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Suppressors of Oncogenic Cbl in the Drosophila Eye

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Suppressors of Oncogenic Cbl in the Drosophila Eye Suppressors of oncogenic Cbl in the Drosophila eye. Rowena Tenri Sannang ORCID identifier- 0000-0002-9259-5536 Master of Philosophy May 2018 Department of Anatomy and Neuroscience University of Melbourne Submitted in total fulfilment of the requirements of the degree ABSTRACT Cbl is an E3 ligase, and downregulates several cellular signalling pathways, in this role by targeting receptor tyrosine kinases for endocytosis. Mammalian Cbl was first identified as the full-length isoform of v-Cbl, a C-terminal truncated dominant negative oncogene that permits binding of v-Cbl to Cbl targets but does not facilitate their ubiquitination. This results in constitutive activation of the receptor tyrosine kinase. In this thesis, I used a Drosophila analogue of v-Cbl, named Dv-cbl. GMR>Dv-cbl had been used prior to the commencement of this study to screen for modifiers of its rough and overgrown eye phenotype using the Gene search system, a transposon-based inducible expression system. In this study, a subset of the suppressors of the GMR>Dv- cbl phenotype from that screen, and two other representative lines were further investigated. The published interactions and functions of the genes implicated by the GS lines are discussed and a method of suppression of the GMR>Dv-cbl phenotype by each line is suggested. In the published work presented in this thesis, the Akap200 expressing lines EP2254 and GS2208 were further studied. Expression of Akap200 in EP2254 was confirmed via mRNA in situ hybridisation, and its ability to also suppress the Ras85DV12 phenotype was confirmed. The ability of EP2254 to suppress GMR-Dv-cbl and sev-Ras85DV12 coexpression was confirmed. When GMR-Dv-cbl and sev-Ras85DV12 are coexpressed, a phenotype that is greater than the cumulative phenotype of each would suggest arises. In fact, GMR-Dv- cbl (where Dv-cbl was directly driven from the GMR promoter) was used instead of GMR-Gal4, UAS-Dv-cbl (GMR>Dv-cbl) as the coexpression of GMR>Dv-cbl and sev- Ras85DV12 results in lethality, and coexpression of GMR-Dv-cbl and sev-Ras85DV12 did not. Alone, each has a mildly rough eye. I showed that EP2254 was able to suppress this phenotype and that this suppression was partially independent of apoptosis. The endogenous function of Akap200 in the Drosophila eye was then investigated. An mRNA in situ hybridisation experiment showed that endogenous Akap200 is present in the eye disc, and a series of immunohistochemical stains showed that Akap200 was expressed in a subset of photoreceptor cells. Knockdown of Akap200 using RNAi lines i showed that endogenous Akap200 was having a modifying effect on the GMR>Dv-cbl phenotype, as knockdown of Akap200 enhances the GMR>Dv-cbl phenotype. A recent study suggests that Notch is protected from internalisation by Cbl by Akap200, which is consistent with the results in this thesis. ii PREFACE Chapter 4 consists solely of the paper published with myself as the first author, Hannah Robertson and Nicole Siddall as second and third authors respectively, and Gary Hime as the senior author. This paper was published by Molecular and Cellular Biochemistry on 8 July 2012 (online) (and then in the October 2012 issue) and was titled: “Akap200 suppresses the effects of Dv-cbl expression in the Drosophila eye”. As stated in the declaration of thesis with publication form, I contributed 80% of the work towards this paper. I designed and carried out the experiments under the advice of Hannah Robertson and Gary Hime, Nicole Siddall assisted with imaging of Figure 5, and the manuscript was prepared by myself with input from all authors. This work was sponsored by the National Health and Medical Research Council Project Grant 350316 awarded to Gary Hime and Hannah Robertson. iv ACKNOWLEDGEMENTS I would first like to thank my supervisors, Gary Hime and Hannah Robertson, thanks for their guidance, encouragement, and patience through this entire process. I would also like to thank my advisory committee Robb De Iongh and Peter Kitchener, for their help and advice, and Franca Casagranda for help with molecular work. I would like to thank my family, especially my spouse Leo Bullimore, and my mother Meryl Martin, for always being there for me and supporting me. Other family members who I would like to thank for their support and encouragement are: Amri Sannang, Beata Masternak, Neil Martin, Dawn Martin, Carol Bullimore, Brian Bullimore, Erin Dowdle, Joel Stevens, Gemma Stevens, Bronte Stevens, Callum Stevens, and Ava Stevens. I’d also like to thank my friends- Lisa McLennan, Carina Heppell, Anna Johnson, Jessica Peters, Mia De Seram, Mirijana Cipetic, and Aggie Napodowski, and the current and former lab members of the Fly labs in the department during my time there, especially Rebecca Parsons, Marina Kalcina, Tricia Dominado, and Elena Savva for their help with fly care. v TABLE OF CONTENTS ABSTRACT .............................................................................................................................. i DECLARATION .................................................................................................................... iii PREFACE ............................................................................................................................... iv ACKNOWLEDGEMENTS .................................................................................................... v TABLE OF CONTENTS ....................................................................................................... vi INDEX OF TABLES ............................................................................................................... x INDEX OF FIGURES ............................................................................................................ xi COMMON ABBREVIATIONS USED IN THIS THESIS ................................................ xii 1 INTRODUCTION ................................................................................................................ 1 1.1 The Cbl family of genes. ..................................................................................................... 2 1.2 Cbl mutants. ......................................................................................................................... 3 1.3 Cbl function ......................................................................................................................... 6 1.4 Cbl in Drosophila eye development .................................................................................... 7 1.5 The screen performed prior to this study identified a number of suppressors of Dv- Cbl ........................................................................................................................................... 11 1.6 Thesis Aims ....................................................................................................................... 14 1.7 A short word on Drosophila .............................................................................................. 14 1.8 Summary ............................................................................................................................ 15 2 MATERIALS AND METHODS ....................................................................................... 16 2.1 MATERIALS .................................................................................................................... 17 2.1.1 Chemicals and Reagents ................................................................................................. 17 2.1.2 Nucleotides ..................................................................................................................... 17 2.1.3 Antibodies ....................................................................................................................... 18 2.1.4 Drosophila strains .......................................................................................................... 19 2.1.4.1 GAL4 lines .................................................................................................................. 19 2.1.4.2 Mutant and Transgenic lines ....................................................................................... 20 2.1.4.3 Balancer Chromosomes ............................................................................................... 21 2.1.4.4 Lines generated in the course of this project ............................................................... 21 2.1.4.4.1 Mating scheme type 1 ............................................................................................... 21 vi 2.1.4.4.3 Mating scheme type 2 ............................................................................................... 22 2.1.4.4.4 Mating scheme type 3, ‘clean up’ crosses. ............................................................... 23 2.1.5 Media and Buffers .......................................................................................................... 23 2.1.5.1 Bacteria Media ............................................................................................................. 23 2.1.5.2 Buffers and Standard Solutions ................................................................................... 23 2.1.5.3 Drosophila culture medium. ........................................................................................ 24 2.2 METHODS ........................................................................................................................ 24 2.2.1 Drosophila culture and genetics ....................................................................................
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