The cell division cycle is tightly controlled in a fashion coordinated with differentiation and lineage-specific function. Cyclin-dependent kinases (CDKs), activated by regulatory subunits known as cyclins, form the central machinery of the cell cycle, and their activity is regulated by a variety of extracellular signals. Perturbation of CDK regulation could result in not only deteriorated function of the tissue, but possibly tumor formation. Granulosa cells in the ovary continuously undergo serial processes of proliferation, differentiation and cell death. Recent studies have suggested that precise control of the cell cycle machinery in granulosa cells is critical for female fertility and suppression of ovarian tumors. The hypothesis evaluated in this program is: Cyclin D2/CDK4 is critical for pre-ovulatory proliferation of granulosa cells and subsequent ovulation. The ovulation triggering signal i.e. the surge of luteinizing hormone suppresses cyclin D2 expression and induces expression of the CDK inhibitors p27 and p21. These changes in the cell cycle machinery facilitate differentiation and quiescence of granulosa cells. Intriguingly, the principal investigator has shown that CDK4-deficiency or p27-deficiency in mice results in female infertility.
The specific aims are: (1) Determine whether CDK4 activity governs the balance between proliferation and differentiation of granulosa cells, by examining ovaries of CDK4-deficient mice after gonadotropin treatment; (2) Determine whether p27 and p21 synergistically regulate exit of granulosa cells from the cell cycle, by examining proliferation, differentiation and tumorigenesis in ovaries of mice lacking both p27 and p21; (3) Determine whether gonadotropin-dependent regulation of cyclin D2 expression is critical for ovulation, luteinization and proliferation control in granulosa cells, by examining effects of transgenic cyclin D2 expression in granulosa/luteal cells in p27(+/+) or (-/-) background. These studies using unique mouse models should provide significant insight into how complex extracellular signals orchestrate cell cycle progression and differentiation in the ovary, and contribute to molecular basis for designing therapeutic strategies against female infertility and ovarian tumors.
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