C-myb and c-ets-1 have variously been demonstrated to function as protooncogenes. Using a human leukemic cell line, ML-1, we have examined the mechanism by which these genes participate in establishing the sustained proliferation mode that is characteristic of the transformed cell. In the absence of serum, ML-1 cells were found to require IGF-1 and transferrin (TF) for growth and TGF-beta or TNF-alpha plus TF for differentiation. Upon administration of the growth factors, c-myb expression increased within 60 min, whereas after addition of the differentiation factors c-myb expression ceased completely within 3 hr. A correlation was found to exist between the level of c-ets-1 protein in the cells, the extent to which that protein is bound to intron I of the myb gene and the amount of c-myb mRNA that is expressed. Upon administration of growth factors, a sizable increase in the intracellular, and particularly, in the intranuclear level of c-ets-1 protein was observed, whereas a pronounced decrease in the level of this protein occurred after exposure to the differentiation factors. These data demonstrated that the level at which an oncogene-specified transcription factor is expressed can affect the expression of other target oncogenes involved in the regulation of cell proliferation. Stimulated expression of such transcription factor can then lead to the continuous proliferation cycle characteristic of the cancer cell.