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dictyNews Volume 41 Number 05
dictyNews
Electronic Edition
Volume 41, number 5
March 13, 2015
Please submit abstracts of your papers as soon as they have been
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http://dictybase.org/db/cgi-bin/dictyBase/abstract_submit.
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Abstracts
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Neurofibromin controls macropinocytosis and phagocytosis in
Dictyostelium
Gareth Bloomfield, David Traynor, Sophia P. Sander, Douwe Veltman,
Justin A. Pachebat and Robert R. Kay
eLife
Cells use phagocytosis and macropinocytosis to internalise bulk
material, which in phagotrophic organisms supplies the nutrients
necessary for growth. Wildtype Dictyostelium amoebae feed on
bacteria, but for decades laboratory work has relied on axenic
mutants that can also grow on liquid media. We used forward
genetics to identify the causative gene underlying this phenotype.
This gene encodes the RasGAP Neurofibromin (NF1). Loss of NF1
enables axenic growth by increasing fluid uptake. Mutants form
outsized macropinosomes which are promoted by greater Ras and
PI3K activity at sites of endocytosis. Relatedly, NF1 mutants
can ingest larger-than-normal particles using phagocytosis. An
NF1 reporter is recruited to nascent macropinosomes, suggesting
that NF1 limits their size by locally inhibiting Ras signalling.
Our results link NF1 with macropinocytosis and phagocytosis for
the first time, and we propose that NF1 evolved in early
phagotrophs to spatially modulate Ras activity, thereby
constraining and shaping their feeding structures.
Submitted by Gareth Bloomfield [garethb@mrc-lmb.cam.ac.uk]
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Synthesis of prenylated quinolinecarboxylic acid derivatives and
their anti-obesity activities.
Haruhisa Kikuchi, Toshiyuki Suzuki, Masato Ogura, Miwako K. Homma,
Yoshimi Homma, Yoshiteru Oshima
Bioorg. Med. Chem. 2015, 23, 66-72.
Mitochondrial uncoupling is one of the therapeutic strategies used
to control energy metabolism in various metabolic diseases and in
obesity. Ppc-1 (1), a prenylated quinolinecarboxylic acid isolated
from cellular slime molds, shows uncoupling activity in vitro and
anti-obesity activity in vivo. In this study, we synthesized Ppc-1
(1) and its derivatives, and revealed the structure-activity
relationship of uncoupling activities. The triprenylated compound 18
showed mitochondrial uncoupling activity that was more potent than
that of Ppc-1 (1). Compound 18 also suppressed weight gain in mice
without undesired effects such as lesions on tissues. These results
indicate that compound 18 could be used as a seed compound for new
anti-obesity drugs.
Submitted by Haruhisa Kikuchi [hal@mail.pharm.tohoku.ac.jp]
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Weight Loss by Ppc-1, a Novel Small Molecule Mitochondrial Uncoupler
Derived from Slime Mold.
Toshiyuki Suzuki, Haruhisa Kikuchi, Masato Ogura, Miwako K. Homma,
Yoshiteru Oshima, Yoshimi Homma
PLoS ONE 10(2): e0117088.
Mitochondria play a key role in diverse processes including ATP
synthesis and apoptosis. Mitochondrial function can be studied using
inhibitors of respiration, and new agents are valuable for
discovering novel mechanisms involved in mitochondrial regulation.
Here, we screened small molecules derived from slime molds and other
microorganisms for their effects on mitochondrial oxygen consumption.
We identified Ppc-1 as a novel molecule which stimulates oxygen
consumption without adverse effects on ATP production. The kinetic
behavior of Ppc-1 suggests its function as a mitochondrial uncoupler.
Serial administration of Ppc-1 into mice suppressed weight gain with
no abnormal effects on liver or kidney tissues, and no evidence of
tumor formation. Serum fatty acid levels were significantly elevated
in mice treated with Ppc-1, while body fat content remained low. After
a single administration, Ppc-1 distributes into various tissues of
individual animals at low levels. Ppc-1 stimulates adipocytes in
culture to release fatty acids, which might explain the elevated serum
fatty acids in Ppc-1-treated mice. The results suggest that Ppc-1 is
a unique mitochondrial regulator which will be a valuable tool for
mitochondrial research as well as the development of new drugs to
treat obesity.
Submitted by Haruhisa Kikuchi [hal@mail.pharm.tohoku.ac.jp]
----------------------------------------------------------------------
A Conserved Signalling Pathway for Amoebozoan Encystation that was
Co-Opted for Multicellular Development
Yoshinori Kawabe, Christina Schilde, Qingyou Du and Pauline Schaap
College of Life Sciences, University of Dundee, Dundee DD15EH,
Scotland, UK
Scientific Reports, in press
The evolution of multicellularity required novel mechanisms for
intercellular communication, but their origin is unclear.
Dictyostelium cells exchange signals to position specialized cell
types in multicellular spore-bearing structures. These signals
activate complex pathways that converge on activation of
cAMP-dependent protein kinase (PKA). Genes controlling PKA were
detected in the Dictyostelid unicellular ancestors, which like
most protists form dormant cysts when experiencing environmental
stress. We deleted PKA and the adenylate cyclases AcrA and AcgA,
which synthesize cAMP for PKA activation, in the intermediate
species Polysphondylium, which can develop into either cysts
or into multicellular structures. Loss of PKA prevented
multicellular development, but also completely blocked
encystation. Loss of AcrA and AcgA, both essential for
sporulation in Dictyostelium, did not affect Polysphondylium
sporulation, but prevented encystation. We conclude that
multicellular cAMP signalling was co-opted from PKA regulation
of protist encystation with progressive refunctionalization of
pathway components.
Submitted by Pauline Schaap [p.schaap@dundee.ac.uk]
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[End dictyNews, volume 41, number 5]
