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

The cell cycle is a programmedseries of events that enablesa cell to duplicate its contentsand generate 2 daughter cells

Figure 8.3b The Biology of Cancer (© Garland Science 2007)

The Cell Cycle

Resting stage

Gap 1

Synthesis

Gap2

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

Checkpoint Control

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.

Figure 8.4 The Biology of Cancer (© Garland Science 2007)

Cell Cycle Checkpoints : Quality Control

What happens if a damaged cell overrides these checkpoints?

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

Cancer Cells May Lose Checkpoint Controls

Cell death

Figure 8.5a The Biology of Cancer (© Garland Science 2007)

Loss of checkpoint controls result in altered Karyotype

Normal human Rad17 deprived(Rad17 preventsrereplication)

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

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

Restriction Point :

G1 phase checkpoint in the cell cycle of animal cells

Figure 8.1 The Biology of Cancer (© Garland Science 2007)

The Cell Cycle Clock controls the cell cycle

Table 8.4 The Biology of Cancer (© Garland Science 2007)

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

Cyclin +cyclin-dependent kinase (CDK)+ CAK = active complex

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

Table 8.1 The Biology of Cancer (© Garland Science 2007)

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

pRB and cell cycle control

The E2F transcription factor

Transcription factors can turn genes ‘on’

E2F is a transcription factor which can switch on genesthat can cause cell division. Rb can inactivate E2F.

Mutations inactivate pRb, p16 (TSG’s) & the abnormal cell replicates

How can knowledge of the cell cycle can be utilized to develop anticancer drugs?

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.