Cancer part 2 Flashcards
How does a receptor tyrosine kinase become activated
ligand (such as growth factor) binds to the extracellular region, causes conformational change, binding induces dimerisation so two or more receptor molecules to come together and one receptor phosphorylates the intracellular domain of the other receptor. phosphorylates tyrosine acts as a docking site for signalling proteins
What are some examples of mechanisms of oncogenic activation of growth factor induced pathways
hyperactive mutant growth factor
elevated levels of normal growth factor
increased levels of RTK
mutation in RTK to be constituently active or hyperative
activation of RTK by a viral protein
loss of RTK regulatory elements
What do high levels of epidermal growth factor (EGFR) result in
associated with carcinomas, metastasis and resistance to treatment
Explain what happens when EGFR is activated to switch off the signal
activated EGFR recruits the ubiquitin ligament CBL which helps switch off the signal
receptor becomes ubiquitinylated and internalised
receptor is degraded by hydrolytic enzymes in the lysosomes
What pathways are activated when EGFR binds to its ligand
the RAS/RAF pathway
the P13/AKT pathway which is linked to cell proliferation
Which abnormalities in EGFR signalling pathway can result in cancer
increased EGF ligands
increased EGFR levels on the surface - can occur due to gene amplification, binding of p53
mutations giving rise to constantly active receptors
What is EGFR variant III?
loss of extracellular binding domain so loss of the ligand binding region. receptor can actively dimerise without the need for binding to a ligand
strongly and persistently activated the p13/AKT signalling pathway, increased cell survival, proliferation and motility
What type of mutations cause the drive of oncogenesis
gain of function mutations in signal transduction molecules (RAS, P13-kinase, RAF)
loss of function mutations in growth inhibitory molecules (p53, RB, PTEN)
What is the role of PTEN and what happens when it is lost
in response to activated growth factors, PIP2 is converted to PIP3 and PTEN switches off this pathway to dephosphorylate PIP3 to PIP2
loss of PTEN means cells are more motile and aggressively migrate to new sites (as PTEN is a growth inhibitory molecule)
What are the two routes of apoptosis and which is most commonly disrupted in cancer
intrinsic/mitochondrial
extrinsic/death receptor mediated
intrinsic is most commonly disrupted in cancer
What factors determine whether the intrinsic pathway for apoptosis is activated
depends on the release of cytochrome c from the mitochondria - regulated by a balance between pro-apoptotic and anti-apoptotic molecules
What are examples of pro-apoptotic molecules
BAX
BAK
BAD
p53
What are examples of anti-apoptotic molecules
BCL-2
BCL-XL
What is the pathway of intrinsic induction of apoptosis and which
cytochrome C is released and activated BAX or BAL
recruitment of procaspase 9 molecules to form the apoptosome
and becomes activated
caspase cascade leading to apoptosis
How can the intrinsic pathway be deregulated
overexpression of anti-apoptotic molecules due to activating mutations in these genes
loss of activity of pro-apoptotic molecules
