GENETIC SUPPRESSOR ELEMENTS - NEW TOOLS FOR MOLECULAR ONCOLOGY - 13THCORNELIUS-P-RHOADS-MEMORIAL-AWARD-LECTURE

Genetic suppressor elements (GSEs) are short biologically active gene fragments that encode dominantly acting peptides or inhibitory antisen se RNAs. GSEs can be isolated from a single gene or from a multigene c omplex by constructing a library of short random fragments of the targ et gene(s) in an expression vector, followed by expression selection f or the desired phenotype in a suitable cellular system. GSE selection from a single gene allows one to develop efficient and specific inhibi tors of the gene function and to identify functional protein domains. GSE selection from a multigene complex, such as a normalized (uniform abundance) cDNA population from mammalian cells, makes it possible to identify genes that are involved in selectable cellular phenotypes. Th e potential of GSE selection for uncovering novel gene functions was f irst demonstrated using bacteriophage lambda as a model system. GSE se lection in retroviral expression vectors has been applied in mammalian cells to identify genes responsible for sensitivity to etoposide and other chemotherapeutic drugs. GSE selection is also useful for cloning and analysis of tumor suppressor genes and can be applied to identify ing tumor-specific targets for future anticancer drugs. Investigators should find this experimental strategy applicable to many different ar eas of medical and biological research.