The role of the 5′ untranslated region of an mRNA in translation regulation during development

Cap-dependent ribosomal scanning occurs on the majority of cellular 5 ' UTRs. This process is severely hampered on long 5 ' UTRs, containing AUGs and secondary structure. These characteristics are often found in mRNAs encoding regulatory proteins like proto-oncogenes, growth factors, their receptors, and homeodomain proteins. A number of these mRNAs use an alternative mechanism of translation initiation, involving an internal ribosomal entry site (IRES). Cellular mRNAs containing a complex 5 ' UTR or an IRES share all intriguing characteristic: their translational efficiency can be very specifically regulated by their 5 ' UTR, providing post-transcriptional regulation. During embryonic development, the 5 ' UTRs of Antp, Ubx, RAR beta 2, c-mos and c-myc regulate protein expression in a spatio-temporal manner. Translation initiation on a number of growth factor RNAs (IGFII, PDGF2, TGF beta, FGF-2 and VEGF) is specifically regulated during differentiation, growth, and stress. Furthermore, 5 ' UTR activity, mutations in the 5 ' UTR, or the occurrence of alternative 5 ' UTRs have been implicated in the progression of various forms of cancer. The mechanisms involved in 5 ' UTR mediated control are not well understood. Binding of trans-acting factors could mediate translation stimulation or repression. Furthermore, the precise localization of upstream AUGs and the activity of the cap-binding initiation factor 4E are suggested to be important for translation regulation of these mRNAs. This review focuses on 5 ' UTRs whose activity is regulated, the processes during which this regulation occurs, and as far as known the mechanisms involved. (C) 1999 Elsevier Science Ltd. All rights reserved.