Checkpoint controls II Flashcards
(42 cards)
What are the 3 DNA damage checkpoints?
- G1/S
- S
- G2/M
What are the additional checkpoints in G1, after the R point?
How do cancer cells respond to these checkpoints?
Cells:
- Monitor for their attachment to the ECM (anoikis resistance)
- Assess the presence of adequate nutrient levels
Cancer cells avoid these checkpoints
What is anoikis?
Why is is used?
Cell detachment-induced apoptosis
Self-defence strategy that organisms use to ELIMINATE cells in INAPPROPRIATE locations
As cancer cells are anoikis-resistant, what can they do?
- Can grow in SUSPENSION and in an environment that is completely different to the one they started in
- Can DETACH from the tumour and travel in the blood stream –> lead to the formation of a tumour in a different part of the body
What decisions do the myc proteins govern?
Decisions to proliferate or differentiate
What are myc proteins?
What is the structure?
TRANSCRIPTION FACTORS
bHLH (basic helix loop helix)
Basic DNA binding domain, followed by amino acid sequences forming a-helix, loop and second a-helix
What % of tumours have mutations in myc?
70%
What are the 3 ways of inducing myc expression in cancer?
1) Normal promotor but amplification of gene
2) Chromosomal translocation
3) Pro-virus integration
What determines how and where the bHLH proteins act?
- Form DIMERS (homo- or hetero-)
- Depending on the members in the dimer - association with DIFFERENT promoters of different genes
- Can act as activators OR repressors
What are some of the bHLH transcription factor members?
- Myc
- Max
- Mad
What does the Myc-Max complex do?
Promotes PROLIFERATION
Inhibits DIFFERENTIATION
What does high levels of the bHLH mad do?
Replaces myc in the Myc-Max complex
When is mad expression increased?
When cells are differentiating
What does the Mad-Max complex do?
Inhibits PROLIFERATION
Activates DIFFERENTIATION
How is the balance between proliferation and differentiation controlled?
Two bHLH complexes (dimers):
Myc-Max
Mad-Max
What 3 key components of the cell cycle does the Myc-Max complex regulate?
1) PROMOTES the expression of Cyclin D/CDK4
2) Decreases the expression of E2F TF
3) Promotes the formation of Myc-Miz1
How does the Myc-Max complex decrease the level of E2F transcription factor?
Complex promoted the formation of Cyclin D/CDK4 which leads to pRb HYPOphosphorylation
pRb HYPOphosphoylation inhibits E2F transcription factors by BINDING
What do E2F transcription factors do when they are activated?
DRIVE the PROGRESSION from the G phase to the S phase
Wha does the complex Myc-Miz1 do?
What does this result in?
Mediates the REPRESSION of the transcription of CKI:
- Liberates cyclin E/CDK2 complexes from inhibition
Myc promotes the degradation of p27^Kip:
- Progression through the R point
What is the experiment that allows us to see if my is able to drive cell proliferation on its own?
1) ECTOPICALLY express Myc in cells as a FUSION protein with estrogen receptor
2) Addition of oestrogen receptor ligand –> drives conformational change and Myc translocation to the nucleus (becomes active TF)
3) Oestrogen ligand induces entrance of the cell into G1 and S phase (from G0)
- In the ABSENCE of any other GF
- SO, the activation of Myc is enough to release all constraints on cell proliferation normally present under normal conditions, when the environment is not right
What is needed for cells to be able to sustain cell proliferation?
Why?
Over expression of Myc
Myc is enough to release all the constraints on cell proliferation when the conditions are not right
What is the interaction between TGF-b and pRb?
TGF-b PREVENTS pRb phosphorylation
What is the interaction between TGF-b and pRb?
What does this cause?
TGF-b PREVENTS pRb phosphorylation
BLOCKS cell cycle progression
What is the relationship between TGF-b and Myc?
How does this happen?
TGF-b has opposing effects to Myc:
- Myc blocks CKI
- TGF-b activates CKI
How:
- TFG-b BLOCKS Myc –> prevents it from binding to CKIs
