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Cover The Her-2 3' UTR derepresses translation by the 5' upstream open reading frame (uORF) to up-regulate Her-2 translation efficiency. Shown here is a conceptual closed-loop model of translational derepression by the Her-2 3' UTR, depicting the interaction of the 5' and 3' ends of the Her-2 mRNA (chain-like structure). The closed loop is facilitated by interaction of PABP (orange) bound to the poly(A) tail with the cap-binding complex (purple) at the 5' end of the Her-2 mRNA. Also depicted is the interaction of eRF3 (yellow) with the stop codon near the 3' end of the Her-2 coding region. Translation of a uORF normally results in strong inhibition of Her-2 protein expression (yellow chain). Overexpression of Her-2 is accomplished by derepression of the uORF through association of a protein complex (pink) docked on the 3' UTR of the Her-2 mRNA. The 3'-UTR-bound protein complex consisting of PABP-eRF3-eRF1 (orange, yellow, green) facilitates rapid dissociation of the 80S ribosome (dark blue) at the uUGA, so that the 40S subunit (light blue) remains associated with the Her-2 mRNA. The 40S subunit may retain key translation initiation factors, and may rapidly reacquire eIF2/Met-tRNAi/GTP, to promote efficient reinitiation at the main AUG of the Her-2 coding region. Please note that the molecules in this model are not drawn to scale. (For details, see Mehta et al., p. 939; graphic illustration courtesy of Craig Foster.)