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Poster Full Abstracts - Drosophila Models of Human Diseases
Poster board number is above title. The first author is the presenter
236
interaction, partially opening the molecule to allow further activation. Our study reveals a tumor suppressor function of
pbl
/
Ect2
in inhibiting Rac1 and
identifies an early step in its autoregulation.
384C
Tumorigenesis in the absence of the spindle assembly checkpoint.
Sara Morais da Silva, Ricardo J. Sousa, Claudio E. Sunkel. Laboratory of Molecular
Genetics, Instituto de Biologia Molecular e Celular, Porto, Portugal.
The spindle assembly checkpoint (SAC) mechanism prevents aneuploidy by only allowing mitotic progression if all chromosomes are attached to
microtubules via the kinetochores, and aligned correctly at the metaphase plate. This mechanism ensures that the cell cycle does not proceed unless the
correct conditions for progress are met. We have created a fly model of tumorigenesis where by weakening the SAC system and simultaneously inhibiting
apoptosis we induce hyperplastic discs. The expression of
Bub3
or
BubR1
RNAi in wing discs causes loss of bristles and multiple empty sockets in the adult
thorax associated with cell death. When inhibitors of apoptosis are expressed together with each of the SAC RNAi genes, the wing discs are hyperplastic,
indicating that the absence of SAC together with the inhibition of apoptosis causes overgrowth. These hyperplastic discs when transplanted into adult hosts
appear to grow indefinitely invading most of the abdomen. The cells from the hyperplastic discs as well as from the transplants display aneuploidies. In
addition, gene expression profiling by micro-array technology was obtained for the hyperplastic discs and it has revealed several differentially regulated
genes with roles in apoptosis, aneuploidy and tumorigenesis. We will discuss the link between SAC genes, apoptosis, aneuploidy and tumour development.
385A
Loss of Rabex-5 displays leukemia-like hematopoietic defects that involve dysregulation of Ras, Notch and groucho.
Theresa Reimels. Oncological
Sciences, Mount Sinai School of Medicine, New York, NY.
Leukemia is the most common childhood cancer but presents, and is more difficult to treat, in adults as well. In most cases the mechanisms underlying its
development remain unknown. To address this problem we are examining leukemia-like phenotypes in Drosophila. Homozygous loss of the Ras regulator
Rabex-5 in Drosophila larvae causes dramatic hemocyte phenotypes including overproliferation and mispatterning. When hemocyte lineages in this model of
overproliferation are examined, no change in the percent of crystal cells and a statistically significant decrease in the percent of plasmatocytes coincident
with differentiation of lamellocytes are observed. These data raise the possibility that a less differentiated progenitor hemocyte population is expanding and
imply that Rabex-5 is negatively regulating the proliferation and/or differentiation of hemocytes. The requirement for Rabex-5 in hemocytes at various
stages of their development is being investigated. Preliminary data suggest that Rabex-5 is not required in hemocytes to control proliferation and
differentiation after the expression of the mature hemocyte marker Hemese, although it may make a small contribution potentially through its negative
regulation of Ras activity. Rabex-5 null mutations cause melanotic masses, larval/pupal lethality and genetically interact with Ras, Notch and groucho. Ras,
Notch and Wg are among the pathways involved in hematopoiesis that are implicated in human hematologic cancers. Since Rabex-5 loss results in a
leukemia-like overproliferation of hemocytes and Rabex-5 expression is downregulated in primary human lymphomas and leukemia cell lines, we are
examining Rabex-5 as a potential tumor suppressor in the hematopoietic system.
386B
Gene expression profiling in Drosophila models of human cancers associated with modulation of DCC/frazzled signaling.
Joseph Sarro
1
, Charles
Tessier
2
, Molly Duman-Scheel
1,2
. 1) Biological Sciences and Harper Cancer Inst, Univ of Notre Dame, Notre Dame, IN; 2) Med and Molec Genetics,
Indiana Univ Sch Medicine, South Bend, IN.
We recently characterized two Drosophila models of human cancers associated with loss and gain of Deleted in Colorectal Cancer (DCC)/Drosophila
Frazzled (Fra) signaling. In this investigation, we performed microarray analyses to investigate global changes in gene expression resulting from both loss
and activation of Fra signaling. It was hypothesized that combinatorial analysis of these two experiments would reveal common mechanisms in our two
Drosophila models of cancer. Activation of Fra signaling in wing disc clones resulted in 764 statistically significant differentially expressed genes, while
1,897 genes were differentially expressed in fra mutant embryonic cells. Significant genes were further analyzed with DAVID and MetaCore, which grouped
genes into statistically significant disease networks, signaling pathways, and gene ontology (GO) processes. These analyses were performed for each array
experiment separately, as well as for genes identified in both sets of array experiments. In addition to many cancer disease networks, including colorectal and
breast cancer, many GO processes were deemed significant, including cellular morphogenesis, apoptosis, cell motion, axonogenesis, cytoskeletal
organization, spindle organization, cell growth and cell adhesion. A number of Drosophila orthologs of genes that have been linked to human cancers,
including several previously uncharacterized fly genes, were identified in both sets of experiments. These genes, as well as members of the signaling
cascades Wnt, TGFβ, and Notch, all of which were modified in response to loss or activiation of Fra signaling, will be prioritized in ongoing secondary
validation experiments in which gene expression and genetic interaction studies will be used to verify the array data. Analysis of these genes may provide
new insight into human cancers associated with modulation of DCC signaling.
387C
Delineating the function of PRL-1 in
Drosophila
.
Leslie J. Saucedo, Jake Goodchild, Krystle Pagarigan, Travis Edlefsen. Biology, University of Puget
Sound, Tacoma, WA.
In the past decade, Phosphatase of Regenerating Liver (PRL) family members have emerged as molecular markers that significantly correlate to the ability
of cancers to metastasize. In addition, PRLs are promising therapeutic targets; hindering PRL function in transformed cells has shown dramatic reduction in
tumor formation in mice. However, contradictory cellular responses to PRL expression have been reported; in some mammalian cell lines, PRL instead
inhibits cell cycle progression. An obvious culprit for the discrepancy is the use of dozens of different cell lines, including many isolated from tumors or
cultured cells selected for immortalization. These studies each examine PRL in a different genetic environment, which may mean modulators and effectors
of PRL function are missing or mutated. We created transgenic
Drosophila
to study the effects of PRL overexpression in a genetically controlled, organismal
model. Our data support the paradigm that the normal function of PRL is to suppress cell growth. However, genetically altered environments can modulate
the function of PRL; while PRL maintains its growth suppressive effect and counters the activity of the Src oncogene, it instead contributes to the activity of
oncogenic Ras. Ongoing work includes how PRL function may be modified by additional genetic manipulations. In addition, because we have demonstrated