LIFE01200604005 Shri Somnath Ghosh - Homi Bhabha National ...

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CONTENTS Page No. SYNOPSIS…………………………………………………………………………. 1-28 LIST OF FIGURES Fig. 1.1 Pie-chart showing the percentage of radiation exposure…….. 31 Fig. 1.3A Regulation of Cell Cycle by p53 and p21…………………. 50 Fig. 1.3B Pathways of DSB repair……………………………………. 53 Fig. 1.4 Effects of ionizing radiation on cellular response systems….. 62 Fig.1.5. Biological consequences of clustered DNA damage………... 71 Fig. 1.6 Radiation induced bystander effect…………………………. 76 Fig. 3.1.1 Relative radioresistance of three cell line…………………. 96 Fig. 3.1.2 Relative expression of genes in A549 cells……………….. 98 Fig. 3.1.3 Validation of microarray data by RT-PCR………………… 126 Fig.3.1.4 Gene expression of ATM, DNA-PK, Rad52 and MLH1…… 129 Fig. 3.1.5 Repair kinetics as determined by γ-H2AX foci……………… 130 Fig. 3.1.6A Radiation induced foci of DNA damage response proteins... 131 Fig. 3.1.7 Translocation of phospho-p53……………………………….. 133 Fig. 3.1.8 Response of A549 and MCF-7………………………………. 134 Fig.3.1.9 Stabilization of DNA-PK mRNA in A549…………………… 136 Fig.3.1.10 Effect of Rad52 and MLH1…………………………………. 137 Fig.3.2.1 Clonogenic Cell Survival of A549……………………………. 140 Fig.3.2.2 Gene expression of ATM, DNA-PK, ATR, Chk1 and Chk2…. 141 Fig.3.2.3 Immunofluorescence staining and Image analysis…………….. 142 Fig.3.2.4 Gene expression of Bax and Bcl-2…………………………….. 143 Fig.3.3.1.1 Clonogenic Cell Survival of A549 cells……………………... 145 Fig.3.3.1.2 Formation of γ-H2AX foci…………………………………... 147 Fig.3.3.1.3 Phosphorylation of ATM……………………………………. 149 Fig.3.3.1.4 Phosphorylation of ATR…………………………………….. 150 Fig.3.3.1.5 Phosphorylation of BRCA1…………………………………. 151 Fig.3.3.1.6 Phosphorylation of Chk1 and Chk2…………………………. 153 Fig.3.3.1.7a Phosphorylation of ERK…………………………………… 154 Fig.3.3.1.7b Phosphorylation of JNK…………………………………… 155 Fig.3.3.1.8 Apoptosis in carbon irradiated A549 cells…………………... 156 Fig. 3.3.2.1 Clonogenic Cell Survival of A549 cells……………………. 158 Fig. 3.3.2.2 Phosphorylation of H2AX…………………………………. 160 Fig.3.3.2.3 Phosphorylation of ATM…………………………………… 163 Fig.3.3.2.4 Phosphorylation of ATR……………………………………. 164 Fig.3.3.2.5 Phosphorylation of TP53……………………………………. 165 Fig.3.3.2.6 Phosphorylation of Chk2……………………………………. 166 Fig.3.3.2.7 Apoptosis in oxygen irradiated A549 cells………………….. 167 Fig.3.4.1Bystander effect in similar cells (A549 Vs A549)……………... 170 Fig.3.4.2 Bystander effect in dissimilar cells (A549 Vs U937)…………. 171
Fig.3.4.3.1 Gene expression of iNOS, p21, p53 and NF-kB (p65)……… 174 Fig.3.4.3.2 NO production from EL-4 cells……………………………... 175 Fig.3.4.3.3 DNA damage in EL-4 cells………………………………….. 176 Fig. 3.4.3.4a DNA fragmentation assay of EL-4 cells…………………... 177 Fig. 3.4.3.4b Apoptosis assay of EL-4 cells……………………………... 178 Fig.3.4.4a Gene expression of NF-kB (p65) and iNOS gene…………… 180 Fig.3.4.4b DNA damage in EL-4 cells…………………………………... 181 Fig.3.4.5a Gene expression of NF-kB (p65) and iNOS gene…………… 183 Fig.3.4.5b DNA damage in EL-4 cells…………………………………... 184 LIST OF TABLES Table 2.6 The sequences of gene specific primers………………………. 87 Table 3.1.2A List of Up-regulated Genes: Control Vs 5X2Gy…………. 99 Table 3.1.2B List of Down-regulated Genes: Control Vs 5X2Gy……..... 107 Table 3.1.2C List of Up-regulated genes: 2Gy Vs 5X2Gy……………… 111 Table 3.1.2D List of Down-regulated genes: 2Gy Vs 5X2Gy…………... 116 Table 3.1.2E List of Up-regulated genes: 10Gy Vs 5X2Gy…………….. 117 Table 3.1.2F List of Down-regulated genes of 10Gy Vs 5X2Gy……….. 123 CHAPTER 1- INTRODUCTION 1.1. Ionizing Radiation………………………………………………….. 32 1.2. Radiation Therapy…………………………………………………. 34 1.3. DNA damage signaling following irradiation…………………….. 37 1.3.1 Alarm Sensors…………………………………………… 37 1.3.2 Cell Cycle Regulation…………………………………… 49 1.3.3 DNA Repair……………………………………………… 52 1.4. Overview of Radiation induced cell signaling…………………….. 61 1.5. Charged particle irradiation induced Signaling………………….. 70 1.6. Radiation induced Bystander Signaling…………………………… 75 1.7. Aims and Objectives………………………………………………… 78 CHAPTER 2 - MATERIALS & METHODS 2.1 Chemicals............................................................................................. 80 2.2 Cell Lines…………………………………………………………….. 81 2.3 Irradiation............................................................................................ 81 2.4 Clonogenic Cell Survival Assay……………………………………. 84 2.5 Microarray…………………………………………………………... 84 2.6 Semiquantitative RT-PCR…………………………………………. 86 2.7 Immunofluorescence staining………………………………………. 86 2.8 Image analysis using ImageJ software…………………………….. 88 2.9 Western Blotting…………………………………………………….. 89 2.10 Measurement of DNA damage……………………………………. 90
Page 1: RADIATION INDUCED SIGNALING IN MAMM
Page 4 and 5: DECLARATION I, hereby declare that
Page 8 and 9: 2.11 Measurement of NO production
Page 10 and 11: PREAMBLE SYNOPSIS Ionising radiatio
Page 12 and 13: SYNOPSIS Aims and Objectives: To St
Page 14 and 15: SYNOPSIS 2.6 Immunofluorescence sta
Page 16 and 17: SYNOPSIS ATM gene expression, which
Page 18 and 19: SYNOPSIS Percentage Survival 100 80
Page 20 and 21: SYNOPSIS Ratio of Rad52 to Actin Ra
Page 22 and 23: Relative Phosphorylation 45 40 35 3
Page 24 and 25: SYNOPSIS Fig. 3.3A Clonogenic Cell
Page 26 and 27: SYNOPSIS (A) Av No. of phospho BRCA
Page 28 and 29: SYNOPSIS Percentage Survival 120 10
Page 30 and 31: SYNOPSIS Fig.3.4B. Existance of cro
Page 32 and 33: SYNOPSIS Fig. 3.4EDNA damage in EL-
Page 34 and 35: SYNOPSIS subsequent cytotoxicity ca
Page 36 and 37: SYNOPSIS [4] Hall, E. J. Radiobiolo
Page 38 and 39: CHAPTER 1 INTRODUCTION INTRODUCTION
Page 40 and 41: CHAPTER 1 INTRODUCTION 15.8% 9.56%
Page 42 and 43: CHAPTER 1 INTRODUCTION far apart an
Page 44 and 45: CHAPTER 1 INTRODUCTION and are more
Page 46 and 47: CHAPTER 1 INTRODUCTION 1.3 DNA dama
Page 48 and 49: CHAPTER 1 INTRODUCTION associates w
Page 50 and 51: CHAPTER 1 INTRODUCTION are unable t
Page 52 and 53: CHAPTER 1 INTRODUCTION Perhaps one
Page 54 and 55: CHAPTER 1 INTRODUCTION occurs at DS
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CHAPTER 1 INTRODUCTION related prot
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CHAPTER 1 INTRODUCTION damage must
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CHAPTER 1 INTRODUCTION At the prese
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CHAPTER 1 INTRODUCTION predominant
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CHAPTER 1 INTRODUCTION provide a me
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CHAPTER 1 INTRODUCTION hypersensiti
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CHAPTER 1 INTRODUCTION cycle-specif
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CHAPTER 1 INTRODUCTION 1.4 Overview
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CHAPTER 1 INTRODUCTION 1.4.1 Radiat
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CHAPTER 1 INTRODUCTION interaction
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CHAPTER 1 INTRODUCTION p90S6 kinase
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CHAPTER 1 INTRODUCTION CD4 (formerl
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CHAPTER 1 INTRODUCTION unrepaired d
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CHAPTER 1 INTRODUCTION well to the
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CHAPTER 1 INTRODUCTION 1.6 Radiatio
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CHAPTER 1 INTRODUCTION becomes pote
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CHAPTER 2 MATERIALS AND METHODS MAT
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CHAPTER 2 MATERIALS AND METHODS 2.2
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CHAPTER 2 MATERIALS AND METHODS res
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CHAPTER 2 MATERIALS AND METHODS Arr
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CHAPTER 2 MATERIALS AND METHODS PBS
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CHAPTER 2 MATERIALS AND METHODS the
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CHAPTER 2 MATERIALS AND METHODS 2.1
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CHAPTER 3 RESULTS RESULTS 93
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CHAPTER 3 RESULTS fractionated regi
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CHAPTER 3 RESULTS On comparison of
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CHAPTER 3 RESULTS Table 3.1.2A List
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CHAPTER 3 RESULTS 80 NM_002185 IL7R
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CHAPTER 3 RESULTS SAA2 149 AU134977
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CHAPTER 3 RESULTS 221 LOC643167 RNA
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CHAPTER 3 RESULTS 299 BF244402 FBXO
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CHAPTER 3 RESULTS CDK4) 57 AU152107
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CHAPTER 3 RESULTS 134 AL045793 METT
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CHAPTER 3 RESULTS 58 AF237813 ABAT
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CHAPTER 3 RESULTS 127 AI809749 ORMD
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CHAPTER 3 RESULTS 31 BE615699 UNC84
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CHAPTER 3 RESULTS 47 AF026303 SULT1
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CHAPTER 3 RESULTS 117 BF062193 CYor
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CHAPTER 3 RESULTS 187 AL036662 ---
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CHAPTER 3 RESULTS 52 AV686514 EMP2
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CHAPTER 3 RESULTS exposed to 10 Gy
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CHAPTER 3 RESULTS Fig.3.1.4 Gene ex
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CHAPTER 3 RESULTS Fig. 3.1.6 Radiat
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CHAPTER 3 RESULTS Fig. 3.1.7 Transl
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CHAPTER 3 RESULTS 3.1.9 Stabilizati
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CHAPTER 3 RESULTS 23±1.5% (Fig. 3.
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CHAPTER 3 RESULTS whereas only the
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CHAPTER 3 RESULTS with equal doses
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CHAPTER 3 RESULTS Fig.3.3.1.2 Forma
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CHAPTER 3 RESULTS Fig.3.3.1.3 Phosp
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CHAPTER 3 RESULTS (7.5±0.64) (Fig.
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CHAPTER 3 RESULTS Fig.3.3.1.7b Phos
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CHAPTER 3 RESULTS 3.3.2 Oxygen beam
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CHAPTER 3 RESULTS in all the cells.
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CHAPTER 3 RESULTS 3.3.2.3 Radiation
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CHAPTER 3 RESULTS Fig.3.3.2.7 Apopt
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CHAPTER 3 RESULTS PMA stimulated U9
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CHAPTER 3 RESULTS Fig.3.4.2. Exista
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CHAPTER 3 RESULTS up-regulation of
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CHAPTER 3 RESULTS Fig.3.4.3.2 NO pr
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CHAPTER 3 RESULTS 3.4.3.4 Apoptotic
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CHAPTER 3 RESULTS 3.4.4 Bystander e
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CHAPTER 3 RESULTS Fig.3.4.4b DNA da
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CHAPTER 3 RESULTS Fig.3.4.5a Gene e
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CHAPTER 4 DISCUSSION DISCUSSION 185
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CHAPTER 4 DISCUSSION directly expos
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CHAPTER 4 DISCUSSION dose is delive
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CHAPTER 4 DISCUSSION A clear cause
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CHAPTER 4 DISCUSSION 4.2 Proton bea
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CHAPTER 4 DISCUSSION Although the e
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CHAPTER 4 DISCUSSION Similar number
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CHAPTER 4 DISCUSSION the mechanism
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CHAPTER 4 DISCUSSION Thus unlike th
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CHAPTER 4 DISCUSSION different from
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CHAPTER 4 DISCUSSION upregulates ma
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CHAPTER 4 DISCUSSION Numerous studi
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CHAPTER 4 DISCUSSION inhibition of
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CHAPTER 4 DISCUSSION The survival o
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CHAPTER 5 REFERENCES [1] Khan, F. T
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CHAPTER 5 REFERENCES [19] Woo, R. A
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CHAPTER 5 REFERENCES [35] Nghiem, P
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CHAPTER 5 REFERENCES [52] McKay, B.
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CHAPTER 5 REFERENCES [69] Cary, R.
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CHAPTER 5 REFERENCES [84] Uziel, T.
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CHAPTER 5 REFERENCES [98] Liu, Y.;
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CHAPTER 5 REFERENCES [111] Fei, P.;
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CHAPTER 5 REFERENCES [127] Frank, K
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CHAPTER 5 REFERENCES [141] Pierce,
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CHAPTER 5 REFERENCES [156] Roots, R
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CHAPTER 5 REFERENCES [171] Xia, Z.;
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CHAPTER 5 REFERENCES (MAP) kinase c
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CHAPTER 5 REFERENCES phosphorylatio
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CHAPTER 5 REFERENCES [211] Anderson
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CHAPTER 5 REFERENCES [229] Konca, K
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CHAPTER 5 REFERENCES [245] Kastan,
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CHAPTER 5 REFERENCES [261] Miralbel
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CHAPTER 5 REFERENCES [278] Weizman,
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CHAPTER 5 REFERENCES [294] Zhou, H.
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PUBLICATIONS AND PRESENTATIONS Publ
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Mutation Research 729 (2012) 61-72
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S. Ghosh, M. Krishna / Mutation Res
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12 S. Ghosh et al. / Mutation Resea
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Cancer Invest Downloaded from infor
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1568 I. J. Radiation Oncology d Bio
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