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Chapter 8:pRb and Control of the
Cell Cycle Clock
Copyright © Garland Science 2007
Karobi Karobi Moitra (Ph.D)Moitra (Ph.D)NCI Frederick , NIHNCI Frederick , NIHCancer Inflammation ProgramCancer Inflammation ProgramHuman Genetics SectionHuman Genetics SectionFrederick MD.Frederick MD.
The Cell Cycle
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The cell cycle is a programmedseries of events that enablesa cell to duplicate its contentsand generate 2 daughter cells
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Figure 8.3b The Biology of Cancer (© Garland Science 2007)
The Cell Cycle
Resting stage
Gap 1
Synthesis
Gap2
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Figure 8.3a The Biology of Cancer (© Garland Science 2007)
The mitotic cell cycle in newt lung cells
Prophase:ChromosomesCondense (blue)
Prophase:Centrosomesbegin to assemble(green)
Metaphase:Chromosomesalign and attachto spindle fibres
Anaphase:Chromosomehalves are pulled apart
Telophase:Chromatidsdecondenseand nuclearmembraneforms
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Checkpoint Control
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Checkpoint Control
Checkpoint controls in the cell cycle ensure thata new step in the cycle is not undertaken until
the preceding step has been completed.
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Figure 8.4 The Biology of Cancer (© Garland Science 2007)
Cell Cycle Checkpoints : Quality Control
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What happens if a damaged cell overrides these checkpoints?
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Cancer is associated with abnormal cellularproliferation
Cells divide when they should not divide and theylack the normal control systems to shut off unwanted
cell division
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Cancer Cells May Lose Checkpoint Controls
Cell death
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Figure 8.5a The Biology of Cancer (© Garland Science 2007)
Loss of checkpoint controls result in altered Karyotype
Normal human Rad17 deprived(Rad17 preventsrereplication)
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Figure 8.5c The Biology of Cancer (© Garland Science 2007)
Chromosome breaks in cells Lacking ATR (ATR can stall replication to repair breaks)
ATR: ataxia telangiectasia and Rad3 related protein
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Figure 8.6 The Biology of Cancer (© Garland Science 2007)
Once a Cell Advances beyond R- restriction point it is committed to advance through the cell cycle and
divide
Go to MRemain in G1Go to G0
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Restriction Point :
G1 phase checkpoint in the cell cycle of animal cells
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Figure 8.1 The Biology of Cancer (© Garland Science 2007)
The Cell Cycle Clock controls the cell cycle
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Table 8.4 The Biology of Cancer (© Garland Science 2007)
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Figure 8.8 The Biology of Cancer (© Garland Science 2007)
Each cyclin pairs with a specific cyclin dependentkinase (CDK) to carry out the steps in the cell cycle
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Cyclin +cyclin-dependent kinase (CDK)+ CAK = active complex
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Figure 8.12 The Biology of Cancer (© Garland Science 2007)
Coordinated cyclin levels during the cellcycle : levels of different cyclins change
at different stages in the cell cycle
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Table 8.1 The Biology of Cancer (© Garland Science 2007)
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Figure 8.13a The Biology of Cancer (© Garland Science 2007)
p - designation of a tumor suppressor gene
CDK inhibitors block the action of CDK’s at various pointsin the cell cycle
Preventsdamaged cells
to proceed withthe cell cycle and also
causes interchange of CDKsat different stages of the
cell cycle
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pRB and cell cycle control
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The E2F transcription factor
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Transcription factors can turn genes ‘on’
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E2F is a transcription factor which can switch on genesthat can cause cell division. Rb can inactivate E2F.
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Mutations inactivate pRb, p16 (TSG’s) & the abnormal cell replicates
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How can knowledge of the cell cycle can be utilized to develop anticancer drugs?
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The cell cycle is a programmed series of events that enables a cell to duplicate its contents
and generate 2 daughter cells
Checkpoint controls in the cell cycle ensure thata new step in the cycle is not undertaken until
the preceding step has been completed.
Many types of cancer cells have inactivatedone or more of these checkpoint controls to propel
neoplastic growth.