Induction of the 2 early-response genes c-jun and c-fos was investigated in the weakly metastatic T-lymphoma Eb line and the related strongly metastatic lymphomacrophage ESb line to find possible correlations with their different in vitro and in vivo phenotypes. The response of c-jun was elicited by the protein kinase-C activators TPA and A23187 in ESb but not in Eb cells. A much lower response of c-fos was also found in Eb than in ESb cells, in this case by means of scrum and the cAMP elevator forskolin. However, both TPA and the calcium ionophore A23187 were similarly effective in inducing fos-mRNA in both cell lines. The uncoupling of c-jun and c-fos induction in Eb, but not in ESb cells, as well as the uncoupling of c-fos response to different stimulators, point to a differential activation of these 2 early-response genes by the main signal transduction pathways in the 2 cell types. The coordinate/uncoordinate availability of the fos/jun heterodimer may confer distinct regulatory patterns on different target genes in ESb/Eb cells. Activation of these genes may underlie the distinct differentiation phenotypes and in vivo behavior of Eb/ESb cells. © Wiley-Liss, Inc.