L9 Tumour suppressor genes

Question 1

what are the general features of TSGs?

Answer 1

• A gene that inhibits- cell growth, proliferation, cell survival, maintains genomic stability
• loss of function mutations
• inactivation= tumour development by eliminating negative regulation
• tsgs often inhibit same pathways stimulated by oncogenes- work together
• recessive

Question 2

what type of mutations are common in Rb? how is this different to oncogene mutations

Answer 2

nonsense= stop codon= biologically inactive frameshift= insertion/ deletion
splice site= exons not cut properly or introns not joined together properly
oncogene= missense- substitutions

Question 3

how does the cell eliminate both copies of Rb?

Answer 3

first hit= nonsense, frameshift, splice site
second hit= loss of second allele (non-disjunction, recombination, chromosomal loss, deletion) , gene silencing (promoter methylation)

Question 4

how can the cell cause chromosomal loss to the second allele in Rb?

Answer 4

chromosomal loss- losing one chromosome leaving mutant
deletion- random deletion of the wildtype rb gene
non-disjunction- improper splitting of chromsome pairs, needs to delete one
mitotic recombination- exchange of material between wildtype and mutant, 4 recombinations= enp up with loss of heterozygosity in 2 combinations

Question 5

what is the wnt/ beta catenin signalling pathway?

Answer 5

wnt ligand does not bind to frizzled receptor
bea-catenin is bound to destruction complex= proteosome

wnt ligand binds frizzled receptor
ceased destruction complex= accumulation of beta catenin= move to nucleus and activate genes in proliferation

Question 6

how do mutations in apc change wnt signalling pathway?

Answer 6

apc mutation= loss of destruction complex, stabilisation of beta-catenin= expression of wnt target genes= proliferation
apc= tumour suppressor

Question 7

another function of tsgs is preserving genome stability, how does loss of this cause incr risk of cancer?

Answer 7

bi-allelic loss doesnt always = immediate cancer development
tsg also maintain genome integrity and prevent accumulation of mutations. when these are mutated we have an acceleration and incr risk of mutations in oncogenes and other tsgs- dysregulated cell growth and accelerates cancer progression
e.g P53, ATM, BRCA1/2

Question 8

Substitutions in the …. of p53 are its hotspot mutations

Answer 8

dna recognising site

Question 9

inherited cancer predispostition syndrome- p53

Answer 9

Li Fraumeni syndrome
germline mutation of p53
incr risk of cancer- brain and cantral nervous sustem tumours, breast cancer
susceptible to multiple tumour development