oncogenic signlling and tumour suppressor genes Flashcards
% of mutations that cause cancer
only 5-10% of mutations cause cancer
What are mutations that don’t cause cancer?
silent mutations
they don’t change the AA sequence
they’re in non-coding regions of DNA that doesn’t affect gene function
difference between germline and somatic mutations
germline - hereditary, found in egg and sperm, can be passed down from generation and influence a person’s risk for develoing a disease
somatic - occur in non-reproductive cells, cannot be passed on, cancer cells accumulate somatic mutations, damage we do to body
Which more commonly cause cancer - germline or somatic mutations?
somatic
somatic mutations in cell signalling genes
gain of function mutation
gain of function mutation only needs one gene copy to be mutated
mutation in ONE gene causes gene to be permanently switched on
overexpression
-> most common
loss of function mutation
loss of function mutations need both gene copies to be mutated
with ONE mutation, the second gene compensates
requires both genes to be mutated for loss
-> more rare
What is a proto oncogene?
code for proteins that drive normal cell growth, healthy gene
deregulation/if it’s mutated it becomes an oncogenes
What is an oncogene?
codes for protein that causes cancer
functions that oncogenes can have
- point mutation: 1 AA change
- within a control element: growth stimulating protein in excess
- within the gene: hyperactive or degradation resistant protein (only 1 protein produced but hyperactive) - gene amplification - normal protein but in excess
- translocation or transposition - new promoter, permanently on, normal growth stimulating protein in excess
-> gain of function mutations, accelerate growth/signalling/cell cycle in cancer
What are mitogens?
stimulatory signals that stimulate proliferation
provide the stimulatory signal to initiate transcription/translation of proteins and other molecules required for cell division
What is PDGF an example of?
mitogen
examples of mitogens
TGF-beta
PDGF
EGF
EPO
What does TGF-beta do?
inhibits proliferation
direct opposite inhibitors signal
What happens cells in absence of mitogen stimulation?
they can enter G0 phase
What activates tyrosine kinase receptors?
kinase
How does the MAPK signalling pathway work?
- TK R dimerises
- phosphorylation
- RAS - Raf - MEK - ERK
- ERK enters the nucleus
- increased proliferation
What does MAPK stand for?
mitogen activated protein kinase
What does EGFR stand for?
epidermal growth factor receptor
What does EGFR do?
stimulates growth in epidermal and epithelial cells
What type of R is EGFR?
TK R
(activates MAPK, stimulates growth via MAPK)
and HER 1
What signalling does EGFR activate?
MAPK signalling
3 ways EGFR can function as an oncogene
- over expression of EGFR (inc signalling)
- mutation in kinase domain (always active)
- deletion of ligand binding domain EGFR variant III (always active)
cancers associated with EGFR overexpression/upregulation/amplification
adenocarcinoma of lung
rectal cancers
glioblastoma
epithelian tumours of the head and neck
examples of EGFR receptor inhibitors
cetuximab
matuzumab
nimotuzumab
panitumumab
examples of EGFR dimerisation inhibitors (HER2 inhibitors)
trastuzumab
pertuzumab
examples of TKIs
gefitinib
erlotinib
lapatinib
How many parts of the EGFR can be targeted/blocked and where?
3
EGFR R inhibitors (outside)
EGFR dimerisation inhibitors (outside)
TKIs (inside)
What are tumour suppressor genes?
genes that protect cells following damage
suppress cellular proliferation
initiate apoptosis
in response to checkpoints or growth suppression signals
homozygous, heterozygous and loss of heterozygosity in tumour suppressor genes
homozygous - both genes are WT, protein is active, normal
heterozygous - one mutated gene but the other is WT, protein is active, increased risk
loss of heterozygosity (LOH) - 2nd gene is now mutated, protein lost/inactive, cancer likely
-> loss of function
2 hit hypotnesis loss of function theory
Rb1 gene is a tumour suppressor gene
loss of function leads to childhood retinal cancer - retinoblastoma
sporatic mutation (somatic) of 2 chromosomes at the same site is very unlikely
Tx/removal of eye leads to no further cancer in sporadic mutations
inherited Rb mutation leads to x500 increased risk of retinoblastoma occurrence
guardian of the genome
p53
% of cancers that p53 is mutated in
50%
What mutation is most common in p53 in cancers?
missense mutation in one allele
results in high levels of non-functional protein
most commonly mutated tumour suppressor gene in cancer
p53
p53 and the 2 hit hypothesis
it doesn’t follow the 2 hit rule
mutant p53 outcompetes the normal variant
loss of one p53 gene is tolerated
one gene mutated, pp53 function NOT normal
loss of function with one mutation
Is p53 an oncogene?
NO
How does p53 work?
TSG
DNA damage activates p53
p53 activates p21
p21 inhibits cell cycle, reduces proliferation
p53 controlled by MDM2
inhibiting MDM2 enables p53 to function in cancer
What controls p53?
MDM2
example of gene alteration that is inherited in colon cancer
APC gene - familial adenomatous polposis
apoptosis
programmed cell death
cells shrink, condense and fragment
no inflammatory response and undergo phagocytosis
difference between apoptosis and necrosis
necrosis - sudden death, swell and burst which causes inflammatory response
apoptosis - programmed, not sudden, shrink and condense, no inflammatory response, phagocytosis
enzymes that control apoptosis
proteases (end in -ase)
CASPASES
What do caspase contain?
contain cysteine active sites
Where do caspases cleave targets at?
aspartic acid
cASPases
2 types of caspases
- initiator caspases
- executioner caspases
examples of initiator caspases
caspases 8 and 9
examples of executioner caspases
caspases 3, 6 and 7
How do caspases work?
signals trigger initiarot caspases
initiators dimerise and activate
executioner caspases degrate nuclear proteins
caspase activated DNAse (CAD) is activated which cute up DNA in the cell
degrades cell adhesion molecules
CAD
caspase activated DNAse
cuts up DNA in the cell
Can apoptosis be stopped?
NO
once apoptosis starts, it can’t be reversed
