Cell cycle progression and proliferation are controlled by a balance of positive and negative regulators converging on cell cycle kinase cascades (reviewed in; see schematics, Figs. 3 and 7). Interestingly, specific roles for cell cycle regulatory molecules in the control of granulosa cell proliferation and differentiation during follicular development have been elucidated by the altered ovarian phenotypes described in mice null for cyclin D2 and p27Kipi. Cyclin D2 acts as a positive regulator of cell cycle progression by its ability to bind cyclin-dependent kinases (cdks) 4 or 6 and thereby activate a cascade of events that permits progression through G1 phase of the cell cycle; Fig. 3). buy ortho tri-cyclen online
Cyclin E also acts as a positive regulator of cell cycle progression. By binding and activating cdk 2, it regulates the G1 to S phase transition. In contrast, p27Kip1 blocks cell cycle progression by inactivating these same cdk cascades, and cells remain in G1 phase. In mice null for cyclin D2, granulosa cell proliferation is impaired, the ovarian follicles remain small, and ovulation fails to occur. In mice null for p27Kip1, follicular growth is not compromised but granulosa cells do not luteinize properly in response to LH. Therefore, in order to better understand the control of cellular proliferation in the ovary, we analyzed the expression of these cell cycle regulatory molecules and their regulation by hormones during follicular development, specifically when granulosa cell proliferation is rapid and during lu-teinization when cell division has terminated. The results presented highlight the ability of the LH surge to acutely regulate cyclin D2 and p27Kip1 in an inverse manner. Methods for the analysis of cyclin E protein done in the studies presented herein were the same as previously described.
FIG. 3. Cyclin D2/cyclin E and p27Kip1 exert opposing actions on cdk activity and cell cycle progression. Increased synthesis and binding of cyclin D2 activate cdk4/6 activity. Subsequently cyclin E binds and activates cdk2, enabling progression through G1 phase of the cell cycle. Conversely binding of p27KIP1 blocks cdk activity, and the cell cycle is arrested in G1.