Induction and desensitization of plasminogen activator gene expression by tumor promoters

Tumor promoting phorbol esters and mezerein strongly induced plasminogen activator (urokinase, uPA) synthesis in porcine kidney cell cultures (LLC-PK1). Induction was due to increased uPA-mRNA levels which rose from 10 to 300 molecules/cell within 2 h of exposure to 16 nM phorbol myristate acetate. We have compared the action of tumor promoters with that of 8-bromo-cAMP, another potent inducer of uPA; the similarities between the two kinds of induction were: both involved transcriptional activation of the uPA gene; both were rapid in onset, changes in transcription rate being detectable within 10-20 min; the initial rates of transcription and uPA-mRNA accumulation were substantial and in the same order of magnitude; neither class of inducer required protein synthesis to stimulate uPA transcription. The main contrast between the two types of agents was that the uPA response to tumor promoters was transient whereas that to cAMP compounds was sustained: cultures rapidly lost their response to tumor promoters within 2 h after initial exposure while retaining responsiveness to cAMP-related agents. The cells developed a specific drug-induced desensitization which was slowly reversed after tumor promoters were removed from the culture medium. Since protein kinase C is now well established as the receptor for phorbol-derived and several other tumor promoters it will be of interest to determine whether desensitization occurs at the level of receptor.