Antisense oligodeoxyribonucleotide targeting cAMP response element-binding protein inhibits growth of rat submandibular gland in vitro

The transcription factor, cyclic response element-binding protein (CREB), occurs in the nuclei of acinar cells of the rat submandibular gland during the early postnatal periods. To elucidate the role of CREB in the growth of submandibular gland, the effect of an antisense oligodeoxyribonucleotide (ODN) targeting CREB was examined in the organ culture system of neonatal rat submandibular gland. In the presence of antisense-CREB ODN in the culture media for 48 hr, a significant decrease in the growth of cultured gland was observed in terms of both the area of acinar epithelial tissue and H-3-thymidine-labeling index of acinar cells, with concomitant decrease in AMP (CREB), the nuclear immunoreactivity for CREB without any degenerative changes in the histology of the gland. In contrast, sense-CREB ODN exhibited no effect on acinar growth. Administration of the beta -adrenergic agonist isoproterenol (IPR) induced enhanced proliferation of acinar cells, which was also inhibited by antisense-CREB ODN. In contrast, the proliferation of connective tissue cells was neither enhanced by IPR nor inhibited by antisense-CREB ODN. These results suggest that the transcription factor CREB plays specific roles in the proliferation of submandibular gland acinar cells during the early postnatal periods.