The parathyroid hormone-like peptide (PLP) gene is widely expressed in normal and neoplastic tissues. Previous studies have demonstrated that PLP gene expression is regulated by serum and cycloheximide, features common to the regulation of a number of different early response genes. We now report that PLP mRNA transcripts are induced within 5 min of exposure of rat keratinocytes to serum, return to control values at 20 min, and then increase and remain elevated for at least 4 h, following which they return to baseline levels. The PLP mRNA t_½ was approximately 90 min in both serum-deprived and serum-stimulated cells. The serum induction was blocked by actinomycin D. Cycloheximide alone induced PLP gene expression; however, PLP mRNA transcripts were not superinduced in the presence of both serum and cycloheximide. Dexamethasone and 1,25-dihydroxyvitamin D₃ inhibited the basal levels of PLP mRNA transcripts but did not eliminate the serum induction of PLP gene expression. Epidermal growth factor or transforming growth factor-β alone induced PLP mRNA transcripts, but no induction was observed following exposure of cells to epidermal growth factor and transforming growth factor-β together. Treatment with 12-O-tetradecanoylphorbol-13-acetate for 90 min did not induce PLP mRNA transcripts, but 12-O-tetradecanoylphorbol-13-acetate blocked the rapid serum induction of PLP gene expression. These features of PLP gene expression suggest that PLP is a member of the growth factor-regulated early response gene family. The rapid serum stimulation of PLP gene expression raises the possibility that PLP may contribute in an autocrine fashion to the early cellular response to growth factor stimulation.