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dictyNews Volume 22 Number 06
Dicty News
Electronic Edition
Volume 22, number 6
March 5, 2004
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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Tissue-specific G1 phase cell cycle arrest prior to terminal differentiation
in Dictyostelium.
Guokai Chen, Gad Shaulsky and Adam Kuspa
Verna and Marrs McLean Department of Biochemistry and Molecular Biology,
and
Department of Molecular and Human Genetics,
Baylor College of Medicine, One Baylor Plaza, Houston TX 77030.
Development, in press
The cell cycle status of developing Dictyostelium cells remains unresolved
because previous studies have led to conflicting interpretations. We propose
a new model of cell cycle events during development that accounts for most of
the previous data and is based on experiments in which multiple parameters of
cell cycle status were monitored. We observe little mitosis during the first
twelve hours of development, followed by division of fifty percent of the
cells between twelve and eighteen hours of development. Cellular DNA content
profiles obtained by flow cytometry and quantification of extra-chromosomal
and chromosomal DNA suggest that the daughter cells have half the chromosomal
DNA of vegetative cells. Furthermore, we detect little chromosomal DNA
synthesis during development indicating that no S phase occurs and suggesting
that dividing cells arrest within the G1 phase of the cell cycle. The DNA
content in cells sorted by fluorescent tissue-specific reporters indicates that
prespore cells divide first and later encapsulate as G1-arrested spores.
Consistent with this, we show by fluorescence in situ hybridization that
germinating spores have one copy of their chromosomes and they replicate their
chromosomes before mitosis of the emergent amoebea. The DNA content of mature
stalk cells suggests that they also attain a G1 state prior to terminal
differentiation. Since prestalk cells appear to be in G2 up to 22 hours of
development, our data suggests that they divide just prior to stalk formation.
Our results suggest tissue-specific regulation of G1 phase cell cycle arrest
prior to terminal differentiation in Dictyostelium.
Submitted by: Adam Kuspa [akuspa@bcm.tmc.edu]
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Overexpression of sphingosine-1-phosphate lyase or inhibition of sphingosine
kinase in Dictyostelium discoideum results in a selective increase in
sensitivity to platinum based chemotherapy drugs
Junxia Min, Andrew L. Stegner, Hannah Alexander and Stephen Alexander
Division of Biological Sciences, University of Missouri, Columbia,
MO 65211-7400
Eukaryotic Cell, in press
The efficacy of the chemotherapy drug cisplatin is often limited due to
resistance of the tumors to the drug, and increasing the potency of cisplatin,
without increasing its concentration could prove beneficial. A previously
characterized Dictyostelium discoideum mutant with increased resistance to
cisplatin was defective in the gene encoding sphingosine-1-phosphate (S-1-P)
lyase, which catalyzes the breakdown of S-1-P, an important regulatory
molecule in cell function and development and the regulation of cell fate.
We hypothesized that the increased resistance to cisplatin was due to an
elevation of S-1-P, and predicted that lowering levels of S-1-P should
increase sensitivity to the drug. We generated three strains that stably
overexpress different levels of the S-1-P lyase. The overexpressor strains
have reduced growth rate, and confirming the hypothesis, showed an
expression dependent increase in sensitivity to cisplatin. Consistently,
treating the cells with D-erythro N,N, dimethylsphingosine, a known inhibitor
of sphingosine kinase, increased the sensitivity of mutant and parent cells
to cisplatin, while addition of exogenous of S-1-P or 8-Br-cAMP made the
cells more resistant to cisplatin. The increased sensitivity of the
overexpressors to cisplatin was also observed with the cisplatin analog
carboplatin. In contrast, the response to doxorubicin, 5-flurouracil or
etoposide was unaffected, indicating that the involvement of the sphingolipid
metabolic pathway in modulating the response to cisplatin is not part of a
global genotoxic stress response. The augmented sensitivity to cisplatin
appears to be the result of an intracellular signaling function of S-1-P,
since D. discoideum does not appear to have EDG(S-1-P) receptors. Overall,
the results show that modulation of the sphingolipid pathway at multiple
points can result in increased sensitivity to cisplatin, and has the
potential for increasing the clinical usefulness of this important drug.
Submitted by: Hannah Alexander [alexanderh@missouri.edu]
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[End Dicty News, volume 22, number 6]
