Cellular differentiation is a complex process for which the molecular mechanisms are poorly understood. How changes in growth potential are related to expression of the differentiated phenotype is at present unknown. We have focused our attention on questions such as the role of oncogenes in the differentiation process of murine erythroleukemia (MEL) and F9 teratocarcinoma cell lines. We were able to demonstrate that in both cell lines, high levels of expression of a transfected c-myc gene blocks HMBA, DMSO or Retinoic Acid (RA) induced differentiation. Based on these finds and the published reports on the homology between C, N, and L-myc protooncogenes, we investigated the ability of the related L-myc gene to substitute for c-myc in blocking MEL differentiation. Our results clearly indicated that constitutive high levels of transfected L-myc mRNA block inducer in our laboratory with N-myc transfectants. These studies strongly suggest that down regulation of c-myc expression in these cell lines is a necessary event for mutants of the c-myc gene for mapping the regions(s) responsible for its apparent critical role in MEL and F9 teratocarcinoma cell differentiation. In addition, we are developing a new approach for identifying proteins that interact with the c-myc protein during differentiation.