dictyNews
Electronic Edition
Volume 32, number 7
March 13, 2009
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Abstracts
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The carboxy-terminal domain of Dictyostelium C-module-binding factor
is an
independent gene regulatory entity
J. Lucas (1), A. Bilzer (1), L. Moll (2), I. Zündorf (3), T.
Dingermann (3),
L. Eichinger (2), O. Siol (1), T. Winckler (1)
(1) School of Biology and Pharmacy, Institute of Pharmacy, Department of
PharmaceuticalBiology, University of Jena, Semmelweisstrasse 10,
07743 Jena, Germany
(2) Institute for Biochemistry I, Medical Faculty, University of
Cologne,
Joseph-Stelzmann-Strasse 52, 50931 Cologne, Germany
(3) Institute of Pharmaceutical Biology, University of Frankfurt,
Max-von-Laue-Strasse 9, 60438 Frankfurt am Main, Germany
PLoS ONE, in press
The C-module-binding factor (CbfA) is a multidomain protein that
belongs to
the family of jumonji-type (JmjC) transcription regulators. In the
social
amoeba Dictyostelium discoideum, CbfA regulates gene expression during
the
unicellular growth phase and multicellular development. CbfA and a
related
D. discoideum CbfA-like protein, CbfB, share a paralogous domain
arrangement
that includes the JmjC domain, presumably a chromatin-remodeling
activity,
and two zinc finger-like (ZF) motifs. On the other hand, the CbfA and
CbfB
proteins have completely different carboxy-terminal domains, suggesting
that the plasticity of such domains may have contributed to the
adaptation
of the CbfA-like transcription factors to the rapid genome evolution
in the
dictyostelid clade. To support this hypothesis we performed DNA
microarray
and real-time RT-PCR measurements and found that CbfA regulates at least
160 genes during the vegetative growth of D. discoideum cells.
Functional
annotation of these genes revealed that CbfA predominantly controls the
expression of gene products involved in housekeeping functions, such as
carbohydrate, purine nucleoside/nucleotide, and amino acid metabolism.
The CbfA protein displays two different mechanisms of gene regulation.
The
expression of one set of CbfA-dependent genes requires at least the
JmjC/ZF domain of the CbfA protein and thus may depend on chromatin
modulation. Regulation of the larger group of genes, however, does not
depend on the entire CbfA protein and requires only the carboxyterminal
domain of CbfA (CbfA-CTD). An AT-hook motif located in CbfA-CTD, which
is known to mediate DNA binding to A+T-rich sequences in vitro,
contributed to CbfA-CTD-dependent gene regulatory functions in vivo.
Submitted by: Thomas Winckler [[log in to unmask]]
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The mood stabiliser lithium suppresses PIP3 signalling in
Dictyostelium and
human cells
Jason S. King, Regina Teo, Jonathan Ryves, Jonathan V. Reddy, Owen
Peters,
Ben Orabi, Oliver Hoeller, Robin S. B. Williams2 and Adrian J. Harwood
Disease Models & Mechanisms, in press
Bipolar mood disorder (manic depression) is a major psychiatric disorder
whose molecular origins are unknown. Mood stabilisers offer patients
both
acute and prophylactic treatment, and experimentally, they provide a
means
to probe the underlying biology of the disorder. Lithium and other mood
stabilisers deplete intracellular inositol and it has been proposed that
bipolar mood disorder arises from aberrant inositol (1,4,5)-
trisphosphate
[IP3, also known as Ins(1,4,5)P3] signalling. However, there is no
definitive
evidence to support this or any other proposed target; a problem
exacerbated
by a lack of good cellular models. Phosphatidylinositol (3,4,5)-
trisphosphate
[PIP3, also known as PtdIns(3,4,5)P3] is a prominent intracellular
signal
molecule within the central nervous system (CNS) that regulates neuronal
survival, connectivity and synaptic function. By using the genetically
tractable organism Dictyostelium, we show that lithium suppresses
PIP3-mediated signalling. These effects extend to the human neutrophil
cell line HL60. Mechanistically, we show that lithium attenuates
phosphoinositide synthesis and that its effects can be reversed by
overexpression of inositol monophosphatase (IMPase), consistent with
the inositol-depletion hypothesis. These results demonstrate a lithium
target that is compatible with our current knowledge of the genetic
predisposition for bipolar disorder. They also suggest that lithium
therapy
might be beneficial for other diseases caused by elevated PIP3
signalling.
Submitted by: Adrian Harwood [[log in to unmask]]
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[End dictyNews, volume 32, number 7]
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