Oncogenes and Tumour Suppressor Genes Flashcards
what are the biggest drivers of cancers?
mutations
what is the difference between germline mutations and somatic mutations?
germline are hereditary mutations -they are found in the germ cell, also known as the egg and sperm
somatic mutations occur in nonreproductive cells in the body and cannot be passed down from parent to child
what is the most common mutation in cancer?
somatic
what is gain/ loss of function?
GAIN of function mutations (dominant), needs only
ONE gene copy to be mutated
*LOSS of function mutations (recessive), needs BOTH
gene copies to be mutated
what happen when there is a mutation in one gene?- gain of function
causes gene to be permanently switched on
causes overexpression
what happens with one mutation in loss of function?
*With ONE mutation
the second gene
compensates.
*Requires BOTH
genes to be
mutated for loss
*More rare
*(LOSS)
what are proto-oncogenes?
code for proteins that drive normal cell growth
what are oncogenes and how are they formed?
deregulation of proto-oncogenes gives rise to oncogenes
oncogenes code for proteins that cause cancer
what do oncogenes code for?
code for proteins involved in cell signalling pathways
what do gain of function mutations accelerate?
growth, signalling and cell cycle in cancer
give an example of a well known oncogene
MY
EGFR
what are miogens?
MITOsis+GENesis - Stimulatory signals that stimulate proliferation
give an example of a mitogen
TGF-B
what do mitogens do?
Mitogens provide the stimulatory signal to initiate transcription / translation of
proteins and other molecules required for cell division
what happens in the absence of mitogen?
simulation cells can enter G0 phase
how do receptor tyrosine kinases work?
1- inactive receptor tyrosine kinase
2-kinase activity stimulated through dimerized RTK
3-RTK is activated via autophosphyorylation
4- signal relayed by activated signalling proteins into the cells interior
what is the MAPK signalling pathway?
Mitogen Activated Protein Kinases
*One of THE most important & studied pathways of all
how does the MAPK signalling pathway work?
*RTK receptor dimerises
*Relays Phosphorylation
*RAS -> Raf -> MEK -> ERK
*ERK enters the nucleus
*Increased Proliferation
what happens in the MAPK signalling pathway once the cell receives the signal at receptor level?
*Each event triggers the next
*Transfers signal from the outside
–Starting with receptor signal
*Through the cell
–Signalling in the cytoplasm
*To the nucleus
–Activates gene transcription
*Biological response Occurs
increase in cyclin D
what is EGF?
epidermal growth factor
*Stimulates growth in epidermal and epithelial cells
how many major receptors are there for EGF?
4 major receptors
what does EGFR activate?
MAPK signalling
mutations that lead to EGFR overexpression have been associated with:
adenocarcinoma of lung
rectal cancers
gioblastoma
epithelian tumours of the neck and head
why is knowledge of these molecular mechanisms so important in oncology?
as we can inhibit them
1- EGRF receptor inhibitors eg cetuximab
2- EGFR dimerisation inhibitors- eg trastumab
3-tyrosine kinase inhibitors- eg gefitinib
what is the problem with signalling molecule mutation?
sometimes downstream molecules also mutate
what are tumor suppressor genes?
TSGs – the genes that protect the cells following damage
*Suppress cellular proliferation
*Initiate apoptosis
In response to checkpoints or growth suppression signals
what is the most commonly known tumor suppressor gene?
p53
how are TSG mutated?
either lost OR become non functional due to change in DNA
what is the ‘two hit’ loss of function theory?
it is an observation based of retinoblastoma
Rb1 gene is a tumor suppressor gene
loss of function leads to childhood retinal cancer
mutations of two at same site is incredibly unlikely
this mutation demonstrates a 500 fild increased risk of retinoblastoma occurence
what responses does p53 have to possible mutagens?
cell cycle arrest
DNA repair
block of angiogensis
apoptosis
how often is p53 mutated in cancers?
mutated in aproxx 50% of cancers
- typically a missense mutation in one allele
results in high levels of a non-functional protein
what is p53 mutations linked to?
poor response to therapy
does p53 obey the 2 hit rule?
no
Loss of one p53 gene is tolerated
*MUTANT p53 out competes the normal variant
*Loss of function with ONE mutation
*p53 Initially thought to be an oncogene!
how does p53 work?
*p53 is a tumour
suppressor gene
*DNA damage activates
p53
*p53 activates p21 (CKI)
*p21 inhibits cell cycle –
reduces proliferation
*p53 is controlled by
MDM2
*Inhibiting MDM2
enables p53 to
function in cancer
what is apoptosis controlled by?
Apoptosis is Controlled by a family of protease enzymes (so end -ase)
*Contain Cysteine active site and cleave targets at aspartic acids – so are
called CASPASES
what are executioner proteins?
Executioner caspase catalyse over a 1000 proteins
during apoptosis
–Degrades Nuclear proteins
–Caspase Activated DNAse (CAD) is activated which cuts up
DNA in the cell – recall cell cycle checkpoints!
–Degrades Cell-cell adhesion molecules (rounding up of cells
and detach from neighbours)
what does p53 activate?
intrinsic apoptosis
what are the examples of gain of function oncogenes?
–Mitogens in excess levels (e.g. EGF)
–Receptors auto activates (EGFR)
–Signalling molecules autophosphorylate (Ras, Raf)
–Uncontrolled gene transcription
–Cell cycle driven in excess
what are examples of loss of function tumor suppressor genes?
–Deregulated cell cycle (p21)
–Loss of cell cycle checkpoints (p53)
–Deregulated apoptosis (p53 and caspase)
–DNA damage not repaired
–Increased proliferation due to lack of “brakes”
