Tumour supressor genes Flashcards
how does p53 work
when the DNA is damaged it acts as a transcription factor and makes proteins for cell cycle arrest e.g. p21
what is p21 and what does it do?
it is a protein that causes cell arrest by inhibiting CDKs and cyclins
what other proteins does p53 make
proteins for DNA repair so when the cell is arrested it can repair its DNA, proteins for apoptosis incase cell cannot repair itself
what happens when p53 is inactivated
no proteins for cell arrest, repair or apoptosis. cell therefore goes into cell cycle and surpass checkpoints
what do TSGs do
act as a brake to stop healthy cells becoming cancerous by inhibiting cell division, repairing DNA or apoptosis
what is p120 (GAP) and what does it do
it is a GTPase activating protein that inactivates ras
what is neurofibromin 1 (NF1) and what does it do
a mutant form of p120 (GAP) that fails to inactivate ras-GTP signalling
what is the two hit hypothesis
both copies of TSGs must be mutated for a cell to be considered cancerous
what is loss of heterozygosity (LOH)
loss of one parents contribution to the cell, allowing the expression of the recessive mutation is TSGs
allelic imbalance
heterozygous somatic cells become homozygous as an allele is lost
what can allelic imbalance lead to
inactivation of the secondary TSG - 2 hit hypothesis
6 stimulators of p53
- lack of nucleotides
- UV
- ionising radiation
- oncogene signalling
- hypoxia
- blockage of transcription
what can cell cycle arrest lead to (2)
senescence or return to proliferation
4 functions of p53
- cell cycle arrest
- DNA repair
- block angiogenesis
- apoptosis
why can mice be used for drug discovery
they have a similar genome to humans
how many molecules of p53 are needed for it to function
4 - tetramer
how is p53 protein stability mediated
post translational modifications
how is p53 degraded
by binding mdm2 that targets it for ubiquitylation
p53 half life in tumours
it is increased by inhibition of mdm2-mediated p53 degradation
how is the binding between p53 and mdm2 inhibited
phosphorylation
what does ARF do
prevents nuclear export of mdm2, no p53 degradation
how do you inhibit mdm2 mediated degradation of p53 (4)
- nuclear exclusion
- interaction with viral proteins
- interaction with overexpressed mdm2 protein
- inactivation of ARF, this sequesters mdm2 to the nucleus preventing p53-Ub’n in the cytosol
what causes p53 to be upregulated after DNA is damaged
DNA damage results in ATM and ATR kinases being activated so p53 is upregulated and there are more p53-mdm2 complexes and therefore more active p53
p53 target genes - in cell cycle
p21
p53 target genes - DNA repair
PCNA and XPC
p53 target genes - apoptosis
Bax, FASR, PUMA
targetting p53 in cancer - novel chemo
small molecules used to turn mutated into the original protein, downstream genes then activated as normal
targetting p53 in cancer - gene therapy
research shows that mice that over express p53 are resistant to tumour formation BUT age prematurly
4 more ways of targetting p53 in cancer
- mutant adenovirus
- target mutant p53
- stimulate immune response to mutant p53
- drugs that disrupt the interaction between p53 and mdm2 or E6 proteins
why don’t we like p53 degradation
no stopping of the cell cycle so therefore uncontrolled cell division
what does E6 do to p53
forms a complex and degrades it
what protein in cells infected by adenoviruses shuts down p53
E1b
what gives rise to variants of p53
splicing
what is conserved in p73
residues within the central domain that are frequently mutated in p53
