The human insulin-like growth factor II leader 1 contains an internal ribosomal entry site

Insulin-like growth factor II is a small peptide growth hormone, encoded by four mRNAs with unique 5' untranslated regions and identical coding regions. The 5' untranslated region transcribed from promoter 1 is 598 nt (leader 1). The properties of this leader 1 suggest a strong regulation of translation; the high G + C-content, the presence of an upstream open reading frame, and the length of the 5' UTR are 3 elements which prohibit efficient translation and which may modulate expression. In this paper we show that the human IGFII leader 1 harbours sequence elements that allow translation initiation to occur by internal initiation on the IGF sequence. This mode of initiation was described first for picornaviral mRNAs, that are naturally uncapped. The IGFII leader I-dependent expression in HeLa cells was resistant to infection with poliovirus; abrogation of cap-dependent initiation by poliovirus had apparently no effect on IGFII expression. Moreover, a downstream CAT-cistron in a bicistronic construct was translated upon insertion of the leader 1 sequence. The translational properties of the IGFII leader 1 suggest that internal initiation on this leader may be modulated during proliferation or differentiation, enabling cell-stage dependent expression of IGFII.