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The Role of Sin1 in Cell Survival

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The Role of Sin1 in Cell Survival The role of Sin1 in cell survival A thesis submitted the University of Manchester for the degree of Doctor of Philosophy In the Faculty of Life Sciences 2014 Blanca Paramo Table of Contents The role of Sin1 in cell survival ............................................................................ 1 Table of Contents ................................................................................................... 2 List of Figures ........................................................................................................ 4 List of Tables .......................................................................................................... 5 Abstract .................................................................................................................. 6 Author’s Declaration .............................................................................................. 7 Copyright statement .............................................................................................. 7 Autobiographical statement ................................................................................. 8 Acknowledgements ............................................................................................... 9 Abbreviations ....................................................................................................... 10 1. Introduction ................................................................................................... 13 1.1 The mammalian target of rapamycin (mTOR) .................................................. 14 1.1.1 mTOR complexes .......................................................................................... 14 1.1.2 Signalling via mTORC1 ................................................................................. 16 1.1.3 Signalling via mTORC2 ................................................................................. 19 1.2 The stress-activated protein kinase interacting protein Sin1 ........................ 20 1.2.1 Cloning and description ................................................................................. 20 1.2.2 Characteristics ............................................................................................... 21 1.2.3 Functions ....................................................................................................... 23 1.3 Programmed cell death ...................................................................................... 27 1.3.1 Mechanisms of PCD ...................................................................................... 27 1.3.2 Apoptosis ....................................................................................................... 27 1.3.3 Autophagic cell death .................................................................................... 29 1.3.4 Necroptosis ................................................................................................... 31 Aims and objectives ............................................................................................ 32 2. Materials and methods ................................................................................. 33 2.1 Materials .............................................................................................................. 33 2.2 Methods ............................................................................................................... 33 2.2.1 Cell culture .................................................................................................... 33 2.2.2 Genotyping .................................................................................................... 34 2.2.3 Sin1 deletion .................................................................................................. 35 2.2.4 Treatments .................................................................................................... 35 2.2.5 Preparation of cell lysates ............................................................................. 35 2.2.6 Bradford assay .............................................................................................. 36 2.2.7 Akt kinase assay ........................................................................................... 36 2.2.8 Immunoblotting .............................................................................................. 37 2.2.9 Caspase 3 assay ........................................................................................... 38 2.2.10 MTT assay ................................................................................................... 38 2.2.11 LDH assay ................................................................................................... 39 2.2.12 Cell counting and cell size measurement .................................................... 39 2.2.13 Cell proliferation assay ................................................................................ 39 2.2.14 β-galactosidase assay ................................................................................. 40 2.2.15 Immunofluorescence staining ...................................................................... 40 2.2.16 Quantitative Real time PCR ........................................................................ 41 2.2.17 Hoechst staining .......................................................................................... 42 2.2.18 Cellular fractionation .................................................................................... 42 2.2.19 Microarrays .................................................................................................. 42 2.2.20 Statistical analysis of microarray data ......................................................... 43 2 2.2.21 Statistical analysis ....................................................................................... 43 Results .................................................................................................................. 44 3. Sin1 in the survival of mitotic cells ............................................................ 44 3.1 Methodology used to study the role of Sin1 in cell survival .......................... 44 3.2 Sin1 can be conditionally inactivated in MEFs after 4OHT treatment ........... 45 3.3 The loss of Sin1 decreases Akt activity in response to mitogens in MEFs .. 47 3.4 mTOR kinase inhibition decreases pSer437 .................................................... 49 3.5 The loss of Sin1 decreases cell survival .......................................................... 51 3.6 CreER activation affects MEFs proliferation ................................................... 56 3.7 Discussion .......................................................................................................... 58 4. Sin1 in neuronal survival ............................................................................. 61 4.1 Methodology to study the role of Sin1 in neuronal survival .......................... 61 4.2 Conditional inactivation of Sin1 decreases Akt S473 phosphorylation in neurons ........................................................................................................................ 62 4.3 Loss of Sin1 increases apoptotic neuronal death .......................................... 66 4.4 Autophagy is not increased in Sin1 ko neurons ............................................. 68 4.5 The loss of Sin1 does not increase necroptotic neuronal death ................... 70 4.5.1 The loss of Sin1 does not affect neuronal polarisation .................................. 72 4.6 The loss of Sin1 does not affect Synaptophysin level ................................... 74 4.7 Discussion .......................................................................................................... 76 5. Sin1 and gene expression in neurons ........................................................ 80 5.1 Methodology used to study the role of Sin1 in gene expression .................. 80 5.2 Functional analysis of genes down-regulated in absence of Sin1 ................ 82 5.3 Array validation by RT-PCR .............................................................................. 87 5.3.1 Discussion ..................................................................................................... 90 Discussion ............................................................................................................ 93 6.1 Future directions ................................................................................................ 96 References ............................................................................................................ 97 Appendix ............................................................................................................. 112 A List of genes ........................................................................................................... 112 B Primer efficiency .................................................................................................... 117 Word count: 34,118 3 List of Figures Figure 1.1 mTOR and the mTOR complexes. ....................................................... 15 Figure 1.2 mTORC1 activation .............................................................................. 17 Figure 1.3 mTORC1 and mTORC2 function in cells. ............................................. 19 Figure 1.4 The stress-activated protein kinase-interacting protein Sin1 ................ 22 Figure 1.5 Role of Sin1 in Akt regulation. .............................................................
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