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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD038085-02
Application #
6388163
Study Section
Biochemical Endocrinology Study Section (BCE)
Program Officer
Taymans, Susan
Project Start
2000-06-01
Project End
2003-04-30
Budget Start
2001-05-01
Budget End
2002-04-30
Support Year
2
Fiscal Year
2001
Total Cost
$202,285
Indirect Cost
Name
University of Illinois at Chicago
Department
Genetics
Type
Schools of Medicine
DUNS #
121911077
City
Chicago
State
IL
Country
United States
Zip Code
60612
Gillam, M P; Nimbalkar, D; Sun, L et al. (2015) MEN1 tumorigenesis in the pituitary and pancreatic islet requires Cdk4 but not Cdk2. Oncogene 34:932-8
Ray, Dipankar; Terao, Yasuhisa; Christov, Konstantin et al. (2011) Cdk2-null mice are resistant to ErbB-2-induced mammary tumorigenesis. Neoplasia 13:439-44
Aronovitz, Amy; Josefson, Jami; Fisher, Amanda et al. (2008) Rapamycin inhibits growth factor-induced cell cycle regulation in pancreatic beta cells. J Investig Med 56:985-96
Kiyokawa, Hiroaki; Ray, Dipankar (2008) In vivo roles of CDC25 phosphatases: biological insight into the anti-cancer therapeutic targets. Anticancer Agents Med Chem 8:832-6
Shehu, Aurora; Mao, Jifang; Gibori, Gil B et al. (2008) Prolactin receptor-associated protein/17beta-hydroxysteroid dehydrogenase type 7 gene (Hsd17b7) plays a crucial role in embryonic development and fetal survival. Mol Endocrinol 22:2268-77
Ray, Dipankar; Kiyokawa, Hiroaki (2008) CDC25A phosphatase: a rate-limiting oncogene that determines genomic stability. Cancer Res 68:1251-3
Osmundson, Evan C; Ray, Dipankar; Moore, Finola E et al. (2008) The HECT E3 ligase Smurf2 is required for Mad2-dependent spindle assembly checkpoint. J Cell Biol 183:267-77
Ray, Dipankar; Kiyokawa, Hiroaki (2007) CDC25A levels determine the balance of proliferation and checkpoint response. Cell Cycle 6:3039-42
Ray, Dipankar; Terao, Yasuhisa; Nimbalkar, Dipali et al. (2007) Hemizygous disruption of Cdc25A inhibits cellular transformation and mammary tumorigenesis in mice. Cancer Res 67:6605-11
Ray, Dipankar; Terao, Yasuhisa; Fuhrken, Peter G et al. (2007) Deregulated CDC25A expression promotes mammary tumorigenesis with genomic instability. Cancer Res 67:984-91

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