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Category Archives: Ovarian Cells

Hormonal Control of the Cell Cycle in Ovarian Cells: MECHANISMS OF CELL CYCLE CONTROL(4)

CELL CYCLE CONTROL(4)

Paradoxically, activin has been shown to down-regulate cyclin D2 in plasmacytic cells, and targeted deletion of the activin pB subunit in mice did not result in an overt ovarian phenotype. Conversely, mice null for the het-erodimeric molecule inhibin (a/pA or a/pB) develop ovarian tumors at the time of puberty that are dependent on gonadotropin support. These observations indicate that the unopposed actions of activin in the presence of cAMP or steroid are tumorigenic. Insulin-like growth factor-1 (IGF-1) has also been implicated in granulosa cell proliferation. However, large antral follicles are present in the ovaries of mice null for IGF-1, indicating that IGF-1 may be more important for differentiation than for proliferation. buy asthma inhaler

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Hormonal Control of the Cell Cycle in Ovarian Cells: MECHANISMS OF CELL CYCLE CONTROL(3)

Additionally, the cAMP/protein kinase A cascade controls the exit from mitosis by regulating the degradation of cyclin B. Thus, not only can the presence or level of hormone, i.e., FSH versus LH, alter the amount of a regulatory molecule; it can also exert effects at multiple points within the cell cycle machinery, at G1-S and M-G1 (Fig. 7).

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Hormonal Control of the Cell Cycle in Ovarian Cells: MECHANISMS OF CELL CYCLE CONTROL(2)

CELL CYCLE CONTROL(2)

In contrast, the Ink4 family of cdk inhibitors bind only cdk4 and cdk6, making them specific inhibitors of G1 phase.

Even in this basic scheme it is clear that regulation of the cell cycle is complex and occurs at many levels. Not only are many different types of molecules involved, but many are families of molecules that are expressed in overlapping as well as tissue-specific patterns. In the ovary, cy-clin D2 is highly expressed specifically in granulosa cells, as is cdk4, while cyclin D1 and cyclin D3 are barely detectable and mice lacking cyclin D1 exhibit normal ovarian function. In contrast, cyclin D1 and cyclin D3 are expressed in an overlapping pattern, with both expressed at the highest levels in theca cells. Both p27 and a related family member, p21Cip1, are highly expressed in the corpus luteum with only slightly different patterns of induction.

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Hormonal Control of the Cell Cycle in Ovarian Cells: MECHANISMS OF CELL CYCLE CONTROL(1)

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

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Hormonal Control of the Cell Cycle in Ovarian Cells: REGULATION OF CYCLIN D2, CYCLIN E, AND P27KiP1(2)

CYCLIN E, AND P27KiP1(2)

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.

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Hormonal Control of the Cell Cycle in Ovarian Cells: REGULATION OF CYCLIN D2, CYCLIN E, AND P27KiP1(1)

To characterize the hormonal regulation of cyclin D2, cyclin E, and p27 in the ovary, we used the hypophysec-tomized rat, in which the effects of estradiol, FSH, and LH on granulosa cell proliferation and differentiation have been well characterized. In situ hybridization of ovarian sections from hormone-treated hypophysecto-mized (H) rats showed that cyclin D2 and p27 exhibit distinctly regulated patterns of expression in granulosa cells (Fig. 4). The results were verified by Western analysis of protein obtained from granulosa cells or luteal cells of these same animals. Specifically, cyclin D2 mRNA and protein are expressed at high levels in granulosa cells of preovulatory follicles of H rats treated with estradiol and FSH (HeF). When HEF rats are injected with hCG, cyclin D2 is down-regulated within 4 h and remains low throughout luteinization. As shown by in situ localization, the down-regulation of cyclin D2 mRNA occurs specifically in granulosa cells of preovulatory follicles that are destined to ovulate and undergo terminal differentiation or luteinization. Cyclin D2 mRNA continues to be expressed in smaller growing follicles that lack LH receptors.

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Hormonal Control of the Cell Cycle in Ovarian Cells: Proliferation Versus Differentiation(3)

Proliferation Versus Differentiation(3)

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

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Hormonal Control of the Cell Cycle in Ovarian Cells: Proliferation Versus Differentiation(2)

This pattern of granulosa cell proliferation and differentiation that characterizes the natural growth of follicles can be mimicked in hypophysectomized rats by a specific hormonal regimen. Injections of estradiol (1.5 mg for 3 days) followed by FSH (1.0 ^g for 2 days) stimulate granulosa cell proliferation and follicle growth to the preovulatory stage. A subsequent ovulatory dose of hCG (10 IU) triggers ovulation and luteinization.

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Hormonal Control of the Cell Cycle in Ovarian Cells: Proliferation Versus Differentiation(1)

Proliferation Versus Differentiation(1)

The growth of ovarian follicles, ovulation, and the formation of the corpus luteum are complex processes that involve dramatic changes in granulosa cell function. The changes are sequential and are dictated by specific, tightly regulated responses to gonadotropins, steroids, and growth factors. One of the most dramatic changes in granulosa cell function is the rapid switch from the highly proliferative stage characterizing granulosa cells of preovulatory follicles to the nonproliferative, terminally differentiated phase of luteal cells. Some of the cell cycle regulatory mechanisms mediating this switch, as well as their control by hormones, are the topics of this minireview. buy ortho tri-cyclen

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