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dictyNews Volume 28 Number 06
dictyNews
Electronic Edition
Volume 28, number 6
March 9, 2007
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.
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Abstracts
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Mitochondrial Biology and Disease in Dictyostelium
Christian Barth, Phuong Le and Paul R. Fisher
Department of Microbiology, La Trobe University, Melbourne, Australia
Int. Rev. Cytol., in press.
Over the last dozen years, the social amoeba or cellular slime mould
Dictyostelium discoideum has become an increasingly useful model for the
study of mitochondrial biology and disease. Dictyostelium is an amoebozoan,
a sister clade to the animal and fungal lineages. Like other aspects of its
biology, the mitochondrial biology of Dictyostelium exhibits some features
which are unique, others which are common to all eukaryotes, and still others
that are otherwise found only in the plant or the animal lineages. The AT-rich
mitochondrial genome of Dictyostelium is larger than its mammalian counterpart
and contains 56 kb (compared to 17 kb in mammals) encoding tRNAs, rRNAs and 33
polypeptides (compared to 13 in mammals). The mode of expression is reminiscent
of metazoan mitochondrial genomes and involves production of a single primary
transcript that is cotranscriptionally processed into multiple mono-, di- and
tricistronic mRNAs, tRNAs and rRNAs. The mitochondrial fission mechanism
employed by Dictyostelium involves both the extramitochondrial dynamin-based
system used by plant, animal and fungal mitochondria and the ancient FtsZ-based
intramitochondrial fission process inherited from the bacterial ancestor of all
modern mitochondria. The mitochondrial protein import apparatus is homologous
to that of other eukaryotes. As in mammalian cells, the mitochondria in
Dictyostelium play an important role in the programmed cell death pathways
used by the organism. Mitochondrial disease in Dictyostelium has been created
both by targeted gene disruptions and by antisense RNA and RNAi inhibition of
expression of essential nuclear-encoded mitochondrial proteins. This has
revealed a regular pattern of aberrant mitochondrial disease phenotypes that
are caused not by ATP insufficiency per se, but by chronic activation of the
universal eukaryotic energy-sensing protein kinase AMPK. This novel insight
into the cytopathological mechanisms of mitochondrial dysfunction suggests
new possibilities for therapeutic intervention in mitochondrial and
neurodegenerative diseases.
Submitted by Paul R. Fisher [P.Fisher@latrobe.edu.au]
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Chemoattractants and chemorepellents act by inducing opposite polarity in
phospholipase C and PI3-kinase signaling
Ineke Keizer-Gunnink, Arjan Kortholt and Peter J.M. Van Haastert
Department of Molecular Cell Biology, University of Groningen, Kerklaan 30,
9751NN Haren, the Netherlands
J Cell Biology, in press
During embryonic development cell movement is orchestrated by a multitude of
attractants and repellents. Chemoattractants applied as a gradient, such as
cAMP with Dictyostelium or fMLP with neutrophils, induce the activation of
phospholipase C (PLC) and PI3-kinase at the front of the cell, leading to
the localized depletion of PI(4,5)P2 and the accumulation of PI(3,4,5)P3. We
show here using Dictyostelium that chemorepellent cAMP-analogues induce
localized inhibition of PLC thereby reversing the polarity of PI(4,5)P2. This
leads to the accumulation of PI(3,4,5)P3 at the rear of the cell and
chemotaxis occurs away from the source. We conclude that a PLC polarity
switch controls the response to attractants and repellents.
Submitted by Peter Van Haastert [p.j.m.van.haastert@rug.nl]
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Regulation of phagocytosis in Dictyostelium by the inositol 5-phosphatase
OCRL homologue Dd5P4
Harriet M. Loovers, Arjan Kortholt, Hendrie de Groote, Leslie Whitty,
Robert L. Nussbaum and Peter J.M. van Haastert
Traffic, in press
Phosphoinositides are involved in endocytosis in both mammalian cells and
the amoeba Dictyostelium discoideum. Dd5P4 is the Dictyostelium homologue of
human OCRL; both have a RhoGAP domain and a 5-phosphatase domain that acts
on PI(4,5)P2/PI(3,4,5)P3. Inactivation of Dd5P4 inhibits growth on liquid
medium and on bacteria. Dd5p4 null cells are impaired in phagocytosis of
yeast cells. In wild-type cells PI(3,4,5)P3 is formed and converted to
PI(3,4)P2 just before closure of the phagocytic cup. In dd5p4 null cells
a phagocytic cup is formed upon contact with the yeast cell, and PI(3,4,5)P3
is still produced, but the phagocytic cup does not close. We suggest that
Dd5P4 regulates the conversion of PI(3,4,5)P3 to PI(3,4)P2 and that this
conversion is essential for closure of the phagocytic cup.
Phylogenetic analysis of OCRL-like 5-phosphatases with RhoGAP domains reveal
that D. discoideum Dd5P4 is a surprisingly close homologue of human OCRL,
the protein responsible for Lowe syndrome. We expressed human OCRL in dd5p4
null cells. Growth on bacteria and axenic medium is largely restored,
whereas the rate of phagocytosis of yeast cells is partly restored,
indicating that human OCRL can functionally replace Dictyostelium Dd5P4.
Submitted by Peter Van Haastert [p.j.m.van.haastert@rug.nl]
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Attenuation of Phospholipid Signaling Provides a Novel Mechanism for the Action
of Valproic Acid
Xuehua Xu1, Annette Mueller-Taubenberger2, Kathryn E. Adley3, Nadine Pawolleck4,
Vivian W. Lee5, Claudia Wiedemann6, Talvinder S. Sihra5, Markus Maniak4,
Tian Jin7 and Robin S.B. Williams3,8*
1. Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown
University Medical School, Washington, DC 20057, USA.
2. Institut fuer Zellbiologie (ABI), Ludwig-Maximilians-Universitaet Muenchen,
80336 Muenchen, Germany.
3. Department of Biology and the Wolfson Institute for Biomedical Research,
University College London, London, WC1E 6BT, UK.
4. Abt. Zellbiologie, Universitaet Kassel, 34132 Kassel, Germany.
5. Department of Pharmacology, University College London, London, WC1E 6BT, UK.
6. Centre for Molecular Cell Biology, Royal Free and UCL Medical School,
NW3 2PF, UK.
7. Laboratories of Immunogenetics, National Institute of Allergy and Infectious
Diseases, National Institutes of Health, Rockville, MD 20852, USA.
8. Present address: School of Biological Sciences, Royal Holloway University
of London, Egham, TW20 0EX, UK.
*Corresponding author:
Euk. Cell., in press
Valproic acid (VPA) is used to treat epilepsy and bipolar disorder, and to
prevent migraine. It is also undergoing trials for cancer therapy. However,
the biochemical and molecular biological actions of VPA are poorly understood.
Using the social amoeba Dictyostelium discoideum, we show that an acute affect
of VPA is the inhibition of chemotactic cell movement, a process partially
dependent upon phospholipid signaling. Analysis of this process shows that VPA
attenuates the signal-induced translocation of PHCrac-GFP from cytosol to
membrane, suggesting the inhibition of the
phosphatidylinositol-(3,4,5)-trisphosphate (PIP3) production. Direct labeling
of lipids in vivo also shows a reduction in PIP and PIP2 phosphorylation
following VPA treatment. We further show that VPA acutely reduces endocytosis
and exocytosis - processes previously shown to be dependent upon PIP3
production. These results suggest that in Dictyostelium, VPA rapidly
attenuates phospholipid signaling to reduce endocytic trafficking. To examine
this effect in a mammalian model, we also tested depolarization-dependent
neurotransmitter release in rat nerve terminals and show that this process is
also suppressed upon application of VPA and an inhibitor of
phosphatidylinositol 3-kinase (PI3K). Although a more comprehensive analysis
of the effect of VPA on lipid signaling will be necessary in mammalian systems,
these results suggest that VPA may function to reduce phospholipid signaling
processes and thus may provide a novel therapeutic effect for this drug.
Submitted by: Robin Williams [robin.williams@rhul.ac.uk]
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Dictyostelium as a biomedical model
Katrina Boeckeler, University College London, UK
Robin SB Williams, Royal Holloway, University of London, Sussex, UK
Encyclopedia of Life Sciences, in press
The social amoeba, Dictyostelium discoideum, has been commonly used to
investigate cell motility, signal transduction, cell type differentiation
and development. With the recent completion of the genome and the increasing
number of experimental tools available for the organism, it has now become
an attractive model for examining some well defined biomedical questions.
Submitted by: Robin Williams [robin.williams@rhul.ac.uk]
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[End dictyNews, volume 28, number 6]
