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 are 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 findings and the published reports on the homology between C, N, and L-myc in blocking MEL differentiation. Our results clearly indicate that constitutive high levels of transfected L- and N- myc mRNAs block inducer-mediated differentiation. These studies strongly suggest that down regulation of c-myc expression in MEL cells is a necessary event for terminal differentiation. We used a number of deletion mutants of the human c-myc gene for mapping the regions responsible for its apparent critical role in MEL and F-9 teratocarcinoma cell differentiation. In MEL cells, our results suggest that the first 40 amino acids of the c-myc protein are dispensable for blocking differentiation, the other domains of the protein are necessary for this function. In addition, we are developing a new approach for identifying proteins that interact with the c-myc protein during differentiation.