When HEF rats were injected with an ovulatory dose of hCG, cyclin E levels remained high at 4 h and 24 h; however, by 48 h after hCG, cyclin E was low in the luteinized granulosa cells. buy antibiotics online
Collectively, these data suggest that one putative mechanism by which the LH surge terminates granulosa cell proliferation involves the rapid inhibition of cyclin D2 transcription. As shown in Figure 1, granulosa cell exit from the cell cycle occurs within 4 h of the LH surge, coinciding with the drastic down-regulation of cyclin D2, but prior to the down-regulation of cyclin E and the induction of p27. Regulation of cyclin D2 is highly probable as the primary regulatory event controlling granulosa cell proliferation, since 1) cyclin D2, but not cyclin D1 or cyclin D3 (which have redundant functions ), is expressed in granulosa cells and 2) the absence of cyclin D2, but not the absence of cyclin D1, markedly impairs granulosa cell proliferation. Additionally, cyclin E, a downstream mediator of cell cycle progression, continues to be expressed in luteinizing granulosa cells long after the rapid disappearance of cyclin D2.
Therefore, the down-regulation of cyclin D2 in response to LH would presumably prevent the first step in cell cycle progression, thereby initiating granulosa cell exit from the cell cycle before reaching the cyclin E-regulated checkpoint. The temporal expression pattern for p27 suggests that a second mechanism by which LH terminates granulosa cell proliferation is by increasing the level of this cdk inhibitor. In addition, the increase in p27 may control some aspect of granulosa cell differentiation or maintenance of luteal cell differentiation. In summary, these data indicate that the LH surge terminates granulosa cell proliferation and initiates differentiation by inverting the balance of these positive and negative regulators of cell cycle progression (Fig. 6). LH coordinately down-regulates expression of cyclin D2, followed by cyclin E, as it increases the levels of p27. The ovarian phenotypes of the mice lacking cyclin D2 or p27 support such a model. The loss of cyclin D2 results in the absence of FSH- and estradiol-stimulated granulosa cell proliferation, which normally leads to large, preovulatory follicles. The loss of p27 results in impaired differentiation as seen by the inability of granulosa cells to luteinize normally and produce sufficient progesterone to support pregnancy.
FIG. 6. The LH surge inverts the balance of positive versus negative cell cycle regulators and triggers granulosa cell exit from the cell cycle concurrent with luteinization.