Cellular Defenses Against Radiation-Induced Carcinogenesis:

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In yeast, only a single CDK is used by a sequence of different cyclins that are briefly transcribed and then quickly degraded at specific points in the cell cycle. The cyclin is, therefore, the important regulatory component determining the specificity of the CDK. In mammalian cells, multiple CDKs appear to be involved: CDK4 functions early (in response to growth factors) CDK2 is required to start DNA replication CDC2 is essential for mitosis Cyclin D E and/or A A and B NCI REB <strong>Radiation</strong> Epidemiology Course, May 14, 2007 TJJ
Cyclin/CDK complexes seem to be regulated by a variety of feedback mechanism, both positive and negative, that include: • Transcription of cyclin • Degradation of cyclin • Phosphorylation of CDKs Negative feedback occurs during development, differentiation, and senescence. It probably acts to stop cell cycle progression when the integrity of the genome has been compromised for some reason. NCI REB <strong>Radiation</strong> Epidemiology Course, May 14, 2007 TJJ
Page 1 and 2: Cellular Defenses Against Radiation
Page 3 and 4: GOALS: • Provide an overall descr
Page 5 and 6: NCI REB Radiation Epidemiology Cour
Page 9 and 10: Cancer cells “evolve” into a hi
Page 11 and 12: WHY CHECKPOINTS Fidelity of cell di
Page 15: NCI REB Radiation Epidemiology Cour
Page 19 and 20: • At least two checkpoints are re
Page 21 and 22: DO DEFECTIVE CHECKPOINTS CAUSE CANC
Page 23 and 24: Radiation-Induced G2 delay in lymph
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 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
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NER PATHWAY GENES GENE ALIASES DESC
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Skin cancers have unique p53 mutati
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For BCC, PTCH may be even a bigger
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Gorlin Syndrome • Nevoid basal ce
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Verónica Martín, Graciela Carrill
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Taipale J and Beachy PA Nature 411:
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PTCH may play a role in cell cycle
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NCI REB Radiation Epidemiology Cour
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Aszterbaum et al. Nature Med. 5:128
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Shh, PTCH, and SUFU mutations produ
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Thomas et al., J. Postgrad Med. 49:
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NCI REB Radiation Epidemiology Cour
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Veratrum californicum (corn lily) N
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Frank-Kamenetsky et al. J. Biol. 1:
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CONFOUNDERS: AGE SKIN COLOR DOSE NC
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• A disease of accelerated aging.
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Age-Dependent Reactive Oxygen Speci
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SKIN COLOR GENETICS NCI REB Radiati
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Am J Epidemiol 155: 614, 2002 Melan
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Melanocortin 1 Receptor gene (MC1R)
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SKIN COLOR GEOGRAPHY Photograph by
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DOSE NCI REB Radiation Epidemiology
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National Geographic Magazine April
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Aging genes (I.e. non-DNA repair) A
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RR for XP patients by age 8000 8000
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