We have undertaken studies of the regulation of the secretion and cytoplasmic mRNA of chromogranin-A (CgA) and calcitonin (CT) in cells that secrete both substances in order to determine if they are regulated through the same mechanisms. Studies were conducted in cell lines derived from a human medullary thyroid carcinoma (MTC) and a human lung cancer (M103). Treatment with phorbol-12-myristate-13-acetate (PMA) resulted in a dose-dependent increase in the secretion of both CT and CgA by the two cell lines. Phorbol at 1000 nM resulted in 4- and 10-fold increases in CgA secretion and 3- and 5-fold increases in CT secretion by the MTC and M103 cells, respectively. The secretory patterns were similar for CgA and CT. In the M103 cells the same treatment resulted in a 100% increase in CgA-specific cytoplasmic RNA and a 70% increase in CT-specific cytoplasmic RNA. The secretion of CgA and CT was coordinately regulated by phorbol in both MTC and M103 cells, and related mRNA changes could be detected in the M103 cells. These observations support the hypothesis that CT and CgA secretion and gene expression are under similar regulatory controls.