Signal Transduction Laboratory 

Director
John S. Davis, Ph.D.

Overview

The theme of this laboratory, under the direction of John S. Davis, is engaged in multiple projects which are funded by the NIH National Institute of Child Health and Development, the Department of Veterans Affairs Medical Research Program, the Department of Defense and the Olson Center for Women’s Health. The central theme of this laboratory is to identify the cellular and molecular mechanisms that are responsible for relaying the actions of gonadotropins, growth factors, and cytokines in ovarian cells. The laboratory is examining novel intracellular signal transduction pathways that govern cell survival and death (apoptosis), cell proliferation, cellular differentiation, gene expression, and steroidogenesis. Ovarian steroids play a prominent role in the regulation of women’s health.

A thrust of this laboratory is to characterize the intracellular signaling systems that mediate the growth and differentiating properties of the pituitary gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH). FSH regulates follicle growth, differentiation, and estrogen secretion. LH is responsible for stimulating ovulation, corpus luteum development, and the maintenance of progesterone and peptide secretion. Both hormones activate distinctive cascades of intracellular signals that stimulate cell proliferation, cell survival, and gene expression. These signaling cascades involve the activation of enzymes that phosphorylate proteins or lipids such as tyrosine protein kinases, serine/threonine protein kinases (PKA, PKB (Akt), PKC, MAPK, Akt, etc), and lipid kinases such as phosphatidylinositol 3-kinase (PI 3-kinase). Knowledge of these signaling mechanisms is critical to fully understand the mechanisms that promote fertility and regulate ovarian steroidogenesis. Ovarian steroids, in addition to their role in reproduction, play a prominent role in the regulation of other aspects of women’s health, including bone mineralization and cardiovascular disease. Another thrust of this laboratory is to understand how growth factors and cytokines regulate ovarian function. Specific growth factors, such as insulin-like growth factor-I (IGF-I), promote cell proliferation and augment the action of gonadotropins. This involves activation of growth factor receptors, tyrosine kinases, PI 3-kinase and inhibition of programmed cell death (apoptosis). In contrast, environmental stresses and cytokines such as tumor necrosis factor alpha (TNFa), Fas ligand (FasL) and interferon gamma (IFNg) interfere with cell growth, promote cell death, prevent differentiation, and inhibit steroidogenesis. The identification of signaling elements that interfere with gonadotropin action may provide important clues to critical links in the regulation of fertility, menopause, and aging.

Chorionic gonadotropin (CG) is the placental member of the glycoprotein hormone (GPH) family that includes thyroid stimulating hormone, follicle stimulating hormone and luteinizing hormone.  Members of the GPH family are comprised of a common a-subunit and a hormone-specific b-subunit that confers biological specificity.  CG plays a vital role in the maintenance of pregnancy in humans (h) and higher primates by stimulating the ovary to produce progesterone, which rescues the corpus luteum of pregnancy.  Recent studies show that CG also supports pregnancy maintenance by facilitating blastocyst implantation into the uterine wall in a manner distinct from its role of ovarian support of pregnancy.   hCG activity is mediated via a G protein coupled receptor (the LH/CG-R) that is capable of regulating multiple signal transduction pathways such as PKA-, PLC/PI3K/AKT- and MAPK- mediated events.  Being interested in CG structure-function relationships, we have initiated studies on how modifications in CG structure and/or conformation modulate CG-mediated signal transduction pathways.

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