dictyNews
Electronic Edition
Volume 40, number 14
June 6, 2014
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Abstracts
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Defects in the synthetic pathway prevent DIF-1 mediated stalk lineage
specification cascade in the non-differentiating social amoeba,
Acytostelium subglobosum.
Mohri K, Hata T, Kikuchi H, Oshima Y, Urushihara H.
Biology Open. Posted Online May 29, 2014
http://bio.biologists.org/content/early/2014/05/23/bio.20148359.long
Separation of somatic cells from germ-line cells is a crucial event for
multicellular organisms, but how this step was achieved during evolution
remains elusive. In Dictyostelium discoideum and many other
dictyostelid species, solitary amoebae gather and form a multicellular
fruiting body in which germ-line spores and somatic stalk cells
differentiate, whereas in Acytostelium subglobosum, acellular stalks
form and all aggregated amoebae become spores. In this study,
because most D. discoideum genes known to be required for stalk cell
differentiation have homologs in A. subglobosum, we inferred functional
variations in these genes and examined conservation of the stalk cell
specification cascade of D. discoideum mediated by the polyketide
differentiation-inducing factor-1 (DIF-1) in A. subglobosum. Through
heterologous expression of A. subglobosum orthologs of DIF-1
biosynthesis genes in D. discoideum, we confirmed that two of the three
genes were functional equivalents, while DIF-methyltransferase (As-dmtA)
involved at the final step of DIF-1 synthesis was not. In fact, DIF-1 activity
was undetectable in A. subglobosum lysates and amoebae of this species
were not responsive to DIF-1, suggesting a lack of DIF-1 production in
this species. On the other hand, the molecular function of an
A. subglobosum ortholog of DIF-1 responsive transcription factor was
equivalent with that of D. discoideum and inhibition of polyketide synthesis
caused developmental arrest in A. subglobosum, which could not be
rescued by DIF-1 addition. These results suggest that non-DIF-1
polyketide cascades involving downstream transcription factors are
required for fruiting body development of A. subglobosum.
Submitted by Hideko Urushihara [[log in to unmask]]
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Specific growth suppression of human cancer cells by targeted delivery
of Dictyostelium mitochondrial ribosomal protein S4
Junji Chida1, Hikaru Araki2 and Yasuo Maeda3,*
* Corresponding author: Yasuo Maeda [log in to unmask]
1 Division of Molecular Neurobiology, Institute for Enzyme Research,
The University of Tokushima, Kuramoto-cho, Tokushima 770-8503, Japan;
E-mail: [log in to unmask]
2 Division of Enzyme Chemistry, Institute for Enzyme Research,
The University of Tokushima, Kuramoto-cho, Tokushima 770-8503, Japan;
E-mail: [log in to unmask]
3 Department of Developmental Biology and Neurosciences,
Graduate School of Life Sciences, Tohoku University, Aoba,
Sendai 980-8578, Japan; E-mail: [log in to unmask]
Cancer Cell International, accepted
Background
In general, growth and differentiation are mutually exclusive but are
cooperatively regulated throughout development. Thus, the process
of a cell’s switching from growth to differentiation is of great importance
not only for the development of organisms but also for malignant
transformation, in which this process is reversed. We have previously
demonstrated using a Dictyostelium model system that the
Dictyostelium mitochondrial ribosomal protein S4 (Dd-mrp4) gene
expression is essential for the initiation of cell differentiation:
Dd-mrp4-null cells fail to initiate differentiate, while the initial step of
cell differentiation and the subsequent morphogenesis are markedly
enhanced in mrp4OE cells overexpressing the Dd-mrp4 in the
extramitochondrial cytoplasm. This raised a possibility that the
ectopically enforced expression of the Dd-mrp4 in human cells might
inhibit their growth, particularly of malignant tumor cells, by inducing
cell differentiation.
Methods
Four kinds of human tumor cell lines were transfected by three kind
of vector constructs (the empty vector: pcDNA3.1 (Mock);
pcDNA3.1-rps4 bearing Dictyostelium cytoplasmic ribosomal protein S4;
pcDNA3.1-mrp4 bearing Dictyostelium mitochondrial ribosomal protein S4).
As controls, four kinds of human primary cultured cells were similarly
transfected by the above vector constructs. After transfection, growth
kinetics of cells was analyzed using cell viability assay, and also the
TUNEL methods was used for evaluation of apoptotic cells.
Results
Ectopically expressed Dd-mrp4 suppressed cell proliferation through
inducing apoptotic cell death specifically in the human lung
adenocarcinoma (A549), epithelial cervical cancer (HeLa), hepatocellular
carcinoma (HepG2) and colonic carcinoma (Caco-2), but not in primary
cultured normal cells, such as human brain microvascular endothelial
cells (HBMECs); human umbilical vein endothelial cells (HUVECs) and
human normal hepatocytes (hHepsTM), with one exception (human
cardiac fibloblasts (HCF).
Conclusion
The present finding that the ectopically enforced expression of Dd-mrp4
in human several tumor cell lines specifically suppresses their proliferation
suggests strongly that the Dd-mrp4 gene derived from Dictyostelium
mitochondria may provide a new promising therapeutic strategy for
disrupting cell viability pathways in human cancers.
Keywords: Mitochondrial ribosomal protein S4 (MRP4); Dd-mrp4;
Anticancer action; Apoptosis; Proliferation; Differentiation;
Human tumor; Dictyostelium discoideum
Submitted by Yasuo Maeda [[log in to unmask]]
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[End dictyNews, volume 40, number 14]
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