TYROSINE KINASE INHIBITION DECREASES MUC-1 EXPRESSION IN MOUSE EPITHELIAL-CELLS

Mouse uterine epithelial cells (UEC) express high levels of both messe nger RNA (mRNA) and protein encoding the polymorphic mucin glycoprotei n, Muc-1, under most conditions in vivo and in vitro. Although steroid hormones modulate Muc-1 expression in vivo, it is not clear if these actions are mediated directly by steroid hormone receptors or indirect ly by modulation of key intracellular signal transduction cascades. To address the latter issue, we examined the effects of a wide variety o f modulators of signal transduction cascades on the expression of Muc- 1 in primary cultures of polarized mouse UEC. Transient exposure of UE C to agents that inhibit tyrosine kinases by distinct mechanisms, i.e. , tyrphostin, genistein, and staurosporine, consistently and significa ntly reduced Muc-1 expression. In contrast, a variety of agents that m odulate protein kinase A- or C-dependent pathways had little or no eff ect on Muc-1. The effect of tyrphostin proved to be similar in magnitu de at both the level of Muc-1 protein and mRNA expression. Transient t ransfection assays of mouse UEC and a murine mammary epithelial cell l ine, NMuMG, with mouse Muc-1 promoter-CAT reporter constructs demonstr ated a similar (50-60%) degree of tyrphostin inhibition. These observa tions suggested an action al the level of Muc-1 gene expression. Level s of 100,000g soluble tyrosine kinase activity in mouse UEC freshly is olated from estrous stage (high-level Muc-1 expression) and day 4 of p regnancy (low-level Muc-1 expression) correlated with Muc-1 expression . Furthermore, pretreatment of day 4 pregnant mice with the anti-proge stin, RU486, an agent previously shown to restore or maintain high lev els of Muc-1 expression, also restored soluble tyrosine kinase activit y to levels similar to that observed in estrous stage mice. Collective ly, these results indicate that tyrosine kinase activity is required t o maintain high level Muc-1 expression in mice. (C) 1997 Wiley-Liss, I nc.