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Estrogen Induces Early and Timed Activation of Cyclin-Dependent Kinases 4, 5, and 6 and Increases Cyclin Messenger Ribonucleic Acid Expression in Rat Uterus¹

Institute of General Pathology and Oncology, Faculty of Medicine and Surgery, Second University of Naples, Naples, Italy

Address all correspondence and requests for reprints to: Alessandro Weisz, Istituto di Patologia Generale e Oncologia, Facolta’ di Medicina e Chirurgia, Seconda Universita’ di Napoli, Larghetto S. Aniello a Caponapoli, 2, I-80138 Naples, Italy. E-mail: a.weisz{at}area.ba.cnr.it

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 phosphodephosphorylation 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 17ß-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 p27^Kip1, 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.

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