Prostanoids, a family of lipid mediators with multiple and diverse biological actions, are formed by the action of cyclooxygenase (COX) on arachidonic acid. A single gene product, encoding a G protein coupled receptor (GPCR) has been identified for prostacyclin (the IP), PGF2α (the FP) and TxA2 (the TP), while four distinct GPCRs for PGE2 (the EP1-4), and two for PGD2 (DP1 and DP2), have been cloned.
Our laboratory is interested in the novel pathways directing the function and regulation of prostanoid receptors. Over the past decade the paradigm of GPCR homo- and hetero- dimerization has become and accepted phenomenon. We have show dimerization of IP and TP to form homo- and hetero- dimers with consequent changes in TP signaling and regulation. More recently we have identified formation of DP1 and DP2 homo- and hetero- dimers (but not IP-DP heterodimers) at comparable affinities. Currently we are investigating the molecular and cellular events that regulate prostanoid receptor dimerization in normal settings and cardiovascular disease.
A second major resarch focus of our laboratory emerged from the recent interest in the inducible COX-2 isoform and it partner in PGE2 generation, mPGES-1, as a chemopreventative or chemotherapeutic target in human cancer. Epidemiological reports demonstrate a reduction in the risk of mammary cancer with co-incident used of COX inhibitors. Our research examines the role of COX-1 and COX-2, in mammary cancer, and cancer related thrombosis, using mice engineered to lack specifically COX-2 or mPGES-1 expression the mammary epitheilium or in macrophages. Inititation, progression and metastasis of mammary tumors, and the incidence of cancer-related thrombosis, is currently under examination.
Khan A, Li D, Ibrahim S, Smyth E and Woulfe DS. : The physical association of the P2Y12 receptor with PAR4 regulates arrestin-mediated Akt activation. Mol Pharmacol. 86: 1-11, 2014.
Chen EP, Markosyan N, Connolly E, Lawson JA, Li X, Grant GR, Grosser T, FitzGerald GA and Smyth EM.: Myeloid Cell COX-2 deletion reduces mammary tumor growth through enhanced cytotoxic T-lymphocyte function. Carcinogenesis 35: 1788-97, 2014.
Frey, AJ Ibrahim, S, Gleim, S, Hwa, J and Smyth, EM: Biased Suppression of Thromboxane A2 Receptor Homodimerization and Signaling Through Disruption of a Transmembrane GxxxGxxxL Helical Interaction Motif. J Lipid Rresearch 54(6): 1678-1690, Jun 2013.
Ibrahim, S, Markosyan, N, McCartney, A, and Smyth, EM: Heterodimerization With The Prostacyclin Receptor Triggers Thromboxane Receptor Relocation to Lipid Rafts. Arterioscler. Thrombosis. Vasc. Biol. 33: 60-66, Jan 2013.
Markosyan N, Chen EP, Evans RA, Ndong N, Vonderheide RH and Smyth EM.: Mammary carcinoma cell derived cyclooxygenase 2 suppresses tumor immune surveillance by enhancing intratumoral immune checkpoint activity. Breast Cancer Research in press, 2013.
Siangjong L, Gauthier KM, Pfister SL, Smyth EM, Campbell WB: Endothelial 12(S)-HETE vasorelaxation is mediated by thromboxane receptor inhibition in mouse mesenteric arteries. Am J Physiol Heart Circ Physiol 304(3): H382-392, 2013.
Nune Markosyan; Edward Chen; Victoire Ndong; Yubing Yao; Christopher J. Sterner; Lewis A. Chodosh; John A. Lawson; Garret A. FitzGerald; Emer M. Smyth: Deletion of cyclooxygenase 2 in mouse mammary epithelial cells delays breast cancer onset through augmentation of type 1 immune responses in tumors
Carcinogenesis Page: in press, 2011.
Salam I, Tetruashvily M, Frey AJ, Wilson SJ, Stitham J, Hwa J, Smyth EM: Dominant negative actions of human prostacyclin receptor variant through dimerization: Implications for cardiovascular disease. Arteriosclerosis, Thrombosis, and Vascular Biology 30(9): 1802-1809, 2010.
Wilson SJ, Cavanagh CC, Lesher AM, Frey AJ, Russell SE, Smyth EM: Activation-dependent stabilization of the human thromboxane receptor: Role of reactive oxygen species. J Lipid Res 50(6): 1047-1056, Jun 2009.
McGillicuddy FC, Chiquoine EH, Hinkle CC, Kim RJ, Shah R, Roche HM, Smyth EM, Reilly MP: Interferon gamma attenuates insulin signaling, lipid storage, and differentiation in human adipocytes via activation of the JAK/STAT pathway. J Biol Chem 284(46): 31936-31944, 2009.
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Last updated: 10/06/2015
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