dictyNews Electronic Edition Volume 39, number 27 September 20, 2013 Please submit abstracts of your papers as soon as they have been accepted for publication by sending them to dicty@northwestern.edu or by using the form at http://dictybase.org/db/cgi-bin/dictyBase/abstract_submit. Back issues of dictyNews, the Dicty Reference database and other useful information is available at dictyBase - http://dictybase.org. Follow dictyBase on twitter: http://twitter.com/dictybase ========= Abstracts ========= Cyclic Di-Nucleotide Signalling Enters The Eukaryote Domain. (Review) Pauline Schaap, College of Life Sciences, University of Dundee, UK Abstract. 3Õ5Õ-diguanylic acid (c-di-GMP) is the prevalent intracellular signalling intermediate in bacteria. It triggers a spectrum of responses that cause bacteria to shift from a swarming motile phase to sessile biofilm formation. However, additional functions for c-di-GMP and roles for related molecules, such as c-di-AMP and c-AMP-GMP continue to be uncovered. The first usage of cyclic-di-nucleotide (c-di-NMP) signalling in the eukaryote domain emerged only recently. In Dictyostelid social amoebas, c-di-GMP is a secreted signal that induces motile amoebas to differentiate into sessile stalk cells. In humans, c-di-NMPs, which are either produced endogenously in response to foreign DNA or by invading bacterial pathogens, trigger the innate immune system by activating the expression of interferon genes. STING, the human c-di-NMP receptor, is conserved throughout metazoa and their closest unicellular relatives, suggesting protist origins for human c-di-NMP signalling. Compared to the limited number of conserved protein domains that detect the second messengers cAMP and cGMP, the domains that detect the c-di-NMPs are surprisingly varied. Submitted by Pauline Schaap [p.schaap@dundee.ac.uk] --------------------------------------------------------------------------- Naringenin inhibits the growth of Dictyostelium and MDCK-derived cysts in a polycystin-2 (TRPP2)-dependent manner A Waheed,1 M H R Ludtmann,2 N Pakes,2 S Robery,2 A Kuspa,3 C Dinh,3 D Baines*,4 R S B Williams*,2¦ M A Carew*1¦ 1. School of Pharmacy & Chemistry, Kingston University, Penrhyn Road, Kingston upon Thames, Surrey, KT1 2EE, UK. 2. Centre for Biomedical Science, School of Biological Sciences, Royal Holloway University of London, Egham, Surrey, TW20 0EX, UK. 3. Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, U.S.A. 4. Biomedical Sciences, St George's University of London, Cranmer Terrace, Tooting, London, UK. *joint last author ¦ joint corresponding author British Journal of Pharmacology, in press Background and purpose: Identifying and characterising potential new therapeutic agents to target cell proliferation may provide improved treatments for neoplastic disorders such as cancer and polycystic diseases. Experimental approach: We used the simple, tractable biomedical model Dictyostelium to investigate the molecular mechanism of naringenin, a dietary flavonoid with antiproliferative and chemopreventive actions in vitro and in animal models of carcinogenesis. We then translated these results to a mammalian kidney model, MDCK renal tubule cells, growing in culture and as cysts in a collagen matrix. Key results: Naringenin inhibited Dictyostelium growth, but not development, with an EC50 of 50-100 uM. Screening of a library of random gene knockout mutants identified a mutant lacking polycystin-2 that was resistant to the effect of naringenin on growth and random cell movement. Polycystin-2 (TRPP2) is a divalent cation channel, where mutations in the protein give rise to type 2 autosomal dominant polycystic kidney disease. Naringenin inhibited MDCK cell growth with an EC50 of 28 uM, and inhibited cyst growth with an EC50 of 3-10 uM. Knockdown of polycystin-2 levels by siRNA in this model conferred partial resistance to naringenin such that cysts treated with 3 and 10 uM naringenin were larger following polycystin-2 knockdown compared to controls. Naringenin had no significant effect on forskolin-induced chloride secretion in MDCK monolayers. Conclusions and implications: The action of naringenin on cell growth in the phylogenetically diverse systems of Dictyostelium and mammalian kidney cells, suggests a conserved effect mediated by polycystin-2 (TRPP2). Further studies will investigate naringenin as a potential new therapeutic agent in autosomal dominant polycystic kidney disease. Submitted by Robin Williams [robin.williams@rhul.ac.uk] ============================================================== [End dictyNews, volume 39, number 27]