Regulation of the cell cycle within any cell type is complex, involves the balance of many regulatory molecules, and can be altered by numerous external signals acting at multiple steps in the cycle. In the ovary, estradiol, FSH, and LH are essential signals for the growth of preovulatory follicles and their subsequent terminal differentiation as corpora lutea. Each hormone acts via specific receptors and intracellular signaling pathways. Additionally, FSH and LH act by controlling distinct levels of cAMP and the activation of the A-kinase pathway. The pivotal roles of cyclin D2 and p27 in ovarian follicular growth and differentiation are indicated by their selective expression and regulation in the ovary and their critical and opposing effects on cdk activity that controls entry and progression through G1 of the cell cycle. However, as briefly summarized below (see reviews ), other regulatory molecules control progression through additional checkpoints of the cell cycle, and some of these are likely to be critical in the ovary as well (Fig. 7). buy prednisone
Early in G1 phase, the presence of D-type cyclins activates cdk4 or cdk6, while the accumulation of cyclin E later in G1 phase activates cdk2. Progression through S phase is regulated by cyclin A complexes followed by the initiation of M by cyclin B-cdc2 complexes. The binding of cyclin D and cdk4/6 results in the formation of a complex that is then phosphorylated by cdk-activating kinase (CAK). The active cyclin-cdk complex in turn phosphorylates cellular substrates that regulate DNA synthesis. The best-known example is the retinoblastoma protein, Rb, which in a hypo-phosphorylated state acts as a suppressor of cell division by binding to DP/E2F transcription factors, thereby preventing the transcription of genes necessary for replication and cell division. The repression of transcription by Rb appears to be mediated by its ability to recruit histone de-acetylase. However, hyperphosphorylation of Rb by cyclin D-cdk4/6 and cyclin E-cdk2 relieves its suppressive abilities, and the cell cycle is able to progress past the restriction point (R), from G1 to S phase, at which time the cell is irreversibly committed to divide.
The Cip/Kip family of cdk inhibitors, which includes p27, acts to block cell cycle progression by binding and inhibiting the activity of cdks. The Cip/Kips (p21Cip1, p27Kip1, p57Kip2) have relatively broad specificity and are able to bind not only cdk4/6, but also cdk2 and cdc2, enabling them to inhibit the activity of several kinase cascades and thereby block cell cycle progression at multiple points.
FIG. 7. Schematic of known cell cycle events and factors regulated in ovarian cells by gonadotropins and estradiol. Solid arrows depict events shown herein to be regulated by FSH, LH, and estrogen during follicular growth and luteinization. Dashed arrows show events likely to be controlled by FSH/cAMP and estrogen on the basis of studies described in the text. Other arrows indicate the sequence of regulatory steps in the cell cycle as summarized from numerous reviews cited in the text. T-shaped lines indicate inhibitory actions.