Some thoughts about translational regulation: forward and backward glances.

This review discusses the need to re-examine some popular but unproven ideas about regulation of translation in eukaryotes. Translational control is invoked often on superficial grounds, such as a discrepancy between mRNA and protein levels which could be explained instead by rapid turnover of the protein. It is essential to verify that there is translational control (i.e., essential to rule out alternative mechanisms) before asking how translation is regulated. Many of the postulated control mechanisms are dubious. It is easy to create artifactual regulation (a slight increase or decrease in translation) by over-expressing recombinant RNA-binding proteins. The internal-initiation hypothesis is the source of other misunderstandings. Recent claims about the involvement of internal ribosome entry sequences (IRESs) in cancer and other diseases are discussed. The scanning model for initiation provides a more credible framework for understanding many aspects of translation, including ways to restrict the production of potent regulatory proteins which would be harmful if over-expressed. The rare production in eukaryotes of dicistronic mRNAs (e.g., from retrotransposons) raises questions about how the 3' cistron gets translated. Some proposed mechanisms are discussed, but the available evidence does not allow resolution of the issue.