Resisting cell death hallmark of cancer Flashcards
What will p53 do if DNA damage is too severe to repair?
Will perform P53-instigated apoptosis to cause the cells to die
e.g. When sunburnt, the peeling of the skin occurs as the cells are too damaged by UV to be repaired= apoptosis
P53 can work on the intrinsic apoptosis pathway:
- Inhibits the BCLX-2 protein- this is a pro-survival protein, keeps cells alive. if this is inhibited, apoptosis is promoted
- Can also activate BAX which is a cell death effector. Activation causes mitochondrial outermsmbrane permeabilisation and release of cytochrome c into the cytosol. This triggers the Caspase-3 pathway which causes the cell to be dismantled.
- halts the cell cycle to look for DNA damage
Roles of p53 in apoptosis:
P53 can work on the intrinsic apoptosis pathway:
- Inhibits the BCLX-2 protein- this is a pro-survival protein, keeps cells alive. if this is inhibited, apoptosis is promoted
- Can also activate BAX which is a cell death effector. Activation causes mitochondrial outermsmbrane permeabilisation and release of cytochrome c into the cytosol. This triggers the Caspase-3 pathway which causes the cell to be dismantled.
- halts the cell cycle to look for DNA damage and allow for repair of mutations and damage
What factors can regulate p53?
- DNA damage
- Hypoxia
- Cell-cycle abnormalities
- MDM2- regulates p53 to cause two pathways:
Cell-cycle arrest->DNA repair-> cell cycle restart
OR
apoptosis-> breakdown of cells
both of these promote genetic and cellular stability
Which cancers commonly have high p53 mutations?
ovary
oesophagus
colon
head and neck
pancreas
lung
What mutations usually occur in p53?
Missense mutations- When a change in a singular nucleotide base produces a codon that codes for a different amino acid.
This disrupts DNA binding?
- Also can be mutations that cause amplification of the MDM2 gene- MDM2 targets p53 for degradation by proteasome. So if there is an increase in MDM2= p53 cant apoptose
