Our lab is investigating the intricate physiological mechanisms regulating gene expression at the translational (RNA to protein) level. The transcripts of genes controlling cell proliferation and survival contain complex 5’-untranslated sequences which function essentially as “RNA promoters”, with structural features and regulatory protein binding sites that make possible the modulation of translational efficiency of individual mRNAs. Our research is assessing how such gene-specific translational control mechanisms may be altered in human tumor cells, focusing in particular on the proto-oncogenes IGF1R and c-myc. The human IGF1R mRNA contains an extraordinarily long (1,038 nucleotides) 5’-untranslated region, which is inherently a very poor substrate for translation initiation mediated by conventional ribosomal scanning. However, we have determined that the IGF1R mRNA can also be translated through the use of an internal ribosomal entry site (IRES), which maps to an 85 nucleotide segment of the 5’-UTR just upstream of the IGF1R initiation codon. We are profiling the sequence-specific RNA-binding proteins that differentially control IRES activity, and accumulating evidence that changes in the activities of these IRES-regulatory proteins may be responsible for IGF1R over-expression in a proportion of human breast tumors.
We have also begun to characterize a previously hypothetical protein, designated mrtl, which is encoded within the “5’-untranslated” region of the c-myc mRNA, upstream of the Myc coding sequence. Confocal imaging and co-immunoprecipitation data indicate that mrtl is closely associated with ribosomes and translation initiation factors, and results obtained utilizing northwestern analyses, inducible ectopic over-expression, and a dominant negative strategy suggest that mrtl may function physiologically to regulate Myc translation and localization to the nucleus. Current studies are addressing the potential contribution of mrtl to Myc-associated breast oncogenesis. We are exploring both the IGF1R IRES and the mrtl-Myc relationship as potential targets for development of novel molecular therapeutic interventions.