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Research Interests
Signaling pathways by which theprototypical glycoprotein
hormones follicle stimulating hormone (FSH) and lutenizing hormone
(LH) signal to initiate cellular responses of differentiation and
proliferation.
Research Summary
The focus of my lab is to elucidate the signaling pathways by which the glycoprotein hormones follicle stimulating hormone (FSH) and luteinizing hormone (LH) initiate cellular responses of differentiation and proliferation. In response to FSH, granulosa cells produce steroid hormones, protein hormones, and growth factors that regulate the hypothalamic/pituitary axis and promote oocyte maturation, development of the follicle to a preovulatory phenotype, and uterine receptivity. All of the documented responses to FSH appear to be mediated by cAMP and its predominate intracellular target, cAMP-dependent protein kinase (PKA). Indeed, granulosa cells offer one of the best examples of a cellular model whose responses are orchestrated by PKA. Signaling by PKA is confined to specific locations in cells by virtue of a multi-gene family of A-kinase anchoring proteins (AKAPs) that localize pools of PKA, their substrates, and interconnected signaling enzymes such as phosphodiesterases (PDEs) that limit the broadcast of cAMP and phosphatases that dynamically regulate substrate phosphorylation. Our studies focus on the signaling pathways and downstream transcriptional targets by which FSH initiates maturation of granulosa cells as well as the AKAPs that anchor PKA to facilitate these responses. We are also interested in pathways by which LH signals to initiate ovulation and luteinization and the associated AKAPs that participate in these pathways.
Research Publications
2005-2009
Alam, H., J. Weck, E. Maizels, Y. Park, E.J. Lee, M. Ashcroft, and M. Hunzicker-Dunn, Role of the phosphatidylinositol-3-kinase and extracellular regulated kinase pathways in the induction of hypoxia-inducible factor (HIF)-1 activity and the HIF-1 target vascular endothelial growth factor in ovarian granulosa cells in response to follicle-stimulating hormone. Endocrinology, 2009. 150(2): p. 915-28.
Hernandez Gifford, J.A., M.E. Hunzicker-Dunn, and J.H. Nilson, Conditional deletion of beta-catenin mediated by Amhr2cre in mice causes female infertility. Biol Reprod, 2009. 80(6): p. 1282-92.
Flynn, M.P., E.T. Maizels, A.B. Karlsson, T. McAvoy, J.H. Ahn, A.C. Nairn, and M. Hunzicker-Dunn, Luteinizing hormone receptor activation in ovarian granulosa cells promotes protein kinase A-dependent dephosphorylation of microtubule-associated protein 2D. Mol Endocrinol, 2008. 22(7): p. 1695-710.
Parakh, T.N., J.A. Hernandez, J.C. Grammer, J. Weck, M. Hunzicker-Dunn, A.J. Zeleznik, and J.H. Nilson, Follicle-stimulating hormone/cAMP regulation of aromatase gene expression requires beta-catenin. Proc Natl Acad Sci U S A, 2006. 103(33): p. 12435-40.
Hunzicker-Dunn M , and Maizels ET. (2006) FSH Signaling Pathways in Immature Granulosa Cells that Regulate Target Gene Expression: Branching out from Protein Kinase A. Cell Signaling 18, 1351-1359.
Hunzicker-Dunn M, Mayo K. (2006) Gonadotropin in signaling in the ovary. THe Physiology of Reproduction, 3rd Edition, Jimmy D. Neil, editor, Elsevier, Inc., San Diego, CA.
Park Y, Maizels ET, Feiger ZJ, ALam H, Peters CA, Woodruff TK, Unterman TG, Lee Ej, Jameson JL, Hunzicker-Dunn M. (2005) Induction of cyclin D2 in rat granulosa cells requires FSH-dependent relief from FOXO1 repression coupled with positive signals from Smad. J Biol Chem. 280(10):9135-48
Salvador LM, Flynn MP, Avila J, Reierstad S, Maizels ET, Park Y, Alam H, Scott JD, Carr DW, and Hunzicker-Dunn M. (2004) Neuronal microtubule-associated protein 2D is a functional RI A-kinase anchoring protein in rat ovarian granulosa cells. J Biol Chem 279, 27621-27632.