Research / Clinical
Summary
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Joan Heller Brown, PhD
Professor, Pharmacology
Cancer Biology Program
Contact by Email
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Diseases/Research Topics
Apoptosis, Growth Control, Molecular Pharmacology, Ras and Rho Oncogenes, Responses to Extracellular Stimuli and Stress, Signal Transduction
We are interested in signal transduction pathways mediated through G-protein coupled receptors (GPCRs) and have focused upon the ability of these receptors to regulate cell proliferation, the actin cytoskeleton, and gene expression. One system we study is a human astrocytoma cell line in which a subset of GPCRs including those for thrombin and lysophospholipid neurohormones (LPA, S1P) are able to induce the aforementioned responses while other GPCRs such as the muscarinic cholinergic receptor do not. We have traced the differences in these receptors to their ability to interact with the heterotrimeric G-protein Gα12/13 and to subsequently activate the small G-protein Rho. Pathways downstream of Rho collaborate with the Ras/MAP kinase pathway in cell cycle progression, and our recent work explores two downstream RhoA targets that appear to mediate proliferative responses to thrombin. One is a RhoA and AP-1 mediated gene, cyr61, the product of which acts as an ECM protein signaling through integrins. We have determined that cyr61 expression is required for thrombin mediated cell proliferation, providing a mechanistic link between GPCRs and integrin signaling. The second pathway regulated by RhoA is a novel phospholipase PLCε, which also serves as a guanine nucleotide exchange factor for Rap1. This pathway is critical for sustained ERK activation and thus the mitogenic effects of thrombin. The other system in which we examine GPCR regulation of cell growth and apoptosis is the cardiomyocyte. Our studies on the mechanisms leading to caridomyocyte apoptosis are currently focused on mitochondrial effects of Akt and hexokinase II, as well as on regulators of Akts, specifically PDK-1 and PHLPP. Studies in the cardiomyocytes are complemented by work in transgenic and knockout mice examining the development of heart failure, a phenomenon associated with apoptotic cell death and loss of mitochondrial integrity.
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