LIFE01200604005 Shri Somnath Ghosh - Homi Bhabha National ...

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CHAPTER 4 DISCUSSION dose is delivered as fractionated irradiation. p53 classically considered to be a tumor suppressor protein, but in this study the results are contradictory. The fact that A549 cells express wild-type p53 protein, it was unable to suppress the proliferation of A549 cells that had been exposed to fractionated irradiation. Wild-type p53 function involves two steps. First, upstream signaling pathways stabilize and activate the p53 protein in response to DNA damage or other forms of cellular stress. In the second step, activated p53 binds to regulatory sequences of its target genes and activates their expression [244]. Either step may be defective in lung adenocarcinoma A549 cells. Defective activation of wild-type p53 after DNA damage could be the mechanism for suppression of p53 function in A549 cells. The response of p53 to DNA damage involves an increase in p53 protein levels due to stabilization of the protein and an increase in p53 functional activity [245, 246]. It is quite likely that there is no defect in regulation of p53 stabilization in response to DNA damage because p53 was stabilized in response to fractionated irradiation in A549 cell line examined, and the steady-state levels of p53 were very high (Fig. 3.1.7A, B & C). The regulation of the functional activity of p53 seems to be defective. These findings are consistent with previous reports showing the function of wild-type p53 protein is apparently compromised in many cancer cells [247, 248]. Moreover, translocation of phospho-p53 into the nucleus could lead to cell cycle arrest, which will allow the cells to repair the DNA damage. Since DNA repair pathways were up-regulated in A549 cells that had been exposed to fractionated irradiation, it was of interest to look at the activation of genes and proteins involved in DNA repair pathways. Results of this study indicated that there is intense activation of repair genes and protein in A549 cells exposed to fractionated irradiation (Fig.3.1.4 and Fig.3.1.6). 189
CHAPTER 4 DISCUSSION These results on DNA-PK are consistent with earlier works where authors have also shown the role of DNA-PK in the radioresistance of lung carcinoma cells [249, 250]. However, these authors have looked at the response only after single dose of irradiation and it is logical to expect these pathways to get activated. In this study it was shown that DNA-PK is also involved in radioresistance if the cells are subjected to fractionated irradiation but the reason for the development of radioresistance still remains an enigma. ATM and BRCA1 have been regarded as primary regulators of homologous recombination repair (HRR) [251]. In this study an intense activation of ATM gene and ATM foci were seen in all the cells exposed to fractionated irradiation and most of the cells showed BRCA1 foci (Fig.3.1.4 and Fig.3.1.6) indicating the fact that HRR pathway was activated in A549 cells and therefore, these proteins could be involved in HRR which can take advantage of the other strand that may be intact. ATM and BRCA1 reside in macromolecular complex and form foci after irradiation. These results are in agreement with earlier works where authors have also shown the role ATM in radioresistance of cancer cells [252, 253]. However, these authors have studied using single dose of irradiation. The repair of DNA at 4h in A549 cells exposed to fractionated irradiation but not in cells that had been exposed to 10 Gy acute dose, indicating the fact that fractionated irradiation induced better repair capability of the cells. Moreover, the DNA repair pathways were activated in A549 cells exposed to fractionated irradiation allow these cells to repair its damage DNA faster than 10 Gy acute dose. 190
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RADIATION INDUCED SIGNALING IN MAMM
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DECLARATION I, hereby declare that
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CONTENTS Page No. SYNOPSIS………
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2.11 Measurement of NO production
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PREAMBLE SYNOPSIS Ionising radiatio
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SYNOPSIS Aims and Objectives: To St
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SYNOPSIS 2.6 Immunofluorescence sta
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SYNOPSIS ATM gene expression, which
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SYNOPSIS Percentage Survival 100 80
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SYNOPSIS Ratio of Rad52 to Actin Ra
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Relative Phosphorylation 45 40 35 3
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SYNOPSIS Fig. 3.3A Clonogenic Cell
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SYNOPSIS (A) Av No. of phospho BRCA
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SYNOPSIS Percentage Survival 120 10
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SYNOPSIS Fig.3.4B. Existance of cro
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SYNOPSIS Fig. 3.4EDNA damage in EL-
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SYNOPSIS subsequent cytotoxicity ca
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SYNOPSIS [4] Hall, E. J. Radiobiolo
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CHAPTER 1 INTRODUCTION INTRODUCTION
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CHAPTER 1 INTRODUCTION 15.8% 9.56%
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CHAPTER 1 INTRODUCTION far apart an
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CHAPTER 1 INTRODUCTION and are more
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CHAPTER 1 INTRODUCTION 1.3 DNA dama
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CHAPTER 1 INTRODUCTION associates w
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CHAPTER 1 INTRODUCTION are unable t
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CHAPTER 1 INTRODUCTION Perhaps one
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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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Page 170 and 171: CHAPTER 3 RESULTS 3.3.2.3 Radiation
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Page 190 and 191: CHAPTER 3 RESULTS Fig.3.4.4b DNA da
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Page 222 and 223: CHAPTER 5 REFERENCES [1] Khan, F. T
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Page 246 and 247: 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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