Disproportionate expression of the two nonallelic rat insulin genes in a pancreatic tumor is due to translational control.

The expression of the two nonallelic but highly homologous rat insulin genes (1 and 2) in a transplantable beta-cell tumor is found to be 10-fold higher for rat1 insulin than rat2 insulin, while in normal pancreatic tissue there are approximately equal amounts of each protein. No large sequence rearrangements of the genes were apparent by restriction analysis of the tumor DNA, and both genes were found to be specifically hypomethylated in the tumor as compared with other nonpancreatic tissue. Equivalent amounts of both insulin 1 and 2 precursor transcripts, as well as stable, mature mRNAs were detected in the tumor. However, two-dimensional gel analysis of immunoprecipitated rat1 and rat2 preproinsulins synthesized in vitro revealed a 10:1 ratio of rat1 to rat2 proteins. A 1:1 ratio was obtained when the tumor mRNA was treated in vitro with vaccinia virus capping extract, suggesting a structural modification at the 5' terminus of the rat2 mRNA. These results are discussed in the context of insulin regulation by glucose, shown to be due to translational control.