein synthesis following genotoxic stress

Initiation of translation of the proto-oncogene c-myc can occur by either t he cap-dependent scanning mechanism or by internal ribosome entry. The latt er mechanism requires a complex RNA structural element that is located in t he 5' untranslated region of c-myc, termed an internal ribosome entry segme nt (IRES). Recent work has shown that IRESs are used to maintain protein ex pression under conditions when cap-dependent translation initiation is comp romised; for example, during mitosis, apoptosis and under conditions of cel l stress, such as hypoxia or heat shock. Induction of genotoxic stress also results in a large reduction in global protein synthesis rates and therefo re we investigated whether the c-myc IRES was active following DNA damage. As expected, in cells treated with either ethylmethane sulphonate or mitomy cin C there was a large reduction in protein synthesis, although this was b rought about by two different mechanisms. However, in each case the c-myc I RES was active and c-Myc protein expression was maintained. Finally we show ed that the proteins required for this process are downstream of the p38 mi togen-activated protein kinase (MAPK)/extracellular-signal-regulated protei n kinase (ERK)/MEK(MAPK/ERK kinase) signalling pathways, since pre-treatmen t of cells with inhibitors of these pathways before DNA damage is initiated inhibits both c-myc IRES activity and expression of c-Myc protein.