A previous report from this laboratory indicated that a transformed fibroblast cell line up-regulated c-myc by as much as 14-fold as cultures approached saturating densities, whereas the untransformed counterparts displayed little alteration in c-myc expression (Cancer Res., 49: 2320, 1989). The results suggested a mechanism for the growth advantage of the transformed cells at postconfluent densities. Similarly, the present results indicate that regulation of c-myc expression during establishment of a quiescent state markedly differed in poorly differentiated versus well-differentiated human colon carcinoma cells. While c-myc expression increased 2- to 3-fold during this period in the poorly differentiated cells, expression levels for this protooncogene showed little variation in the well-differentiated cells. There was, however, no correlation between degree of differentiation and c-myc mRNA levels in growing cultures (i.e., cells in late log phase). Another proliferation-associated mRNA, transforming growth factor alpha (TGF-alpha), was also differentially regulated in the two groups of colon carcinoma cells as cultures approached quiescence. Further, addition of exogenous growth-stimulatory factors (epidermal growth factor plus insulin plus transferrin) to quiescent, well-differentiated cells resulted in an up-regulation of TGF-alpha mRNA levels by 9-fold over a 24-h period. In contrast, poorly differentiated cells displayed little alteration in TGF-alpha mRNA levels under similar conditions. The results suggest that inappropriate kinetic regulation of c-myc and TGF-alpha mRNAs at quiescence may be related to the growth factor independence of the poorly differentiated colon carcinoma cells. Furthermore, altered temporal regulation of c-myc and TGF-alpha expression appears to be more relevant to differentiation status in human colon carcinoma cells than are absolute expression levels.