Skin cancers 4 Flashcards
Why do mutations that lead to activation of oncogenes occur frequently in skin?
UV radiation exposure
What are two mechanisms that out body has developed to resist oncogene mutations?
Oncogene induced cell cycle arrest
Oncogene induced cell apoptosis
Why does the papilloma regress if the TPA treatment is halted?
Oncogene induced cell cycle arrest
Oncogene induced cell apoptosis kick in and cause the tumour to shrink
What is Ras?
A powerful oncogene
What family does Ras belong to?
Small GTPases
What signalling cascade is Ras upstream of?
MAPKinase signalling cascade
What does the MAPKinase pathway control?
Cell proliferation
What % of human cSCCs have activating Ras mutations, caused by UV?
20-25%
WHat genes are also (other than Ras) are amplified in cSCC?
EGFR and other Receptor Tyrosine Kinases
What is the “key player” in the formation of cSCC other than Ras?
p53
What are some cellular stresses that can lead to p53 formation?
UV radiation, lack of nucleotides, hypoxia, ionising radiation, oncogene signalling
Outcomes of p53 formation/activation?
Cell cycle arrest, DNA repair, block of angiogenesis, apoptosis
Two outcomes of p53 mediated cell cycle arrest?
Senescence
Return to proliferation (if the DNA damage is repaired)
What % of human cSCCs have inactivating p53 mutations, caused by UV?
60-90%
What is MDM2?
A ubiquitin ligase?
Role of MDM2?
Regulating p53, ensures that the vels are kept low
How does MDM2 regulate p53?
It ubiquitinates p53, targeting it for proteolytic degradation
Which proteins can inhibit MDM2?
p16INK and p14ARF
Which gene codes for p16INK and p14ARF?
CDKN2a
What happens to CDKN2a in cSCC?
It is mutated, inactivating CDKN2a
What is the result of mutating CDKN2a?
Less p16INK and p14ARF are produced, meaning MDM3 isn’t inhibited, meaning less p53 is present as more of it is being targeted for degradation
Result of too low levels of p53?
Cells start to proliferate out of control
In cSCCs, what causes ARF activation?
Oncogenic signalling which causes ARF activation via activation of EF2 TFs
What effect does ARF have on MDM2?
It inhibits MDM2
