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Scott, Anna (2010)
Languages: English
Types: Doctoral thesis
Subjects: QH301, QL
The molecular mechanisms that control growth appear to be conserved across the animal kingdom, with nitric oxide regulation of cell proliferation and growth being found to be very significant. Indeed, in Drosophila larval development and mammalian systems NO has been shown to be particularly important in these processes, and previous work in our laboratory has identified the Drosophila forkhead transcription factor dFOXO as a critical target through which NO signalling exerts its regulatory effects on growth, although little is currently known concerning the precise mechanisms involved.\ud \ud Accordingly, in this thesis, we investigate the processes through which NO may modulate growth and demonstrate that targeted expression of a constitutively active NO Synthase to whole larval salivary glands or clones of cells within the glands, results in reduced endoreplication and growth as measured by nuclear size. Targeted over expression of dFOXO itself is shown to result in similar phenotypes, and subsequent molecular analysis of potential signalling targets required for this inhibition of growth reveals that dFOXO, Thor and Myc expression are regulated in vivo by NO.\ud \ud To elucidate if NO acts directly on dFOXO, the genetic interaction of components of the insulin signalling pathway is analysed, exploiting RNA interference to assay what components are necessary for the NO signal to be effectively transduced, and it is demonstrated that NO control of growth is not through sGC, one of the most significant known targets for NOmediated regulation in other organisms.\ud \ud We subsequently investigated the roles of Thor, a Drosophila 4E-binding protein, and the kinase, Lk6, homologues of which are known to be important in growth regulation in other organisms, and thus potential effectors of NO and dFOXO. However our data demonstrated that neither Thor nor Lk6 are required for the inhibition of growth by NO.\ud \ud Interestingly a potential anti-oncogenic effect of NO signalling was also revealed following analysis of interactions between NO and Ras or Myc induced growth in which NO was able reduce the overgrowth produce by both these oncogenes.\ud \ud Overall this research confirms dFOXO as an essential target for NO induced inhibition of growth. The work also eliminates two dFOXO transcription targets, Thor and Lk6, as necessary for NO to regulate growth.
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    • Chapter 4: Analysis of signal transduction required for NO dependent growth regulation
    • Chapter 5: Genetic analysis of dFOXO transcriptional targets as possible growth
    • inhibitors ...................................................................................................................................90 5. Introduction ........................................................................................................................90 5.1. Thor .............................................................................................................................90 5.2. Lk6 and eIF4E .............................................................................................................91 5.2. Results .............................................................................................................................93 5.2.1. Is Thor sufficient for NO induced growth inhibition?..............................................93 5.2.2. Is Thor necessary for NO induced growth inhibition? .............................................95
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