Tumor suppressor genes

Question 1

What are tumour suppressor genes?

Answer 1

These are genes that normally function to restrict growth.

Question 2

How do mutations in TSG lead to cancer?

Answer 2

Deletions/point mutations result in no protein or a protein with altered functions. The tumour suppressor protein can no longer restrict cell growth. Mutations are normally recessive in nature.

Question 3

Give an example of how a mutation in a TSG can lead to a hereditary predisposition to cancer

Answer 3

APC mutation and colon cancer

BRAC1 and breast cancer

Question 4

What is retinoblastoma?

Answer 4

rare childhood cancer whereby tumours develop in the retina.

Can either be inherited or sporadic - 40% of cases are inherited.

Question 5

How does loss of function of pRB contribute to cancer?

Answer 5

Loss of function pRB will remove inhibition of E2F transcription factor and so becomes constitutively active and drives transcription of genes required for S phase transition.

Question 6

What is the role of p53?

Answer 6

Controls DNA integrity - responds to DNA damage by DNA repair and apoptosis

Question 7

How is p53 found in normal healthy cells?

Answer 7

Found in low levels, bound to the protein MDM2. If released from this complex it is quickly degraded - can be stabilised by damaged DNA.

Question 8

How is p53 activated and what happens when it is activated?

Answer 8

Stress signals causes activation, phosphorylated and is no longer bound to MDM2. Need four molecules (tetramer) to join together to act in the nucleus as a TF.

Initiates a no. of pathways:

• senscence (cell just sits there and does nothing, allows oppotunity to repair DNA)
• upregulation of Bax (pro apoptopic)
• cell cycle arrest via up regulation of p16 and p21
• in earlier stages can cause differentiation of the cells

Question 9

What is the role of p53 in cancers?

Answer 9

mutations of p53 occurs in >50% of cancers

Mutant p53 is more stable - can block the binding sites of functional p53 and stop its actions.

Question 10

What is Li Fraumeni syndrome?

Answer 10

Is an inherited disorder where patients have mutated p53. Significantly increases a person predisposition to developing cancer.

Question 11

How can mutations in p53 impact on chemotherapy treatment?

Answer 11

Chemotherapeutic agents and radiation rely on inducing apoptosis for their cytotoxic effects - lack of p53 often makes tumor cells resistant through lack of functional apoptotic pathway.

Question 12

What is advexin?

Answer 12

Gene therapy using human wildtype p53 delivered by replicative-defective adenoviruse. FDA fast-tracked its approval for head and neck cancers.