Wk 10: Tumour suppressor gene Flashcards
What are tumour suppressor genes?
Genes that protect cell following damage:
- Suppress cellular proliferation
- Initiate apoptosis
What are wild types?
Correct DNA + protein sequence
What are homozygous?
- Both genes = wild type
- Protein active = normal
What is heterozygous?
- 1 Mutated gene, other wild type
- Protein active = inc risk
What is loss of heterozygosity?
- 2nd gene mutated
- Protein lost/inactive = cancer likely
What happens when tumour suppressor genes mutate?
- Protein lost/non-functional due to change in DNA
- Protein seq./alterations in control mechanism
Loss of the tumour suppressor gene Rb1 leads to what?
Childhood retinal cancer (retinoblastoma)
How is retinoblastoma most likely to occur?
Inherited mutation in Rb1 gene (500 inc risk) rather than sporadic
How is retinoblastoma treated?
Remove eye
p53 gene mutation is linked to what?
Poor response to therapy
What percentage of cancers have a mutation in the p53 gene?
50%
Which tumour suppressor gene doesn’t obey the 2 hit rule?
- p53
- Mutant p53 out competes normal variant = loss of function
What happens when p53 is activated due to DNA damage?
DNA damage activates phosphorylation of p53:
- MDM2 released + activates p53
- p53 activates p21
- p21 inhibits cell cycle - reduces proliferation
What happens when MDM2 is inhibited?
Enables p53 to function in cancer
Outline the colon cancer progression in terms of genes
- Environmental mutagens + hereditary
- APC - loss of function
- Ras - gain of function (oncogene)
- p53 + TGF-β - loss of function
What is apoptosis?
- Programmed death
- Due to damage + infection
- No inflammatory response + undergo phagocytosis
Describe the process of apoptosis
- Cells shrink + chromatin condenses
- Membrane bleb + organelles disintegrate
- Nucleus + organelles collapse
- Apoptotic body form
- Macrophage phagocytosis occurs
What is apoptosis controlled by?
Protease enzymes - contain cysteine active site + cleave at aspartic acid
What triggers apoptosis?
- Adaptor proteins activate initiator caspases
- Initiator dimerise + activates executioner
- Executioner caspases activate apoptosis
Give examples of initiator caspases
Casp 8 + 9
Give examples executioner caspases
Casp 3, 6 + 7
Are caspases activated outside of apoptosis?
No - only activated upon apoptosis
What do executioner caspase do during apoptosis?
- Degrades nuclear proteins
- Caspase activated DNAse (CAD) activated: cuts up DNA in cell
- Degrades cell-cell adhesion molecules
Outline how p53 activates intrinsic apoptosis
- p53 upregulated following damage
- Switches on proteins: puma
- Protein activates p53 in cytoplasm
- Activates mitochondria
- Mitochondria releases apoptosis inducing factors
- Activates caspases
- Activating apoptosis
What is PUMA?
p53 upregulated modulator of apoptosis
What happens when cells gain functions?
- Mitogens in excess (EGF)
- Receptor auto activates (EGFR)
- Signalling molecules autophosphorylates (RAS + RAF)
- Uncontrolled gene transcription
- Cell cycle driven in excess
What happens when cells lose function?
- Deregulated cell cycle (p21)
- Loss of check points (p53)
- Deregulated apoptosis (p53 + caspase)
- DNA damage not repaired
- Inc proliferation
