Cell type-specific induction of cyclin D and cyclin-dependent kinase inhibitor p27(kip1) expression by estrogen in rat endometrium

Cyclins, cyclin-dependent kinases (CDKs) and the CDK inhibitor p-27(kip1) a re known to be involved in the regulation of G(1)/S phase transition by est rogen in the rodent endometrium. Little is known, however. of the cell-spec ific location and regulation of these proteins during this process., or the way they mediate the differential effect of estrogen in the epithelium and stroma of the endometrium. Here we studied the cell-specific regulation of D-type cyclin (D1-3), of cyclin A and E, of CDK2 and p27(kip1) by 17 beta -estradiol in the endometrium of ovariectomized rats. Time-course changes i n these proteins in the endometrium of ovariectomized rats were examined by immunohistochemistry at 2, 4, 8. 11 20, 28 and 32 h after estrogen stimula tion. The expression of proliferation cell nuclear antigen (PCNA) was also studied as a marker of proliferating cells. As expected from previous studi es, all the proteins investigated were up-regulated by estrogen, with peak times from 8 to 32 h. The induction of cyclin D-1 is predominant in the gla ndular epithelium. whereas cyclin D-3 increases mainly in the luminal epith elium. The up-regulation of p27(kip1) is restricted to stromal cells with a 'gradient-like' expression pattern, in which the sub-epithelial (functiona l) layer showed stronger staining than the basal layer. The differential re gulation of cyclins and p27(kip)1 in the epithelium and stroma of the endom etrium appear indicative of distinct actions of estrogen in different cell types in the uterus. as D-type cyclins mediate the proliferative effect of estrogen in epithelial cells while p27(kip1) might help prevent the same ef fect in the stroma. (C) 2001 Elsevier Science Ltd. All rights reserved.