Lecture 29

1.
How do apoptotic mechanisms influence cancer development? 
High rates of apoptosis, reduced sensitivity to apoptosis
2.
What do cells activate during apoptosis?
Caspases
3.
What do caspases activate?
Phospholipase 2 
4.
What does phospholipase 2 activate?
Arachadonic acid
5.
What does release of arachadonic acid form?
Prostaglandin E2
6.
What does prostaglandin E2 (PGE2) do in the presence of COX?
Proliferation
7.
What does proliferation do?
Tumour growth
8.
How are macrophages involved in tissue repair?
Release MMPs, PDGF, VEGF, TGF-beta
9.
What do PDGF and TGF-beta do?
Recruit myofibroblasts, remodel stroma
10.
What does VEGF do?
Angiogenesis
11.
What is the result of apoptosis?
Damaged/mutated cells survive
12.
What happens when mutant cells survive?
Proliferation of mutated cells
13.
What happens as a result of proliferation of mutant cells?
Become invasive
14.
What happens to normal cells when they leave their normal environment?
Anoikis
15.
What happens with anoikis in tumours?
Suppression, metastasis
16.
What is FASR
FAS death receptor
17.
What activates FAS?
FASL (eg. cytotoxic T cell or same cell)
18.
What does FAS activation do?
FADD
19.
What does FADD activate?
Initiator caspases
20.
What do initiator caspases do?
Activate executioner caspases
21.
How is the FAS pathway inhibited?
Mutation of FAS protein
22.
How does inhibiton of FAS lead to cancer?
Cells don't express FASS and don't die through self apoptotic mechanisms, kill cells which express FAS (counter attack on T cells)
23.
How else can cancer suppress FAS pathways?
Downregulate FADD, initiator caspases
24.
What is BCL2?
Translocation of oncotic gene on B cell chromosome
25.
What does BCL2 do?
Suppresses apoptosis
26.
Where can BCL2 go?
Mitochondrial membrane
27.
What does BCL2 do in the mitochondria?
Inhibits BAX
28.
What does BAX do?
Apoptosis
29.
What is often deleted in cancer?
BAX
30.
When is p53 activated?
Cell stress
31.
When is p53 inhibited?= =MDM2 protein
32.
How does DNA damage or abnormal cell cycling affect p53?
Inhibits MDM2
33.
What damages DNA leading to p53 and MDM2 suppression?
IR, carcinogens
34.
How can abnormal cell cycling be stimulated?
Decrease in PRB, increase in RAS
35.
What is the correlation of p53 with cancer?
Mutant p53 is usually present
36.
What does p53 do?
Controls/stimulates apoptosis, stops cell cycle
37.
What does p53 provide negative feedback to?
MDM2
38.
What does p53 activate to stimulate apoptosis?
Activates BAX, FAS, Bid