In neuroblastoma, amplification of the N-myc gene is closely correlated with increased metastatic ability. The mechanism by which N-myc acts to increase neuroblastoma malignancy is poorly understood as yet. It is shown here that transfection of N-myc in a neuroblastoma cell line causes suppression of one isoform of protein kinase C, named delta, and induction of an unusual type of protein kinase C, named zeta. N-myc-transfected neuroblastoma cells were found to be blocked in the activation of both c-fos mRNA and the NF-kappa B transcription factor by phorbol ester. Introduction of a protein kinase C expression vector in N-myc transfected neuroblastoma cells restored inducibility of both c-fos and NF-kappa B by phorbol ester. These observations indicate that changes in protein kinase C gene expression significantly alter the response of N-myc-amplified neuroblastomas to a variety of external signals.