POSTTRANSCRIPTIONAL REGULATION OF INSULIN-LIKE GROWTH-FACTOR-II MESSENGER-RNA

The insulin-like growth factor II (IGF-IT) gene generates multiple mat ure transcripts with different 5'untranslated regions (5'UTR) but iden tical coding regions and 3'UTRs. We have analysed the translational re gulation and decay of the transcripts. Human IGF-II mRNAs provide a pr ovocative example of translational discrimination in which only the mi nor 4.8 kb mRNA is actively engaged in protein synthesis while the maj or 6.0 kb mRNA is present in a 100S RNP particle. The 6.0 kb mRNA exhi bits a structured 5'UTR of 1170 nucleotides that function as a cis-act ing translational attenuator. IGF-II transcripts are processed by endo nucleolytic cleavage 1209 and 2183 nucleotides downstream from the tra nslation termination codons in the rat and human, respectively. The cl eavage site is situated in a highly conserved and structured domain th at exhibits two large hairpins and an intramolecular guanosine quadrup lex. The structural elements may provide binding sites for trans-actin g factors and ensure that the cleavage site is not sequestered in stab le RNA structures. Since expression of IGF-II is initiated from minima l promoters and finished by constitutive secretion from the cell, regu latory events governing IGF-II production are likely to be implemented between the transcriptional and the posttranslational level. The comb ined effect of translational discrimination and endonucleolysis may th erefore play an important role in the regulation of IGF-II expression.