LIFE01200604005 Shri Somnath Ghosh - Homi Bhabha National ...

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CHAPTER 1 INTRODUCTION At the present, much insight is being gained regarding the roles of p53 in DSB repair. Further studies on p53 functioning as the switch from reversible arrest to triggering apoptosis may offer a greater understanding of radioresistance and radiosensitivity [111]. p21 p21 Waf1/Cip1/Sdi1 is the first identified inhibitor of cyclin/cyclin-dependent kinase (CDK) complexes, which regulate transitions between different phases of the cell cycle. p21 was independently isolated as a CDK-binding protein and as a growth-inhibitory gene which is upregulated by wild-type p53 [112] or overexpressed in senescent fibroblasts [113]. Although many other CDK inhibitors have since been discovered [114], p21 appears to be the only inhibitor capable of interacting with essentially all of the CDK complexes. The effects of p21 on CDKs, however, are not limited to simple binding and inhibition. For example, p21 binding, depending on its stoichiometry, may not only inhibit but also stimulate CDK4/6 complexes [115]. On the other hand, p21 affinity towards CDC2/CDK1 (the primary regulator of cellular entry into mitosis) is low, suggesting that p21 may not bind CDC2 under physiological conditions [116]. Nevertheless, p21 expression efficiently inhibits CDC2 in vivo; this effect appears to be mediated at least in part through the interference with the activating phosphorylation of CDC2 at Thr 161 [117, 118]. The first transcriptional target of p53 identified was the Cdk inhibitor p21. That p53 transactivation of p21 does not necessarily yield increased p21 protein levels is another important aspect of the study described by Jascur et al. [119]. DNA damage by ionising radiation results in stabilization of wild-type p53 and subsequent transcriptional 51
CHAPTER 1 INTRODUCTION activation of p21. However, p21 protein levels are not increased when WISp39 is downmodulated with siRNA or Hsp90 is inhibited with the drug geldanamycin following DNA damage. This exciting observation suggests that p21 levels are increased transcriptionally by p53 and at the level of protein stability by WISp39 and Hsp90 suggesting that two events are required to stabilize p21. Counterintuitive to the role of p21 in cell cycle arrest, p21 has also been implicated as a positive regulator of cell survival. For example, loss of p21 sensitizes cells to undergo uncoordinated DNA replication and death induced by anticancer drugs [120]. 1.3.3 DNA Repair Following cell cycle arrest and triggering of the alarm sensors, many DNA repair pathways are activated to repair the damaged DNA. The five major DNA repair pathways are homologous recombination repair (HRR); non-homologous end joining (NHEJ); nucleotide excision repair (NER); base excision repair (BER); and mismatch repair (MMR)[121]. 1.3.3.1 DNA double strand break repair DNA double-strand breaks (DSBs) are a common form of DNA damage and DSB rejoining is a fundamental mechanism of genome protection. Breaks arise through direct action of ionizing radiation or some chemicals, and indirectly as a product of blocked replication forks. The ability to repair DSBs and to ensure that repair is performed with appropriate fidelity is a fundamental part of genome protection. The three known DSB repair pathways are outlined in Fig. 1.3B. The pathways are conserved between Saccharomyces cerevisiae and mammalian cells although the relative importance in each differs considerably. The prevailing view has been that homologous recombination is the 52
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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
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
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Page 52 and 53: CHAPTER 1 INTRODUCTION Perhaps one
Page 54 and 55: CHAPTER 1 INTRODUCTION occurs at DS
Page 56 and 57: CHAPTER 1 INTRODUCTION related prot
Page 58 and 59: CHAPTER 1 INTRODUCTION damage must
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Page 64 and 65: CHAPTER 1 INTRODUCTION provide a me
Page 66 and 67: CHAPTER 1 INTRODUCTION hypersensiti
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Page 70 and 71: CHAPTER 1 INTRODUCTION 1.4 Overview
Page 72 and 73: CHAPTER 1 INTRODUCTION 1.4.1 Radiat
Page 74 and 75: CHAPTER 1 INTRODUCTION interaction
Page 76 and 77: CHAPTER 1 INTRODUCTION p90S6 kinase
Page 78 and 79: CHAPTER 1 INTRODUCTION CD4 (formerl
Page 80 and 81: CHAPTER 1 INTRODUCTION unrepaired d
Page 82 and 83: CHAPTER 1 INTRODUCTION well to the
Page 84 and 85: CHAPTER 1 INTRODUCTION 1.6 Radiatio
Page 86 and 87: CHAPTER 1 INTRODUCTION becomes pote
Page 88 and 89: CHAPTER 2 MATERIALS AND METHODS MAT
Page 90 and 91: CHAPTER 2 MATERIALS AND METHODS 2.2
Page 92 and 93: CHAPTER 2 MATERIALS AND METHODS res
Page 94 and 95: CHAPTER 2 MATERIALS AND METHODS Arr
Page 96 and 97: CHAPTER 2 MATERIALS AND METHODS PBS
Page 98 and 99: CHAPTER 2 MATERIALS AND METHODS the
Page 100 and 101: CHAPTER 2 MATERIALS AND METHODS 2.1
Page 102 and 103: CHAPTER 3 RESULTS RESULTS 93
Page 104 and 105: CHAPTER 3 RESULTS fractionated regi
Page 106 and 107: CHAPTER 3 RESULTS On comparison of
Page 108 and 109: 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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