DIFFERENTIAL EXPRESSION OF THE HUMAN, MOUSE AND RAT IGF-II GENES

The IGF-II gene is a complex transcription unit. Multiple transcripts are synthesized as a result of alternate promoter usage and the splici ng of unique 5' untranslated regions to common coding exons. In order to characterize the mechanisms of IGF-II gene regulation we performed comparative studies to define essential features of IGF-II expression in human, rat and mouse. Homologous promoter regions of the human, mou se and rat IGF-II genes were fused to the luciferase reporter gene and expression was measured in various cell lines that have an endogenous ly active or inactive IGF-II gene expression pattern, respectively. Th e transient promoter activity of the human, mouse and rat IGF-II const ructs was further compared with the endogenous activity of the IGF-II gene in various tissues and cell lines of human, mouse and rat origin. The results indicate that in transient expression assays employing he terologous systems (e.g., mouse promoter in human cells), most IGF-II promoter constructs are active, albeit at low levels. Maximal promoter activity is only observed, however, in homologous systems (e.g., huma n promoter constructs tested in human cells). This suggests that each promoter, despite the strong sequence conservation of the homologous h uman, rat and mouse promoters, is adapted to the levels of the transcr iption factors present in its natural environment. Finally, IGF-II gen e expression is not only regulated at the level of transcription but a lso depends on mRNA stability. We show that human, rat and also mouse IGF-II mRNAs are subjected to specific endonucleolytic cleavage, sugge sting that specific cleavage of IGF-II mRNAs must be of general physio logical importance.