Rutkowski, Rachael (2005) Genetic and cellular analysis of the novel cell proliferation regulator, deflated, in Drosophila. PhD thesis, James Cook University.

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Abstract

The regulation of cell proliferation needs to be coordinated with cell growth and differentiation regulation in multicellular organisms for development to occur properly and tumourogenesis to be avoided. Cell proliferation is regulated through positive and negative signals that influence progression through the cell cycle. The cell cycle is regulated by cyclin dependent kinases that are controlled by the binding of cyclins, whose protein levels oscillate throughout the cell cycle. It is extremely important that progression through the cell cycle is regulated correctly, that mitosis only occurs once DNA replication is completed, and that DNA replication only begins once chromosomes have segregated into daughter cells. While there is great understanding about how the different phases of the cell cycle are controlled, it is still largely unknown how the phases are coordinately regulated, and how the cell cycle is regulated externally during development. An understanding of how cell proliferation is coordinated with cell growth and differentiation requires an examination of how the cell integrates various and sometimes competing signals with the core cell cycle machinery to effect cell proliferation in the right developmental context.

This study describes the identification of deflated as a novel cell proliferation regulator. Taking a genetic and cell biological approach, the role that deflated plays in regulating cell proliferation was examined. deflated alleles were generated by P-element mobilisation and P-element induced male recombination. The characterisation of four different alleles and the expression pattern of deflated mRNA suggested a role for deflated in regulating cell proliferation and cell signalling. These findings were further supported by genetic interactions observed between deflated and cell proliferation regulators and cell signalling components. Examination of deflated function in Ras signalling demonstrated that deflated may be a negative regulator of Ras signalling. The findings that DEFLATED::GFP protein localised to nuclei and mitotic spindles in embryos and to the apical surface of wing imaginal discs, further support a role for deflated in cell proliferation and cell signalling.

When taken together, these data suggest both a direct and an indirect role for deflated in regulating cell proliferation. It appears that DEFLATED may be involved in regulating re-replication and thus link DNA synthesis completion with M-phase entry. DEFLATED may also regulate spindle function and formation, possibly by forming a complex with Ran and clathrin, two proteins that are predicted to bind DEFLATED and have roles in spindle function. deflated may also regulate cell proliferation indirectly through involvement in Ras signalling, the Ran pathway, or through endocytosis. While these are many roles to ascribe to DEFLATED it may be able to carry them all or a subset out by functioning as an adaptor protein at the intersection of different cellular pathways.

This initial analysis is the first to characterise deflated function in any model system and it is clear that deflated is a novel regulator of cell proliferation. Further elucidation of its function will enable an understanding of how sensing and signalling pathways communicate with one another to ensure that cell proliferation occurs correctly. In particular, the study of deflated will enable further understanding on how Ras signalling regulates cell proliferation and how M-phase and the mitotic spindle are regulated.

Item ID:	17563
Item Type:	Thesis (PhD)
Keywords:	Drosophila, genetic analysis, cellular, analysis, novel cell proliferation, regulation, deflated, regulator, cell signalling, pathways, mRNA expression, DNA synthesis, spindle function, alleles
Date Deposited:	28 Nov 2011 23:22
FoR Codes:	06 BIOLOGICAL SCIENCES > 0601 Biochemistry and Cell Biology > 060103 Cell Development, Proliferation and Death @ 100%
SEO Codes:	97 EXPANDING KNOWLEDGE > 970106 Expanding Knowledge in the Biological Sciences @ 50% 97 EXPANDING KNOWLEDGE > 970111 Expanding Knowledge in the Medical and Health Sciences @ 50%
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