RETINOID REGULATION OF HUMAN ECTOCERVICAL EPITHELIAL-CELL TRANSGLUTAMINASE ACTIVITY AND KERATIN GENE-EXPRESSION

Cornified envelope formation, the level of transglutaminase activity and the pattern of cytokeratin gene expression are important biochemical markers of cervical epithelial cell differentiation in vivo. In the present study we examine the effects of retinoid treatment on transglutaminase (TG) activity and keratin gene expression in cultured human ectocervical epithelial cells (ECE cells). All-trans-retinoic acid (RA) and a synthetic retinoid, Ro 13-6298, suppress TG activity by 85-90% with half-maximal inhibition at 0.1 nM Ro 13-6298 or 1 nM RA. In contrast, the predominant circulating retinoid, retinol, does not inhibit TG activity. The level of type I transglutaminase protein, measured using a type I TG-specific antibody, decreases in parallel with the decrease in activity as does the level of the TG RNA transcript. Cytokeratin K16 decreases more than 20-fold while the level of K7, K8 and K19 increase 5 to 10-fold in the presence of 10 nM RA. Studies using cDNAs encoding K5, K13, K16 and K19 indicate that the RNA transcript levels change in parallel with the change in keratin protein production. Thus, all-trans-retinoic acid suppresses ectocervical epithelial cell differentiation in vitro, a result that suggests an in vivo role for retinoids in regulating cervical cell differentiation.