Down-regulation of AP1 activities after polarization of vas deferens epithelial cells correlates with androgen-induced gene expression

Vas deferens epithelial cell subcultures were used to study the sequential regulation of jun/fos proto-oncogene expression and AP1 activities during c ell proliferation, polarization and androgen-induced expression of a termin al differentiation marker, i.e, the mvdp gene. Proliferation of epithelial cells is associated with a high expression in the nucleus of most Jun and F os oncoproteins, After cell seeding on an extracellular matrix which allows polarization and expression of the mvdp gene in response to androgens, AP1 protein accumulation is greatly altered and consists in a loss of JunB, Fr a1, FosB and a decrease in c-Fos, c-Jun and Fra2, while JunD remained at th e same level. This was correlated with a drop in AP1 binding activity as ev aluated by gel shift assay using either API consensus sequence or AP1 bindi ng sites of the mvdp gene promoter region, and in AP1 transactivating activ ity, as estimated by stable transfection experiments using an AP1 responsiv e promoter (TRE-TK-luc). Androgens did not significantly influence AP1 acti vities. On the contrary, stimulation of AP1 proteins by the tumor-promoting phorbol ester caused a decrease in androgen-induced mvdp mRNA accumulation , and this effect was reversed by staurosporine, a potent inhibitor of PKC, Our data suggest that a down-regulation of AP1 activities induced by epith elial cell differentiation is a prerequisite to androgen-induced mvdp gene expression. The high AP1 activities observed during proliferative state or induced in TPA-treated polarized cells, exert a repressive effect on androg en action. (C) 2000 Elsevier Science Ltd. All rights reserved.