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Cheryl S. Watson, Ph.D. Credentials
Currently:
Membership in Graduate Programs:
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Rapid actions of steroids are particularly relevant to cells of the neuroendocrine system and to hormone-responsive cancer cells. We investigate the actions of both physiological estrogens and estrogen mimetics (xenoestrogens such as environmental estrogens and phytoestrogens) on the rapid nongenomic signaling cascades initiated by estrogens and other steroids.
We study a novel membrane form of the estrogen receptor-α. In pituitary tumor cells this receptor mediates the rapid secretion of prolactin, in part via increases in intracellular calcium entering the cell through L-type calcium channels. Actions through the membrane estrogen receptor also activate a series of kinases, culminating in activation of the MAP kinase ERK. We have identified cell surface estrogen receptors immunocytochemically (fluorescence, confocal, and digital image deconvolution microscopy), and via inhibitory antibody and antisense knockdowns of functional responses. The figure below (right) illustrates one type of immunocytochemical labeling. A sub-population of GH3 pituitary tumor cells enriched for the membrane estrogen receptor has been selected via immunopanning and limiting dilution subcloning. The level of membrane estrogen receptors has been correlated with the ability of these cells to rapidly secrete prolactin.
Membrane estrogen receptors on a GH3/B6
pituitary tumor cell: Cy3 red fluorescent labeling
of secondary antibody to the primary rat
estrogen receptor antibody R3 (see epitope map below). These cells were in the
G1 phase of the cell cycle, where membrane ER expression is enhanced.
Hormone, cell density, and serum also regulate the expression of this receptor.
A functional domain map of the intracellular
estrogen receptor-α is shown in the
cartoon below.
Functional domain map (according to the functions of intracellular estrogen receptors): The location of epitopes which are also represented in the membrane estrogen receptor-α are shown by the symbols at the top of the diagram. The functions of the designated domains in the membrane-associated receptor remain to be determined.
Xenoestrogens (shown in comparison to 17ß estradiol in the figure at the left) also are very potent signaling ligands through the nongenomic response pathway. Most of them can activate ERK and cause cellular calcium influx via L type channels at picomolar-nanomolar concentrations in pituitary tumor cells.
Other cell types and membrane steroid receptors: Breast cancer cells (MCF-7) also have membrane estrogen receptors. In these cells the level of membrane estrogen receptors correlates with the ability of estrogens to activate several signaling cascades which initiate from the membrane and affect cell numbers. More recently we have participated in the demonstration that mast cells respond to both physiological and environmental estrogens via nongenomic signaling mechanisms (with the lab of Dr. Terumi Midoro-Houriuti). Neuronal type cells (PC-12) have membrane forms of ERα, ERß. and 7TMER.
Collaboratively we have worked with Dr. Bahiru Gametchu on the membrane glucocorticoid receptor which is involved in glucocorticoid-induced therapeutic apoptosis of leukemia and lymphoma cells.
For an updated pubmed search see:
Watson, C.S. (editor) The Identities of Membrane Steroid
Receptors. Kluwer Academic Publishing Co. 2003.
Watson, CS and Gametchu, B. Proteins of multiple classes
participate in nongenomic steroid actions. Experimental Biology and
Medicine, 228:1272-81, 2003.
Bulayeva NN, Gametchu B, and Watson CS. Quantitative measurement
of estrogen-induced ERK 1 and 2 activation via multiple membrane-initiated
signaling pathways. Steroids 69 (3):181-192, 2004.
Koldzic-Zivanovic N, Seitz PK, Watson CS, Cunningham KA, and Thomas ML.
Intracellular signaling involved in estrogen regulation of serotonin reuptake.
Mol Cell Endocrinology
226 (1-2) 1-66, 2004.
Bulayeva NN, and CS Watson.
Xenoestrogen-induced ERK 1 and 2 activation via multiple membrane-initiated
signaling pathways. Environmental Health Perspectives 112:1481-1487, 2004
Zivadinovic D, Gametchu, B, and Watson, CS Membrane estrogen receptor levels in
MCF-7 breast cancer cells predict cAMP and proliferation responses. Breast Can
Res 7:R130-R144 (DOI 10.1186/bcr959), 2005.
Zivadinovic D and Watson, CS Membrane estrogen receptor levels in MCF-7 breast
cancer cells predict MAP kinase (ERK) activation and cell proliferation. Breast
Cancer Res
7:R130-R144
(DOI 10.1186/bcr959), 2005.
Bulayeva NN, Wozniak AL, Lash L, and CS Watson. Mechanisms of membrane estrogen
receptor-α-mediated rapid estrogenic stimulation of Ca2+ and
prolactin release in a pituitary cell line. American Journal of Physiology –
Endocrinology & Metabolism 288:E E388-E397, 2005.
Wozniak, A, Bulayeva, N, and
Watson, CS. Xenoestrogens trigger membrane-estrogen receptor-α
mediated calcium fluxes and prolactin release in GH3/B6 pituitary tumor cells.
Env Health Perspectives,
113:431-439, 2005.
CS Watson and CA Lange. Steadying the boat: Integrating mechanisms of membrane
and nuclear steroid signaling. EMBO Reports
6:116-119, 2005.
Watson, CS, Alyea, RA, Hawkins, BE, Thomas, ML, Cunningham, KA, and Jakubas, AA
Estradiol effects on the dopamine transporter -- protein levels, subcellular
location, and function. J.
Molecular Signaling.
doi:10.1186/1750-2187-1-5,
2006 .
Zaitsu M, Narita S, Lambert KC, Grady JJ, Curran EM, Estes DM, Brooks EG, Watson
CS, Goldblum RM, Midoro-Horiuti T. Estradiol activates mast cells via a
nongenomic estrogen receptor-α and calcium influx. Molecular Immunology.
44:1987-1995, 2007
Narita, S-I., Goldblum R.M., Brooks E.G., Watson C.S, Estes, DM,
Curran, EM, and Midoro-Horiuti, T. Environmental estrogens induce mast cell
degranulation and enhance IgE-mediated release of allergic mediators Env.
Health Perspectives, 115:48-52, 2007
CS
Watson, NN Bulayeva, AL Wozniak, and RA Alyea. Xenoestrogens are potent
activators of nongenomic estrogenic responses. Steroids, 72(2):124-134,
2007
YB Wetherill, B Akingbemi, J Kanno, JA McLaughlan, A Nadal, C
Sonnenschein6, CS Watson7, RT Zoeller, SM Belcher. In vitro molecular mechanisms
of bisphenol A action. Reproductive Toxicology, in press 2007.
CS Watson, RA Alyea, Y-J Jeng, and MY Kochukov. Nongenomic actions of low
concentration estrogens and xenoestrogens on multiple tissues. Accepted to
Molecular & Cellular Endocrinology, 2007
Dr. Watson in her Habitat Garden in
Galveston:
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