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 an 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.
van der Velden
A W
AW
Department of Molecular Cell Biology, Utrecht University, The Netherlands. a.w.vandervelden@bio.uu.nl
Thomas
A A
AA
D020121:5' Untranslated Regions; D000818:Animals; D051943:Antennapedia Homeodomain Protein; D001260:Ataxia Telangiectasia / Q000235:genetics; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000235:genetics; D029721:Drosophila Proteins; D016228:Endothelial Growth Factors / Q000235:genetics; D039561:Eukaryotic Initiation Factor-4E; D016222:Fibroblast Growth Factor 2 / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D016258:Genes, mos; D016259:Genes, myc; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism; D007938:Leukemia / Q000235:genetics; D008222:Lymphokines / Q000235:genetics; D008297:Male; D009687:Nuclear Proteins; D010448:Peptide Initiation Factors / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics*; D018168:Receptors, Retinoic Acid / Q000235:genetics; D014157:Transcription Factors; D016212:Transforming Growth Factor beta / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014981:Xenopus / Q000196:embryology / Q000254:growth & development
D020121:5' Untranslated Regions; D051943:Antennapedia Homeodomain Protein; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D016228:Endothelial Growth Factors; D039561:Eukaryotic Initiation Factor-4E; D018398:Homeodomain Proteins; D008222:Lymphokines; D009687:Nuclear Proteins; D010448:Peptide Initiation Factors; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C066177:Ubx protein, Drosophila; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C082925:retinoic acid receptor beta; D016222:Fibroblast Growth Factor 2; D007335:Insulin-Like Growth Factor II