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May 16, 2008 |
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Faculty
JOAN
HELLER BROWN
- Chair and
- Professor of Pharmacology
FAX: 858-822-0041
email: jhbrown@ucsd.edu
Ph.D., Albert Einstein College of Medicine
http://pharmacology.ucsd.edu/faculty_site/brown
Key Words: G-Protein Coupled Receptors; Gq and G12; Rho; Cell Proliferation and Hypertrophy; Apoptosis
My laboratory studies signal transduction mechanisms through which G-protein coupled receptors (GPCRs) regulate cell growth and gene expression. One focus of our work is on the role of heterotrimeric GPCRs such as those for thrombin, LPA and S1P, which couple to the G12/13 proteins and to the low molecular weight G-protein Rho. Cell and molecular techniques including immunocytochemistry, adenoviral infection, cDNA microarrays and transgenic and knockout mice are utilized to screen for signaling molecules and genes selectively regulated by these growth promoting GPCRs. We study astroglial cells and primary mouse brain astrocytes in which thrombin, LPA and S1P have unique abilities to induce gene expression, elicit cytoskeletal changes and cell migration, and stimulate cell proliferation. Activation of small G-proteins in the Rho family serves to trigger these responses and Rho mediated signals are critical in control of vascular pathophysiology as well as in control of cell injury, inflammation and metastatic cell growth. We also study the signaling pathways that lead to cardiac hypertrophy and heart failure, diseases in which there is dysregulation of cell growth and apoptosis. We use isolated cardiomyocytes, as well as transgenic and knockout mice to identify novel pathways regulating these responses. We are currently interested in the role of the Ca++/CaM dependent kinase in the induction of cardiac gene expression and altered Ca++ homeostasis and in the distinct regulation and function of the nuclear targeted versus cytoplasmic forms of this enzyme. We have demonstrated that GPCRs that couple to Gq mediated phospholipase C activation and InsP3 induced Ca release regulate hypertrophic cell growth, whereas cardiomyocyte survival and protection against ischemic damage are regulated by activation of GPCRs such as that for S1P, which activate Akt. The role of Akt in control of cardiomyocytes apoptosis, in particular its regulation and its direct effect on mitochondrial protein phosphorylation and permeability are currently under study. Our long term goal is to find new pharmacological approaches to modulate signaling pathways implicated in abnormal cell growth and survival, processes that underlie the pathophysiology of heart disease and cancer. |
Selected publications
Wu X., Zhang T., Bossuyt J., Li X., McKinsey T., Dedman J.R., Olson E.N., Chen J., Brown J.H., Bers D.M. Local InsP3-dependent perinuclear Ca2+ signaling in cardiac myocyte excitation-transcription coupling J. Clin Invest. 116:675-82. 2006.
Brown J.H., Del Re D.P., Sussman M.A., The Rac and Rho Hall of Fame: a decade of hypertrophic signaling hits. Circ. Res. 98:730-42. 2006.
Kohlhaas M., Zhang T., Seidler T., Zibrova D., Dybkova N., Steen A., Wagner S., Chen L., Brown J.H., Bers D.M., Maier L.S. Increased sarcoplasmic reticulum calcium leak but unaltered contractility by acute CaMKII overexpression in isolated rabbit cardiac myocytes. Circ Res. 98:235-244, 2006.
Seasholtz T.M., Wessel J., Rao F., Rana B.K., Khandrika S., Kennedy B.P., Lillie E.O., Ziegler M.G., Smith D.W., Schork N.J., Brown J.H., and O’Connor D.T. Rho kinase polymorphism influences blood pressure and systemic vascular resistance in human twins. Role of heredity. Hypertension, 47:937-947, 2006.
Wagner S., Dybkova N., Rasenack E., Jacobshagen C., Fabritz L., Kirchhof P. Maier S., Zhang T., Hasenfuss G., Brown J.H., Bers D., Maier L., Ca2+/calmodulin-dependent protein kinase II regulates cardiac Na+ channels. J Clin Invest. 116/12:3127-3138, 2006.
Radeff-Huang J., Seasholtz T.M., Chang J.W., Smith, J.M., Walsh, C.T. and Brown J.H. Tumor necrosis factor- a-stimulated cell proliferation is mediated through sphingosine kinase-dependent Akt activation and cyclin D expression. J Biol Chem. 282/2:863-870, 2007.
Del Re D.P., Miyamoto S. and Brown J.H. RhoA/Rho kinase upregulate Bax to activate a mitochondrial death pathway and induce cardiomyocyte apoptosis. J Biol Chem. 282/11:8069-8078, 2007.
Means C.K., Xiao C.Y., Li Z., Zhang T., Omens J.H., Ishii I., Chun J., Brown J.H., Sphingosine 1 Phosphate S1P2 and S1P3 receptor-mediated Akt activation protects against in vivo myocardial ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol. 292:2944-2951, 2007.
Citro, S., Radeff-Huang, J., Kelley, G.G., Smrcka, A. and Brown, J.H. Phospholipase C-e is a nexus for Rho and Rap-mediated GPCR induced astrocyte proliferation. Proc Natl Acad Sci U S A. 104:15543-48, 2007.
Miyamoto, S. and Brown, J.H. Akt mediates cardioprotection through phosphorylation of mitochondrial hexokinase-II. (In press, Cell Death Differ), 2007.Adams, Joseph A. Akassoglou, Katerina Bourne, Philip E. Brown, Joan Heller Brunton, Laurence L. Dennis, Edward A. Dixon, Jack E. Evans, Sylvia Feramisco, James R. Guan, Kun-Liang Hook, Vivian Insel, Paul A. Karin, Michael Leffert, Hyam L. McCammon, J. Andrew Newton, Alexandra C. Printz, Morton P. Taylor, Palmer Taylor, Susan Tsien, Roger Y. Tukey, Robert H. Yaksh, Tony L. Yang, Jing Khan, Imran M. Seasholtz, Tammy M. Williams, David S. Abraham, Robert T. Bartfai, Tamas Bonneville, Anne K. Chun, Jerold J. M. Crooke, Stanley T. Cuatrecasas, Pedro Evans, Ronald M. Stevens, Charles F. TenEyck, Lynn F. Vallon, Volker Venter, J. Craig Verkhivker, Gennady Wooley, John C.
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