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BMS247 - Stem cells > Checkpoint controls II > Flashcards

Checkpoint controls II Flashcards

1
Q

What are the 3 DNA damage checkpoints?

A
  • G1/S
  • S
  • G2/M
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2
Q

What are the additional checkpoints in G1, after the R point?

How do cancer cells respond to these checkpoints?

A

Cells:
- Monitor for their attachment to the ECM (anoikis resistance)

  • Assess the presence of adequate nutrient levels

Cancer cells avoid these checkpoints

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3
Q

What is anoikis?

Why is is used?

A

Cell detachment-induced apoptosis

Self-defence strategy that organisms use to ELIMINATE cells in INAPPROPRIATE locations

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4
Q

As cancer cells are anoikis-resistant, what can they do?

A
  • 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
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5
Q

What decisions do the myc proteins govern?

A

Decisions to proliferate or differentiate

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6
Q

What are myc proteins?

What is the structure?

A

TRANSCRIPTION FACTORS

bHLH (basic helix loop helix)
Basic DNA binding domain, followed by amino acid sequences forming a-helix, loop and second a-helix

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7
Q

What % of tumours have mutations in myc?

A

70%

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8
Q

What are the 3 ways of inducing myc expression in cancer?

A

1) Normal promotor but amplification of gene
2) Chromosomal translocation
3) Pro-virus integration

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9
Q

What determines how and where the bHLH proteins act?

A
  • 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
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10
Q

What are some of the bHLH transcription factor members?

A
  • Myc
  • Max
  • Mad
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11
Q

What does the Myc-Max complex do?

A

Promotes PROLIFERATION

Inhibits DIFFERENTIATION

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12
Q

What does high levels of the bHLH mad do?

A

Replaces myc in the Myc-Max complex

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13
Q

When is mad expression increased?

A

When cells are differentiating

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14
Q

What does the Mad-Max complex do?

A

Inhibits PROLIFERATION

Activates DIFFERENTIATION

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15
Q

How is the balance between proliferation and differentiation controlled?

A

Two bHLH complexes (dimers):
Myc-Max

Mad-Max

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16
Q

What 3 key components of the cell cycle does the Myc-Max complex regulate?

A

1) PROMOTES the expression of Cyclin D/CDK4
2) Decreases the expression of E2F TF
3) Promotes the formation of Myc-Miz1

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17
Q

How does the Myc-Max complex decrease the level of E2F transcription factor?

A

Complex promoted the formation of Cyclin D/CDK4 which leads to pRb HYPOphosphorylation

pRb HYPOphosphoylation inhibits E2F transcription factors by BINDING

18
Q

What do E2F transcription factors do when they are activated?

A

DRIVE the PROGRESSION from the G phase to the S phase

19
Q

Wha does the complex Myc-Miz1 do?

What does this result in?

A

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

20
Q

What is the experiment that allows us to see if my is able to drive cell proliferation on its own?

A

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
21
Q

What is needed for cells to be able to sustain cell proliferation?

Why?

A

Over expression of Myc

Myc is enough to release all the constraints on cell proliferation when the conditions are not right

22
Q

What is the interaction between TGF-b and pRb?

A

TGF-b PREVENTS pRb phosphorylation

23
Q

What is the interaction between TGF-b and pRb?

What does this cause?

A

TGF-b PREVENTS pRb phosphorylation

BLOCKS cell cycle progression

24
Q

What is the relationship between TGF-b and Myc?

How does this happen?

A

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

25
Q

What happens in normal cells when TGF-b is expressed?

A

1) BLOCKS Myc expression
2) CKIs are expressed
3) CDKs are inhibited
4) pRb not phosphoylated
5) Cells don’t pass through the R point

26
Q

What happens when Myc levels are elevated in a tumour?

A
  • No longer under the control of TGFb

- Cells aren’t responsive to the inhibitory role of TGF-b

27
Q

What are the 2 strategies which cancers INACTIVATE TGFb signalling?

A

1) DIRECT inhibition of signalling by INACTIVATING SMAD4 (essential for downstream TGFb signalling)
2) Inactivation mutation of TGFbR

28
Q

What happens to the control of pRb function in most cancers?

Why?

A

It is PERTURBED

  • TGFb normally inhibits cell cycle progression by controlling pRb function
  • BUT cancer cells want to be able to proliferate
  • SO, they COUNTERACT this by DEREGULATING the pRb pathway
  • Therefore, it doesn’t matter if the TGFbR is active or not
29
Q

How is the pRb pathway deregulated? (4 different ways)

A

1) INACTIVATION of the pRb gene through mutation
2) Expression of very HIGH levels of cyclin D1
3) DOWNREGULATION of INK4 proteins, causing inappropriate inactivation of pRb
4) Mutations in the CDK4 gene - no longer able to bing the INK4 family of CKIs

30
Q

What does the deregulation of pRb result in?

A
  • Cancer cells with very ACTIVE cyclinD/CDK4 complexes
  • WITHOUT the presence of CKI
  • Leads to the phosphorylation and INACTIVATION of pRb and PROGRESSION through the cell cycle
31
Q

What is p53?

A

A transcription factor - tumor supressor gene that mediates the expression of genes that regulate growth and apoptosis

32
Q

What is the most frequently mutated TSG?

How? What does this result in?

A

p53

Mostly in the DNA binding domain:

  • When mutated - no longer bind to DNA
  • Promotes the transcription of p53 target genes
33
Q

What happens to p53 expression when the cells are experiencing stress?

What does this lead to?

A

Rapid increase in p53 PROTEIN LEVELS

–> Blocks cell cycle progression
If damage cannot be repaired –> apoptosis

34
Q

What is the increase in the p53 protein levels due to?

A

NOT due to increase in mRNA levels (increase in transcription)

Mediated by the post-translational STABILISATION of p53

35
Q

What happens to p53 levels in NORMAL conditions?

How?

A

Levels are very low

Produced and bound by Mdm2, which promotes the UBIQUITINATION and DEGREDATION of p53 - RAPIDLY DESTROYED

36
Q

What happens to p53 levels in STRESS conditions?

How?

A

Levels increase - protected from degradation:

1) ATM/ATR/Chk2 - phosphoylates p53 –> blocks binding to Mdm2 (not degraded)
2) ATM can also phosphoylate Mdm2 –> inactivation

37
Q

Which DNA damage checkpoints does p53 mediate?

A

ALL 3

38
Q

What happens to p53 in the presence of mitogenic/cell survival signals?

How? (2 ways)

A

Kept LOW:
1) Mdm2 transcription induces by mitogenic stimuli

  • More Mdm2 –> more ubiquitination and degredation of p53
    2) GFs mediate the phosphoylation of Mdm2 on a different residue to the one mediated by ATM/ATR
  • Facilitates binding to p53
  • Mediates ubiquitination/degredation
39
Q

How does p53 arrest the cell cycle?

A

By upregulating P21^Cip1

40
Q

What happens to P53 levels when the DNA damage is repaired?

A

Levels drop and the cell cycle can progress

41
Q

What happens to p53 in cancer cells?

What does this cause?

A

Is mutated, even in the presence of DNA damage

Causes:
- p53 levels to increase BUT p53 in UNABLE to bind to the DNA

  • Unable to induce transcription of CKI
  • Cell cycle can progress REGARDLESS of damage
42
Q

What are p53 target genes?

A

CKIs

BMS247 - Stem cells (15 decks)

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