The human colon-cancer cell line Caco-2, though of malignant origin, is still able to express the c-myc proto-oncogene in a regulable fashion. Transition from the logarithmic growth phase into the quiescent, i.e., confluent state, is accompanied by a significant increase in the number of cells in the G0/G1 phase of the cell cycle and a concomitant reduction of c-myc mRNA and of nuclear association of c-myc protein. Conversely, growth stimulation by lowering extracellular [Ca++]0 to 0.25 mM results in up-regulation of c-myc expression levels and consequently inhibition of re-entry of Caco-2 cells into the G0/G1 phase. In contrast, regulation of c-myc in Caco-2 cells is completely resistant to vitamin-D sterols, since the anti-mitogenic action of 1α,25-dihdroxyvitamin D3 (1α,25(OH)2D3) and of 2 synthetic analogs, 1α,25(OH)2–16-ene-23-yne-D3 and 1α,25(OH)2–26,27-F6–16-ene-23-yne-D3, occured independently of any change in c-myc mRNA and nuclear protein levels. Although the anti-proliferative effect of the vitamin-D sterols requires high-affinity binding to the cytoplasmic vitamin-D receptor (VDR), vitamin-D sterols have no effect on VDR mRNA levels in Caco-2 cells. However, VDR mRNA expression changed in an anti-parallel fashion to c-myc regulation upon transition between different growth states. This suggests that VDR mRNA abundance could nevertheless be important for vitamin-D-related c-myc-independent growth control in Caco-2 cells. © 1995 Wiley-Liss, Inc.