These studies are designed to analyze the effects of oncogene expression on cell growth and differentiation. The functions of the proto-oncogenes c-fos and c-myc will be studied by observing the phenotype of both benign (immortalized) and malignant cells when oncogene expression is inhibited. Recombinant DNA vectors designed to produce """"""""antisense RNA"""""""" have been introduced into mouse fibroblast and embryonal teratocarcinoma cell lines. These vectors contain a steroid inducible (MMTV) or metal inducible (Metallothionein) promoter which should allow regulated production of the antisense RNA, or a Rous Sarcoma Virus LTR promoter for constitutive expression. Inhibition of c-fos or c-myc expression with these antisense constructs blocks proliferation of fibroblasts. Preliminary results suggest that antisense c-fos can also inhibit teratocarinoma differentiation. Single stranded antisense DNA oligomers designed to anneal with c-myc mRNA inhibit HL-60 promyelocytic leukemia cell growth and induce early differentiation. Such selective inhibition of c-fos or c-myc expression may further elucidate the role of these proto- oncogenes in normal cellular growth and differentiation.
