PHORBOL ESTER INHIBITION OF ESTROGEN-INDUCED UTERINE DEOXYRIBONUCLEIC-ACID SYNTHESIS

Protein kinase C (PKC) is a key regulatory enzyme in the control of gr owth and differentiated function in many cell types, Recently it has b ecome clear that cross talk occurs between PKC and steroid hormone-act ivated signaling pathways, In this work we have thus used the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) to investigate the re lationship between PKC activation and estrogen-induced proliferation i n an in vivo, model of hormone action, the immature rat uterus, A sing le injection of estradiol (E-2) to immature female animals increases D NA synthesis in all major uterine cell types, Administration of TPA al one, simultaneous administration of TPA and E-2 or administration of T PA 12 h after E-2 did not alter uterine DNA synthesis, However, admini stration of TPA 6 h after E-2 markedly decreased [H-3]thymidine incorp oration and the labeling indices in uterine epithelial, stromal, and m yometrial cells, This inhibition represents a decrease in DNA synthesi s per se rather than a change in the time course of the tissue respons e to the hormone. The inhibitory effect of TPA was reversible within 7 2 h and did not appear to be due to a decrease in the level or degree of occupancy of uterine estrogen receptors. These results suggest that a discrete regulatory event(s) in the pathway of estradiol-induced pr oliferation is inhibited by PKC activation approximately 6 h after hor monal stimulation.