REGULATION AND FUNCTION OF NON-AUG-INITIATED PROTOONCOGENES

A small, yet growing, number of cellular eukaryotic mRNAs encoding imp ortant regulatory proteins, such as c-myc and other proto-oncogenes, i nitiate translation from a non-AUG codon, usually in addition to initi ating at a downstream AUG. The efficiency of non-AUG initiation on the se natural cellular mRNAs varies considerably and appears to be govern ed by several features, including the codon sequence, the context surr ounding the codon and the secondary structure of the transcript. In ad dition to factors which control the overall efficiency of c-myc non-AU G initiation, the relative efficiency of the upstream non-AUG initiati on compared with the AUG initiation changes during the growth of cells . As lymphoid and fibroblast cells approach high densities in culture there is a sustained 5-10-fold induction in the synthesis of the non-A UG-initiated c-Myc 1 protein to levels comparable to or greater than t he AUG-initiated c-Myc 2 protein. This increased efficiency of c-myc n on-AUG initiation, due to methionine depletion of the growth medium, s uggests that the scanning preinitiation complex can be regulated to en hance the recognition of a suboptimal non-AUG codon. The significance of non-AUG initiation for the growth-regulatory genes is illustrated b y the different localizations of the int-2, bFGF and hck non-AUG-initi aled proteins, the disruption of the c-myc and lyl-1 non-AUG initiatio n in tumor-derived cell lines, and the distinct biological function of the non-AUG-initiated forms of bFGE.