Evading growth suppressors hallmark of cancer

Question 1

How do normal cells control their proliferation?

Answer 1

• Through checkpoints and external signals- that check for the favourable environment i.e enough growth factor or mitogen present
• Internal signals- check for DNA damage, if chromosomes are properly attached to the spindle, if all DNA has been replicated

Question 2

What are tumour suppressor genes?

Answer 2

Genes that regulate cell proliferation in cells with damage- signal for apoptosis. Important for putting a break in the cell cycle.

Question 3

What are the 3 main tumour suppressor genes?

Answer 3

• p53
• Retinoblastoma protein
• Cyclin/ cyclin dependent kinases/ cyclin dependent kinase inhibitors

Question 4

How do cyclins act as tumour suppressor genes?

Answer 4

• Cyclins are expressed in different phases of the cell cycle and have to form complexes with certain cyclin-dependent kinase to activate the CDKs
  Each of these complexes phosphorylates a different set of proteins involved in the cell cycle
  Can determine when the cell cycle is halted/breaks and when it is appropriate to go ahead.
  If there is any dysregulation e.g. a mutation in a tumour suppressor gene, the cell cycle will continue to progress even with mutations etc

Question 5

What is Rb?

Answer 5

Retinoblastoma protein

Question 6

How does Rb regulate the cell cycle?

Answer 6

• This protein acts as a break in the cell cycle to keep the cell in the G1 phase by inhibiting the genes needed for progression into the s phase. This checks for and repairs any DNA damage.
• Once retinoblastoma is phosphorylated, the brake is released and the cell cycle can resume.
  This is because normally, Rb holds a E2F transcription factor, but when Rb is phosphorylated and inactivated, (by G1-CDK) it can no longer hold on to E2F. The E2F transcription factor can then enter the nucleus and cause the transcription of the genes needed for the cell’s progression into the S-phase.

Question 7

What happens if the Rb protein is mutated?

Answer 7

The cell cycle will keep going and won’t be halted at the G1 checkpoint, DNA damage won’t be repaired.

Question 8

What is retinoblastoma and its importance in growth suppressor genes?

Answer 8

• Retinoblastoma is a cancer of the eye that is common in children (1-2) and if left untreated, most patients will die within 2 years.
• It was thought that cancers were all caused by oncogenes, however tumour-suppressor genes were discovered through retinoblastoma. They found from a sample of cells from this cancer contained a mutated Rb gene

Question 9

What does it mean if a patient has a deletion of the Rb gene?

Answer 9

• This deletion means cell division will continue due to E2F-mediated transcription of genes needed for s-phase- prevention of cell cycle arrest
  (When RB is absent or inactivated, that restraint is lost, and E2F is constantly available to trigger cell division)

Question 10

What does it mean that the Rb genes is recessive?

Answer 10

That the loss of function is needed in both copies of the gene to have an effect (recessive= needs both)
- If a mutated gene is inherited from one of the parents, later on the other gene will be mutated = cancer
One random chance mutation or chromosomal loss can cause cancer (one more mutation causes tumour development)

Question 11

What is sporadic cancer?

Answer 11

• No known cause, happen by chance
• No known relative has similar cancer

This is most cancers

Question 12

What is familial cancer?

Answer 12

• Combination of genetic and environmental factors
• Relatives do show same type of cancer but there is NO specific pattern of inheritance- not passed from parent to child

Question 13

What are hereditary cancers?

Answer 13

• Occur from an altered gene being passed down in the family from parent to child
• More likely to have relatives with similar types of cancer
• Cancer can occur at an earlier age and may have more than 1 type of cancer

Question 14

What is known as the ‘guardian of the genome’?

Answer 14

P53

Question 15

What is the role of p53 in the cell cycle?

Answer 15

• Is a tumour suppressor gene
  P53 can halt the cell cycle by acting as a break at the g1 phase of the cell cycle by interacting with the p21 cdk inhibitor. This allows for any DNA damage to be repaired
• If there is no DNA damage: P53 is usually bound to MDM2 and will be degraded by the proteasome
• If there is DNA damage, P53 is phosphorylated which involves p21 gene transcription, this CDK complex is now inactive and so the cycle is put in to arrest to allow for repair

Question 16

What happens if there is a mutation in p53?

Answer 16

• The cell cycle will not be stopped and mutations will be passed on through dividing cells leading to cancer progression.

Question 17

What is the effect of the Hepatitis B virus?

Answer 17

HBV can inactivate the tumour suppressor gene p53 and can lead to the development of hepatocellular carcinoma

Question 18

What are the 2 main categories of cancer genes?

Answer 18

• Tumour-suppressor genes- block mitosis and must be knocked out for cancer to occur
• Oncogenes- normally porto-oncogenes signal for cells to grow, but can become stuck on causing oncogenes and cancer

Question 19

What is the difference between Tumor-suppressor genes and oncogenes in terms of alleles?

Answer 19

• Tumour suppressor- Are recessive- mutations cause a loss of functioning both alleles
• oncogenes- are dominant- the mutation usually only effects 1 allele and causes a gain of function