Normal human melanocytes require 12-O-tetradecanoylphorbol 13-acetate (TPA) for prolonged growth in vitro. In contrast, the growth of human malignant melanoma cells is often inhibited by TPA. In this study, we have confirmed and extended these observations. Since protein kinase C (PKC) is an important mediator of the effects of TPA, we have investigated the nature of this differential growth response by examining PKC expression and activity in primary cultures of human neonatal melanocytes and metastatic melanoma cell strains. PKC, when measured by immunoreactivity or a functional assay, was found to be more abundant in melanoma cells than in melanocytes. When specific isotypes were examined by Northern analysis, PKC-alpha and -epsilon were expressed in both melanocytes and melanoma. PKC-beta was expressed in melanocytes, but was undetectable by Northern analysis in 10 out of 11 melanoma cell strains. Southern analysis revealed that no gross deletions or rearrangements of the PKC-beta gene had occurred. These data suggest that down-regulation of the PKC-beta gene occurs frequently during the process of transformation of melanocytes. Furthermore, differential expression of PKC isotypes may explain the different effects of TPA on melanocyte and melanoma cell growth.