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|Title: ||N-Myc pathways in neuroblastoma progression from transcriptome studies, and insights into the GABA A receptor as a target in tumour progression|
|Authors: ||Vacher, Catherine Marie-Odile Simone|
|Issue Date: ||31-Aug-2014|
|Publisher: ||University of Sydney|
Faculty of Pharmacy
|Abstract: ||Neuroblastoma is the most common cancer diagnosed in infancy and represents 15% of paediatric cancer deaths. The N-Myc gene is amplified in approximately 25% of neuroblastomas, which almost halves the survival rate.
The N-Myc-induced transcriptome was studied in vitro and in vivo via microarrays and RT-PCR. An N-Myc-driven carcinogenesis model was proposed whereby N-Myc causes erroneous chromatin modifications, and in particular excessive repressive histone marks on developmental genes through EZH2 overexpression, at the neonatal stage where cell chromatin is still very dynamic. These early changes lock cells into an undifferentiated state. This model explains why N-Myc amplification is a prognostic factor, but N-Myc protein expression at the tumour stage is not.
GABA is mainly known as an inhibitory neurotransmitter, but it is also an inhibitor of the growth of stem cells and progenitors. Our data suggests that N-Myc regulates the GABA pathway by modulating the type of GABAA receptors and their expression at the cell surface, as well as by decreasing the intracellular chloride concentration.
Structural models of putative peripheral neural crest stem cell GABAA receptors were created, to inform the design of ligands that downregulate neuroblastoma cells proliferation. Finally, approved GABAA receptor modulators were considered as potential anticancer drugs.|
|Access Level: ||Access is restricted to staff and students of the University of Sydney . UniKey credentials are required. Non university access may be obtained by visiting the University of Sydney Library.|
|Rights and Permissions: ||The author retains copyright of this thesis. It may only be used for the purposes of research and study. It must not be used for any other purposes and may not be transmitted or shared with others without prior permission.|
|Type of Work: ||PhD Doctorate|
|Type of Publication: ||Doctor of Philosophy Ph.D.|
|Appears in Collections:||Sydney Digital Theses (University of Sydney Access only)|
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|VACHER Catherine - Final Thesis.pdf||Final Thesis||4.68 MB||Adobe PDF|
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