The growing relevance of cap-independent translation initiation in cancer-related genes

Twomainmechanisms for eukaryotic initiation of protein synthesis have been described - the canonical cap-dependent and the alternative cap-independent. They mainly differ in their requirement for 7-methylguanosine cap at 5' end of mRNAmolecules to initiate translation. In cap-independent translation initiation, an element within 5' untranslated region (5'UTR) ofmRNA, defined internal ribosome entry site (IRES), recruits 40S ribosomal subunit directly or close to the start codon without the need for the 5' cap. Some cellular mRNAs - including those encoding for a number of growth factors, oncogenes, receptors, survival proteins, transcription and translation factors - contain IRES elements within their 5' UTR what may allow them to be translated under different physiological or stress conditions (e.g., amino acid starvation, apoptosis, growth arrest, heat shock,mitosis, radiation) when global cap-dependent protein synthesis is suppressed. IRES-dependent translationmay escape the control of checkpoints present in cap-dependent regulation causing improper protein synthesis that can lead to cell apoptosis or disease. A growing number of cancer-related genes have been reported whose translation initiation depends on the presence of IRES element in their mRNA. These findings make the quest for discovering and testing new putative cellular IRESes even more meaningful. A deeper understanding of the role of IRES-dependent translation initiation in cancer etiology could ultimately give us a novel targets for cancer therapy.