A novel parathyroid hormone-related peptide (PTHRP) has been isolated from tumors associated with the syndrome of humoral hypercalcemia of malignancy. The human PTHRP gene appears to use multiple promoters and contains alternatively spliced 3' exons which give rise to three PTHRP mRNA classes, each bearing multiple copies of an AU motif that has been associated with mRNA instability. We report here that inhibition of protein synthesis leads to the super-induction of PTHRP mRNA expression in a number of human and rat cell lines. This phenomenon was found to reflect both an increase in the rate of PTHRP gene transcription and a stabilization of PTHRP mRNAs. The transcriptional mechanism appears to preferentially involve the activity of a short downstream promoter of the gene, which is presumed to be regulated by a labile repressor protein. Our findings indicate that both transcriptional and posttranscriptional mechanisms may be important control points in the regulation of PTHRP expression in normal and malignant cells.