CE L3 Tumour suppressor genes Flashcards
Tumour suppressor genes normally function to
restrict growth
Tumour suppressor genes are usually recessive or dominant?
recessive - you need mutations in both copies
Oncogenes are recessive or dominant?
Dominant - only need mutation in one
What sort of mutations in tumour suppressor genes predispose to cancer?
Loss of funciton
Can you inherit mutations in tumour suppressor genes?
yes- so later in life you lose the second functioning copy.
Inherited predisposition as opposed to inherited disease
Cancer tend to have at least 1 …………. mutation and 1 ………… mutation
1 or more tumour suppressor genes
1 or more oncogene
…….. and ………… mutations result in no protein or protein with altered function
Deletions and point mutations
Mostly deletions as it causes frame shift
6 classes of tumour supressor gene
Growth/development supressor Cell cycle check point protein Cell cycle inhibitors Inducers of apoptosis DNA repair enzymes Developmental pathways
- e.g. of inhereted prdispostions
APC (part of Wnt pathway) - precancerours intestinal polyps
BRACA1 - 60% probability of breast cancer
what leads to retinoblastoma?
loss of pRb
recessive trait
How does pRb and p16 regulate the cel cycle
In G1 phase Growth factor stimulation Cyclin D1 levels rise Cyclin D/CDK4 complex CDK4 phosphorylates pRb pRb releases E2F E2F active
Mutation on pRb has what effect on E2F?
E2F is free all the time to drive S phase and the cell through the cell cycle.
So you don’t need growth factor to drive the pathway
What is E2F
a transcription factor
drives S phase
What is usually the stimulous for E2F to drive the cell cycle
GF/cyclin D
(create a cyclin D/CDK4 complex
What is usually the stimulus for E2F to drive the cell cycle
GF/cyclin D
create a cyclin D/CDK4 complex that phosphorylates pRb. pRb the resleases E2F
What happens in a loss of function of p16?
removes the ability to halt the cell cycle in order to repair DNA
(mutations are passed on to daughter cells and accumulate)
p53 is sometimes called
GUARDIAN OF THE GENOME
evolved to prevent cancer deveopment
Where is p53 normally?
complexed to MDM2
How is p53 released?
Stree signals inhibit MDM2 allwoing activation of p53
p53 is active as a …… and has what function ……
transcriptional regulator
tetramer
p53 is active as a …… and has what function ……
transcriptional regulator
tetramer - it is stabilised by biding to damaged DNA
5 cellular responses to p53
Apoptosis Differentiation DNA repair Senescence Cell cycle arrest
4 Stressos that activate p53 (by inhibiting MDM2 to which it is normally complexed)
DNA damage
Oncogenes
Loss of survival signals
Hypoxia
p53 regualtes expression of (3)
p21 cyclin dependant kinase inhibitor - arrest
MDM2 - autoregulation
Bax - pro-apoptotic
p53 inhibits cell growth through (2)
cell cycle arrest
induction of apoptosis
Mutations in p53 occur in how many cancers
over 50%
Why are mutant p53 problematic
- they are more stable (less liekly to be degraded)
- interfered with wildtype p53
In what disorder is there inhereted mutation in p53
Li Fraumeni syndrome - predisposition to tumour formaiton
How does mutated p53 interfere with wildtype?
It must bind as a tetrameter for transcription. If 1 of 4 is mutated no transcription occurs
What enviromental factors lead to p53 mutation (2)
How?
- Benzo(a) pyrine in cigarette smoke
- Aflatoxin (fungal metablolite)
Both cause G>T transversion at suceptible regions of DNA
What enviromental factors lead to p53 mutation (2)
How?
- Benzo(a) pyrine in cigarette smoke
- Aflatoxin (fungal metablolite)
Both cause G>T transversion at suceptible regions of DNA
Majority of mutation hot spots in p53 are located in …………
Why is this a problem?
the DNA binding region - so it can still dimerise and do other things but not act as a TF
Implications of p53 in cervical cancer
polymorphism increases susceptibility to HPV E6 mutation -
but its easier to just vacinate everyone
Implications of p53 mutation in chemo
chemo damages DNA then relies on an active apoptotic pathway.
So it doesnt work as well with mutated p53. Restoring this function is a theraputic target.
e.g. of p53 target therapy
ADVEXIN
-adenoviral transfer of p53 gene into tumour cells
appears to halt growth/shrink
