lecture 14- tumour supressor genes Flashcards
(27 cards)
is the cancer phenotype dominant or recessive
recessive
why did they used to think the cancer phenotype was dominant
as viral oncogenes have a dominant effect
how did they prove the cancer phenotype
cell fusion -> force 2 alleles together using PEG to form hybrid cell
A normal cell is fused with a cancer cell.
If the resulting hybrid behaves normally → suggests the cancer phenotype is recessive.
If it behaves like a cancer cell, then the phenotype might be dominant.
result was normal cell so recessive
what are TSGs
genes contricting a cells proliferation which are activated during the development of a tumour
what were the arguments for and against TSGs when they were first being discovered
for= easier to lose TSG by a mutation(any LOF mutation) than activate oncogene, needing specific mutation
against = 2 copies of TSG must be lost which seems unlikely to happen
how did scientists understand how two copies of TSGs could be lost
looking at retinoblastoma
what is retinoblastoma
when retinoblast cells dont stop growing in embryogensis
what are the two types of retinoblastoma
sporadic/unilateral - children with no family history (single tumour in one eye)
familial/bilateral - had a parent who suffered (multiple foci in both eyes)
also more susceptible to other tumour development
what was found by analysing the rate of retinoblastoma tumour apperance
unilateral was 2 random events , so 2 sucessive alterations are required to mutate both Rb alleles
bilateral was single random event, Rb mutations present in family so mutation in other copy is enough
what is loss in heterozygosity and how does it cause mutations
loss of a functional allele in a cell that was previously heterozygous.
removes the only working copy, often unmasking disease-causing mutation especially in TSGs
what are the 2 mechanisms of TSGs to stop cancer development
direct suppression of cell proliferation in response to growth inhibitory factors
components of cellular machinery inhibit proliferation in response to metabolic imbalance and DNA damage
What is NF1
a negative regulator of Ras signalling
How does NF1 work
it produces Ras GAP -> which inactivates Ras
How is NF1 normally regulated
GFs reduce NF1 which allows Ras signalling to procede
but then NF1 goes back to normal after an hour
what happens when a loss of heterozygosity occurs in NF1
Ras remains active for longer
mimics effect of mutant Ras oncogenes
what does hyperactivation of Ras lead to
PI3K, Akt, mTOR, S6K -> decreased apoptosis
Raf,MEK,ERK -> increased proliferation
why could mTOR inhibition be a target for NF1 null tumours
cells losing NF1 can have effects reversed by rapamysin (mTOR inhibitor)
What is APC
negative regulator of beta-catenin
describe the first 3 steps in the development of colon cancer
loss of APC
oncogenic Ras mutations
loss of p53
what is the role of APC in crypt cells
facilitates movement of cells so they can die within 4 days
how do the crypt cells have a good defence mechanism
if cells sustain mutations, because they travel out of crypts, they die before harming the intestine
what happens when APC is mutated
beta-catenin not degraded so accumulates, myc produced -> excessive wnt signalling
this traps cells in crypt rather than moving them out
what is the main function of pVHL
promotes destruction of the HIF-1alpha transcription factor
what is the role of pVHL during normoxia
binds to HIF-1alpha to ubiquinate it as it isnt needed
