Cell Cycle and Cancer

Question 1

What does the cell cycle do?

Answer 1

• somatic cells need to replicate and divide therefore the cell cycle allows them to grow and repair
• it ensures genetic integrity
• duplicates the contents of the cell
• involved in cellular differentiation
• a multi step process that proceeds sequentially and is tightly controlled

Question 2

What are different features in the cell cycle?

Answer 2

• defined steps “checkpoints”
• distinct control mechanisms
• regulated by protein complexes that work in a specific order

Question 3

What are the 4 phases of the cell cycle?

Answer 3

1. G1
2. S
3. G2
4. M
   - each phase has its own distinct functions

Question 4

What is G1 phase and what does it use?

Answer 4

• first phase of cell cycle
• start considered to be the point prior to DNA replication
• regulated by “G1 CDK:cyclins” which serve to initiate E2F transcription factors
• E2F target genes encode proteins required for DNA replication (DNA polymerase, nucleotides, etc)

Question 5

How does G1 E2F become activated?

Answer 5

• E2F’s default setting is off which is controlled by pRb
• to activate E2F, the effect of pRb is negated by CDK:cyclins
• mitogenic stimulation increases cyclinD-CDK4 which phosphorylates pRB to allow the release of E2F

Question 6

How can G1 CDK be inhibited?

Answer 6

• cells have an intrinsic ability to counteract the go signal elicited by CDKs
• without this, cells would grow forever
• endogenous inhibitors are activated by cytokines
• they are increased in response to DNA damage and are able to halt cells

Question 7

What happens at the G2/M checkpoint?

Answer 7

• there are not many checkpoints in G2/M transit
• the cell is assumed to be okay if it has gotten this far
• CyB-CDK1 ensures cells are ready for splitting by checking correct alignment of chromosomes and the integrity of spindle fibres
• faults at this point are terminal and are dealt with by mitotic machinery

Question 8

What happens if the cell shows problems at the G2/M checkpoint?

Answer 8

• checkpoint is between transition from metaphase to anaphase
• if chromosomes do not align properly or spindle fibres don’t connect the cells could become cancerous
• mitotic catastrophe can induce cell death to dispose of these cells to ensure their quality

Question 9

What happens if the cell shows problems at the G2/M checkpoint?

Answer 9

• checkpoint is between transition from metaphase to anaphase
• if chromosomes do not align properly or spindle fibres don’t connect the cells could become cancerous
• mitotic catastrophe can induce cell death to dispose of these cells to ensure their quality

Question 10

What is G0?

Answer 10

• the cell cycle is primarily associated with active proliferation
• however, a large proportion of cells lie dormant and are said to be in G0
• these cells:
• contain 1 set of DNA
• don’t actively divide
• are resistant to death
• can re enter cycle

Question 11

How can the cell cycle be tracked?

Answer 11

• cells stained with a DNA dye
• flow cytometry is used to asses the DNA content of individual cells
• peaks formed indicated different stages of the cell
• DNA profile can also inform the state of the cell (eg if its polyploidy or undergoing apoptosis)

Question 12

How do cells become polyploids?

Answer 12

• cell has been manipulated to express cells with abnormal ploidy
• polyploidy is when cells contain more than 2 sets of any of the chromosomes
• occurs when cells lose the G2/M transit checkpoint
• they need to divide before they can move to S phase

Question 13

How is hyper proliferation caused?

Answer 13

• faults can trigger checkpoints whose job is to brake cell cycling
• loss of control of the cell cycle leads to uncontrolled proliferation which can result in cancer
• mutations in the cell cycle result in a direct loss of regulatory function

Question 14

What are 3 mutations that cause hyper proliferation?

Answer 14

1. Decreased p16 = increased cyD-CDK4
2. Decreased pRb = increased E2F
3. Decreased p53 = decreased p21 = increased CDKs

Question 15

How do drugs target cell cycle mutations?

Answer 15

• there are a number of ways to prevent cancer cells from growing:
  1. Counteract the “keep growing” signal
  2. Neutralise the “don’t die” signal
  3. Induce a “die” signal
  4. Disrupt the normal cell cycle processes
• drugs that perform these roles are:
  1. Anti-proliferatives
  2. Anti-metabolites
  3. Cytotoxics

Question 16

Why should we track the cell cycle?

Answer 16

• allows a better understanding of what drugs are doing and how they work
• find ways to improve treatments

Question 17

What can treatments do to the cells?

Answer 17

Cytotoxicity:
- interfere with replication
- disturb alignment of chromosomes
- cause certain cancer cells to die
Cytostasis:
- inhibition of cell growth beyond G2
- prevents transition from G2 into M phase
- doesn’t necessarily cause cell death
Recovery:
- treatments in the future could allow cells to recover instead of killing them completely