Estrogen induces early and timed activation of cyclin-dependent kinases 4, 5, and 6 and increases cyclin messenger ribonucleic acid expression in rat uterus.

ABSTRACT

Cyclin-dependent kinases (cdks) are serine-threonine protein kinases that play a key role in the regulation of the mitotic cycle, in transcription initiation, and in the control of specific metabolic pathways in eukaryotic cells. cdk activity is controlled via phosphode-phosphorylation of the catalytic subunits of these enzymes and their physical association with cyclins and cdk inhibitors. In adult rats, estrogen stimulation results in massive proliferation of endometrial epithelial cells, accompanied by functional and structural modifications in all other tissue components of the uterus. We report here that administration of 17 beta-estradiol (E2) to adult ovariectomized rats induces within the first 25 h significant activation of cdk 4, 5, and 6, but not cdk 2, in the uterus, accompanied by increased expression of D-type (D1-3), A and E cyclin messenger RNAs (mRNAs). Furthermore, expression of the cdk inhibitor p27Kip1, a key regulator of uterine functions, is induced by E2 in this organ. Analysis of RNA extracted from E2-stimulated rat endometria shows early accumulation of D1 and D3, but not D2, cyclin mRNA, preceded by transient accumulation of c-fos mRNA. These results indicate an involvement of cdks and cyclins in estrogen actions in adult rat uterus and suggest that cyclins D1 and D3 are part of the molecular pathway that allows hormonal regulation of G1 progression in endometrial cells.