Estrogen and progesterone regulation of uterine cell proliferation and differentiation

Abstract

Using ovariectomized cyclin D1 null mutant mice, the current studies has shown that cyclin D2 compensates for the loss of cyclin D1 in the uterine responsiveness to estradiol-17beta (E2). Expression of cyclin D2 can be detected in wild type mice, however, its nuclear localization profile is changed after E2 injection based on the cyclin D1 status. Cyclin D2 binds with CDK4 in both wild type and cyclin D1 null cells, although the binding is increased in response to E2 in the cyclin D1 -/- mice compared to wild type mice. In the cyclin D1 null uterus, cyclin D2 can bind with one of the dominant cyclin kinase dependent inhibitor (CKI), p27kip1, releasing cyclin E or cyclin A/CDK2 kinase complex. In summary, we found cyclin D2 can compensate for the cyclin D1 loss in response to E2 in all aspects of the cyclin D1 function in the wild type mice.;To further examine the role of cell cycle inhibition in E2 and progesterone (P4) action, we analyzed the fertility profiles of the two Ink CKI family members: p18Ink4c and p19 Ink4d. Female p18Ink4c and p19Ink4d null mice were fertile, however, male p18Ink4c were infertile. Whether or not Ink4d was present, male animals lacking Ink4c developed hyperplasia of interstitial testicular Leydig cells, which produced reduced levels of testosterone. Because Ink4d-null mice are fertile, increased FSH production by the anterior pituitary is also unlikely to contribute to the sterility observed in Ink4c/ Ink4d double-null males. Instead, our data indicate a collaboration of the two CDK inhibitors in regulating spermatogenesis, helping to ensure mitotic exit and the normal meiotic maturation of spermatocytes.;Using subtractive PCR, a group of genes upregulated by P4 have been identified, including cathepsin D, histidine-decarboxylase, Hoxa-10, which were reported previously. Among them, is immune-response gene 1 (Irg1). Hormone replacement studies of ovariectomized mice showed that it was regulated synergistically by E2 and P4. Interestingly, Protein kinase C (PKC) mediates Irg1 up-regulation since inhibition of PKC activity blocks Irg1 expression. Irg1 expression rises on day 3 of pregnancy, which just precedes implantation. Irg1 has high homology to bacterial protein methylcitrate dehydratase (PrpD), which may be involved in cholesterol and fatty acid metabolism. The rapid induction and cell type expression of Irg1 during early pregnancy suggests alterations in lipid metabolism may play an important role in implantation. (Abstract shortened by UMI.).