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dictyNews Volume 24 Number 09
Dicty News
Electronic Edition
Volume 24, number 9
April 8, 2005
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 Dicty-News, the Dicty Reference database and other
useful information is available at dictyBase - http://dictybase.org.
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Abstracts
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Sphingosine-1-phosphate lyase regulates sensitivity of human cells to
select chemotherapy drugs in a p38-dependant manner
Junxia Min1, Paul P. Van Veldhoven2, Lei Zhang3, Marie H. Hanigan4,
Hannah Alexander1 and Stephen Alexander1*
1Division of Biological Sciences, University of Missouri, Columbia,
MO 6521-7400
2Katholieke Universiteit Leuven, Departement Moleculaire Celbiologie,
Afdeling Farmakologie, B-3000 Leuven, Belgium.
3Tufts University, New England Medical Center, Boston, MA
4Department of Cell Biology, University of Oklahoma Health Sciences
Center, Oklahoma City, OK 73190.
Molecular Cancer Research, in press
Resistance to cisplatin is a common problem that limits its usefulness in
cancer therapy. Molecular genetic studies in the model organism
Dictyostelium discoideum have established that modulation of sphingosine
kinase or sphingosine-1-phosphate (S-1-P) lyase, by disruption or
overexpression, results in altered cellular sensitivity to this widely
used drug. Parallel changes in sensitivity were observed for the related
compound carboplatin, but not for other chemotherapy drugs tested.
Sensitivity to cisplatin could also be potentiated pharmacologically with
dimethylsphingosine, a sphingosine kinase inhibitor. We now have validated
these studies in cultured human cell lines. HEK293 or A549 lung cancer cells
expressing human S-1-P lyase (hSPL) show an increase in sensitivity to
cisplatin and carboplatin as predicted from the earlier model studies. The
hSPL overexpressing (hSPL-OE) cells were also more sensitive to doxorubicin
but not vincristine or chlorambucil. Studies using inhibitors to specific
MAP kinases show that the increased cisplatin sensitivity in the hSPL-OE
cells is mediated by p38, and to a lesser extent by JNK MAPKs. p38 is not
involved in vincristine or chlorambucil cytotoxicity. Measurements of MAPK
phosphorylation and enzyme activity, as well as siRNA inhibition studies,
show that the response to the drug is accompanied by up-regulation of p38
and JNK and the lack of ERK up-regulation. These studies confirm an earlier
model proposing a mechanism for the drug specificity observed in the studies
with D. discoideum, and supports the idea that the sphingosine kinases and
S-1-P lyase are potential targets for improving the efficacy of cisplatin
therapy for human tumors.
Submitted by: Steve Alexander [AlexanderSt@missouri.edu]
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Evolutionary origin of cAMP-based chemoattraction
in the social amoebae
Elisa Alvarez-Curto1, Daniel E. Rozen1,3, Alysson V. Ritchie1, Celine Fouquet1
Sandra L. Baldauf2 and Pauline Schaap1*.
1School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK
2Department of Biology, University of York, PO Box 373, York YO10 5YW, UK
3Current address: Department of Biology, Emory University, 1510 Clifton Road,
Atlanta, GA 30322, USA
*Corresponding author: School of Life Sciences, University of Dundee
MSI/WTB complex, Dundee DD1 5EH, UK; Phone: 44 1382 348078;
Fax: 44 1382 345386; E-mail:p.schaap@dundee.ac.uk
Proc. Natl. Acad. Sci. USA, in press.
Phenotypic novelties can arise if integrated developmental pathways are
expressed at new developmental stages and are then recruited to serve new
functions. We analyse the origin of a novel developmental trait of
Dictyostelid amoebae: the evolution of cAMP as a developmental
chemoattractant. We show that cAMP's role to attract starving amoebae arose
through recruitment of a pathway that originally evolved to coordinate
fruiting body morphogenesis. Orthologues of the high-affinity cAMP receptor,
cAR1, were identified in a selection of species that span the Dictyostelid
phylogeny. The cAR1 orthologue from the basal species D.minutum restored
aggregation and development when expressed in an aggregation-defective
mutant of the derived species D.discoideum that lacks high-affinity cARs,
thus demonstrating that the D. minutum cAR is a fully functional cAMP
receptor. cAR1 orthologues from basal species are expressed during fruiting
body formation and only this process, and not aggregation, was disrupted by
abrogation of cAR1 function. This is in contrast to derived species, where
cAR1 is also expressed during aggregation and critically regulates this
process. Our data show that coordination of fruiting body formation is the
ancestral function of extracellular cAMP signalling, while its derived role
in aggregation evolved by recruitment of a pre-existing pathway to an
earlier stage of development. This most likely occured by addition of
distal cis-regulatory regions to existing cAMP signaling genes.
Submitted by: Pauline Schaap [p.schaap@dundee.ac.uk]
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[End Dicty News, volume 24, number 9] 
