Wk 10: Tumour suppressor gene

Question 1

What are tumour suppressor genes?

Answer 1

Genes that protect cell following damage:

• Suppress cellular proliferation
• Initiate apoptosis

Question 2

What are wild types?

Answer 2

Correct DNA + protein sequence

Question 3

What are homozygous?

Answer 3

• Both genes = wild type
• Protein active = normal

Question 4

What is heterozygous?

Answer 4

• 1 Mutated gene, other wild type
• Protein active = inc risk

Question 5

What is loss of heterozygosity?

Answer 5

• 2nd gene mutated
• Protein lost/inactive = cancer likely

Question 6

What happens when tumour suppressor genes mutate?

Answer 6

• Protein lost/non-functional due to change in DNA
• Protein seq./alterations in control mechanism

Question 7

Loss of the tumour suppressor gene Rb1 leads to what?

Answer 7

Childhood retinal cancer (retinoblastoma)

Question 8

How is retinoblastoma most likely to occur?

Answer 8

Inherited mutation in Rb1 gene (500 inc risk) rather than sporadic

Question 9

How is retinoblastoma treated?

Answer 9

Remove eye

Question 10

p53 gene mutation is linked to what?

Answer 10

Poor response to therapy

Question 11

What percentage of cancers have a mutation in the p53 gene?

Answer 11

50%

Question 12

Which tumour suppressor gene doesn’t obey the 2 hit rule?

Answer 12

• p53
• Mutant p53 out competes normal variant = loss of function

Question 13

What happens when p53 is activated due to DNA damage?

Answer 13

DNA damage activates phosphorylation of p53:

• MDM2 released + activates p53
• p53 activates p21
• p21 inhibits cell cycle - reduces proliferation

Question 14

What happens when MDM2 is inhibited?

Answer 14

Enables p53 to function in cancer

Question 15

Outline the colon cancer progression in terms of genes

Answer 15

• Environmental mutagens + hereditary
• APC - loss of function
• Ras - gain of function (oncogene)
• p53 + TGF-β - loss of function

Question 16

What is apoptosis?

Answer 16

• Programmed death
• Due to damage + infection
• No inflammatory response + undergo phagocytosis

Question 17

Describe the process of apoptosis

Answer 17

• Cells shrink + chromatin condenses
• Membrane bleb + organelles disintegrate
• Nucleus + organelles collapse
• Apoptotic body form
• Macrophage phagocytosis occurs

Question 18

What is apoptosis controlled by?

Answer 18

Protease enzymes - contain cysteine active site + cleave at aspartic acid

Question 19

What triggers apoptosis?

Answer 19

• Adaptor proteins activate initiator caspases
• Initiator dimerise + activates executioner
• Executioner caspases activate apoptosis

Question 20

Give examples of initiator caspases

Answer 20

Casp 8 + 9

Question 21

Give examples executioner caspases

Answer 21

Casp 3, 6 + 7

Question 22

Are caspases activated outside of apoptosis?

Answer 22

No - only activated upon apoptosis

Question 23

What do executioner caspase do during apoptosis?

Answer 23

• Degrades nuclear proteins
• Caspase activated DNAse (CAD) activated: cuts up DNA in cell
• Degrades cell-cell adhesion molecules

Question 24

Outline how p53 activates intrinsic apoptosis

Answer 24

• p53 upregulated following damage
• Switches on proteins: puma
• Protein activates p53 in cytoplasm
• Activates mitochondria
• Mitochondria releases apoptosis inducing factors
• Activates caspases
• Activating apoptosis

Question 25

What is PUMA?

Answer 25

p53 upregulated modulator of apoptosis

Question 26

What happens when cells gain functions?

Answer 26

• Mitogens in excess (EGF)
• Receptor auto activates (EGFR)
• Signalling molecules autophosphorylates (RAS + RAF)
• Uncontrolled gene transcription
• Cell cycle driven in excess

Question 27

What happens when cells lose function?

Answer 27

• Deregulated cell cycle (p21)
• Loss of check points (p53)
• Deregulated apoptosis (p53 + caspase)
• DNA damage not repaired
• Inc proliferation