dictyNews
Electronic Edition
Volume 39, number 27
September 20, 2013
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Abstracts
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Cyclic Di-Nucleotide Signalling Enters The Eukaryote Domain.
(Review)
Pauline Schaap, College of Life Sciences, University of Dundee, UK
Abstract. 3’5’-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 [[log in to unmask]]
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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 [[log in to unmask]]
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[End dictyNews, volume 39, number 27]
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