LIFE01200604005 Shri Somnath Ghosh - Homi Bhabha National ...

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CHAPTER 4 DISCUSSION inhibition of which could revert the cells to radiosensitivity leading to a decrease in survival. Proton beam was found to be more cytotoxic than γ-radiation. Proton beam irradiated cells showed phosphorylation of H2AX, ATM, Chk2 and p53. The mechanism of excessive cell killing in proton beam irradiated cells was found to be upregulation of Bax and down-regulation of Bcl-2. The noteworthy finding of this study is the biphasic activation of the sensor proteins, ATM and DNA-PK and no activation of ATR by proton irradiation. Carbon beam was found to be three times more cytotoxic than γ-radiation despite the fact that the numbers of γ-H2AX foci were same. Percentage of cells showing ATM/ATR foci were more with gamma however number of foci per cell were more in case of carbon irradiation. Large BRCA1 foci were found in all carbon irradiated cells unlike gamma irradiated cells and prosurvival ERK pathway was activated after gamma irradiation but not carbon. The noteworthy finding of this study is the early phase apoptosis induction by carbon ions. Despite activation of same repair molecules, differences in low and high LET damage responses are due to distinct macromolecular complexes of repair proteins such as ATM, BRCA1 etc rather than their individual activation and the activation of cytoplasmic pathways such as ERK. Oxygen beam was found to be three times more cytotoxic than γ-radiation. By 4h there was efficient repair of DNA in A549 cells exposed to 2Gy or 6Gy gamma radiation but not in cells exposed to 2Gy oxygen beam as determined by γ-H2AX counting. Number of ATM foci was found to be significantly higher in cells exposed to 2Gy oxygen beam. 209
CHAPTER 4 DISCUSSION Percentage of cells showing ATR foci were more with gamma however number of foci per cell were more in case of oxygen beam. Oxygen beam irradiated cells showed phosphorylation of Chk1, Chk2 and p53. Many apoptotic nuclei were seen by DAPI staining in cells exposed to oxygen beam. The noteworthy finding of this study is the activation of the sensor proteins, ATM and ATR by oxygen irradiation and the significant activation of Chk1, Chk2 and p53 only in the oxygen beam irradiated cells. The current study is a clear evidence of radiation induced bystander effect being involved in adaptive responses in the bystander cells. Moreover, it also points towards the potential involvement of signaling molecules released into the medium by the irradiated cells which elicit a response in the bystander cells. Also there may be potential involvement of stable free radicals that are produced in the medium as a result of irradiation, in eliciting a response from the bystander cells. The mechanism of which may be via NO generation. Conclusion: Radiation induced signal transduction, as understood presently, is an activation of the existing network, where both positive and negative signals converge and these are interpreted as cell survival and cell death. In spite of the fact that mere phosphorylation by kinases seem to be the basic theme, it is crucial as based on this life or death decisions are taken. Hence enormous cross checking of the ultimate signal must exist. The lung carcinoma cell line A549, a highly radioresistant cell line could be effectively made radiosensitive by inhibiting Rad52, one of the components of its repair pathway. The survival of the cells decreased significantly after doing so. 210
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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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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.3.3.1.6 Phosp
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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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Page 190 and 191: CHAPTER 3 RESULTS Fig.3.4.4b DNA da
Page 192 and 193: CHAPTER 3 RESULTS Fig.3.4.5a Gene e
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Page 222 and 223: CHAPTER 5 REFERENCES [1] Khan, F. T
Page 224 and 225: CHAPTER 5 REFERENCES [19] Woo, R. A
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Page 232 and 233: CHAPTER 5 REFERENCES [84] Uziel, T.
Page 234 and 235: CHAPTER 5 REFERENCES [98] Liu, Y.;
Page 236 and 237: CHAPTER 5 REFERENCES [111] Fei, P.;
Page 238 and 239: CHAPTER 5 REFERENCES [127] Frank, K
Page 240 and 241: CHAPTER 5 REFERENCES [141] Pierce,
Page 242 and 243: CHAPTER 5 REFERENCES [156] Roots, R
Page 244 and 245: CHAPTER 5 REFERENCES [171] Xia, Z.;
Page 246 and 247: CHAPTER 5 REFERENCES (MAP) kinase c
Page 248 and 249: CHAPTER 5 REFERENCES phosphorylatio
Page 250 and 251: CHAPTER 5 REFERENCES [211] Anderson
Page 252 and 253: CHAPTER 5 REFERENCES [229] Konca, K
Page 254 and 255: CHAPTER 5 REFERENCES [245] Kastan,
Page 256 and 257: CHAPTER 5 REFERENCES [261] Miralbel
Page 258 and 259: CHAPTER 5 REFERENCES [278] Weizman,
Page 260 and 261: CHAPTER 5 REFERENCES [294] Zhou, H.
Page 262 and 263: PUBLICATIONS AND PRESENTATIONS Publ
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Mutation Research 716 (2011) 10-19
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