Cellular Defenses Against Radiation-Induced Carcinogenesis:

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HEDGEHOG PATHWAY Overexpression oncogenic in mouse skin N * Shh * Cholesterol Genetic disease mimics Shh mutation Shh Cholesterol PTCH Shh Defective in Gorlin’s Syndrome* Mutation oncogenic in mouse skin * SMOOTHENED SUFU First cloned as an oncogene * from glioblastoma Gli1 Gli3 NCI REB <strong>Radiation</strong> Epidemiology Course, May 14, 2007 TJJ
PTCH may play a role in cell cycle regulation EMBO J. 20:2214, 2001 NCI REB <strong>Radiation</strong> Epidemiology Course, May 14, 2007 TJJ
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Cellular Defenses Against Radiation
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GOALS: • Provide an overall descr
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NCI REB Radiation Epidemiology Cour
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Cancer cells “evolve” into a hi
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WHY CHECKPOINTS Fidelity of cell di
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Cyclin/CDK complexes seem to be reg
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• At least two checkpoints are re
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DO DEFECTIVE CHECKPOINTS CAUSE CANC
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Radiation-Induced G2 delay in lymph
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Page 27 and 28: Rothkamm and Lobrick, PNAS, 2003 NC
Page 29 and 30: Somatic Mutation and Cancer Environ
Page 31 and 32: Major DNA repair pathways: • Non-
Page 33 and 34: NCI REB Radiation Epidemiology Cour
Page 37 and 38: “… the failure of DNA repair in
Page 39 and 40: T. Lindahl and R.D. Wood, Science 2
Page 41 and 42: NER PATHWAY GENES GENE ALIASES DESC
Page 43 and 44: Mismatch repair associated tumors i
Page 45 and 46: Non-Homologous End Joining (NHEJ) N
Page 47 and 48: Illegitimate Recombination NCI REB
Page 49 and 50: TARGET THEORY NCI REB Radiation Epi
Page 51 and 52: A-T CELL CANCER CELL DEATH NCI REB
Page 53 and 54: OTHER TARGET QUESTIONS: • If DNA
Page 55 and 56: Mutations in Chk2 produce the Li-Fr
Page 57 and 58: CASE STUDY: Finding Molecular Targe
Page 63 and 64: Environmental Causes of BCC • UV
Page 65 and 66: UV DAMAGE TO DNA NCI REB Radiation
Page 67 and 68: NER PATHWAY GENES GENE ALIASES DESC
Page 69 and 70: Skin cancers have unique p53 mutati
Page 71 and 72: For BCC, PTCH may be even a bigger
Page 73 and 74: Gorlin Syndrome • Nevoid basal ce
Page 75 and 76: Verónica Martín, Graciela Carrill
Page 77: Taipale J and Beachy PA Nature 411:
Page 83 and 84: Aszterbaum et al. Nature Med. 5:128
Page 85 and 86: Shh, PTCH, and SUFU mutations produ
Page 87 and 88: Thomas et al., J. Postgrad Med. 49:
Page 91 and 92: Veratrum californicum (corn lily) N
Page 93 and 94: Frank-Kamenetsky et al. J. Biol. 1:
Page 95 and 96: CONFOUNDERS: AGE SKIN COLOR DOSE NC
Page 97 and 98: • A disease of accelerated aging.
Page 99 and 100: Age-Dependent Reactive Oxygen Speci
Page 101 and 102: SKIN COLOR GENETICS NCI REB Radiati
Page 103 and 104: Am J Epidemiol 155: 614, 2002 Melan
Page 105 and 106: Melanocortin 1 Receptor gene (MC1R)
Page 107 and 108: SKIN COLOR GEOGRAPHY Photograph by
Page 109 and 110: DOSE NCI REB Radiation Epidemiology
Page 111 and 112: National Geographic Magazine April
Page 113 and 114: Aging genes (I.e. non-DNA repair) A
Page 115 and 116: RR for XP patients by age 8000 8000
Page 117 and 118: Radiation as a Model Carcinogen:
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Cellular Defenses Against Radiation-Induced Carcinogenesis:

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