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Cancer and The Cell Cycle > The G1/S transition and the restriction point checkpoint > Flashcards

The G1/S transition and the restriction point checkpoint Flashcards

0
Q

Cancer involves over-proliferation of cells. How may this happen?

A

Either generating too many new cells or not losing enough existing cells

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1
Q

Development of a tumour first requires loss of control over cell proliferation. What are the main steps between proliferation and metastais?

A

Proliferation -> Invasion -> Adherence -> Metastasis

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2
Q

How do normal cells prevent over-proliferation of a tissue? (basic answer)

A

They have a homeostatic mechanism whereby the number of cells created in a tissue (through mitosis) equals the number of cells lost from that tissue (either through differentiation, apoptosis, or injury)

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3
Q

In a normal cell, what are the two main types of signalling pathways?

A

Survival signalling - promotes generation of new cells and prevents loss of existing cells
Death (negative) signalling - promotes loss of existing cells and prevents generation of new cells

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4
Q

In cancer, how are the survival and death signalling pathways affected?

A

Proto-oncogenes are mutated to oncogenes, leading to increased survival signalling.

Tumour suppressor genes are inactivated, leading to a suppression of death signalling

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5
Q

Where does control over cell proliferation occur?

A

At the restriction point

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6
Q

Which oncogenes may be activated (i.e proto-oncogenes mutated to oncogenes) to promote survival signalling in a cancer?

A

Ras, Raf, BRAF

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7
Q

Where is the restriction point located in the cell cycle?

A

During G1 (growth phase 1)

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8
Q

What are the two possible outcomes after the restriction point?

A

The cells may exit the cell cycle to enter G0 (quiescence), or carry on in the cell cycle

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9
Q

At which stage in the cell cycle will the cell be responsive to different types of growth signal (both mitogenic GFs and TGF-B)?

A

G1

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10
Q

Which kinases are primarily responsible for control of the restriction point?

A

Cyclin D-kinases (Cdk4 and Cdk6)

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11
Q

Which Cyclin are both Cdk4 and Cdk6 dependent on to become active?

A

Cyclin D

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12
Q

During which phase of the cell cycle does DNA start being replicated?

A

S phase

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13
Q

What is the active Cdk2-Cyclin E complex important for?

A

Progression of the cell into the S phase

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14
Q

Which Cdk-Cyclin complex controls passage through the S -phase?

A

Cdk2-Cyclin A

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15
Q

Which Cdk-Cyclin complexes are responsible for entry into mitosis?

A

Cdk1-Cyclin A

Cdk1-Cyclin B

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16
Q

How does the cell cycle differ between adults and early embryos?

A

Early embryos don’t have gap phases: they move straight from S phase into mitosis, using Cdk2 to pass through S phase, and Cdk1 to pass through mitosis.
Adults have gap phases (G1 and G2)

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17
Q

Why do adult cell cycles comprise gap (growth) phases whilst early embryo cell cycles do not?

A

The growth phases allow response to replication errors as it enables tighter control of entry into the next phase in the cell cycle. This is not required in early embryos as they are more protected in a womb environment than, for example, a skin cell that is exposed to UV light.

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18
Q

Restriction point control, i.e. the progression from G1 to S phase is dependent on the action of which Cdks? And what happens if each of these is absent?

A

Cdk2 (drives cells into S phase)
- absence results in cell cycle pausing
Cdk4
- absence may result in cell differentiation or death
Cdk6
- absence may result in cell differentiation or death

19
Q

Replication errors detected in G2 result in inhibition of which Cdk?

A

Cdk1

20
Q

Eukaryotic chromosomes have many “origins of replication”. What happens to the replication bubbles produced by this?

A

They eventually fuse

21
Q

What is meant by the statement “Some origins are ‘early firing’”?

A

This means that replication starts earlier at some origins, whilst at ‘late firing’ origins, replication will begin later

22
Q

What defines origins of replication?

A

The DNA sequence

23
Q

What is the collective term for the proteins that origins of replication recruit?

A

Origin recognition complexes (ORCs)

24
Q

What does the pre-replicative complex contain?

A

ORC (origin recognition complexes) and other proteins

25
Q

What do eukaryotic chromosomes require for replication?

A

Origins of replication

26
Q

What is meant by ‘firing of an origin’?

A

Initiation of the replication process

27
Q

Assembly and activation of the pre-replicative complex (Pre-RC) is temporally separated. What does this mean?

A

During S-phase, pre-RCs are activated to initiate replication.

During G1-phase, new pre-RCs are assembled

28
Q

What reflects S phase beginning? (in terms of replication)

A

The pre-RCs are activated: i.e. they recruit additional proteins (e.g. DNA polymerase; actual enzymes that carry out replication) to form preinitiation complexes. Then replication begins, i.e. the replication forks start extending in both directions. As the pre-RCs become activated to initiate replication, it falls off the structure: the ORC proteins and accessory factors fall off the DNA. That means that the origin is no longer licensed (it is no longer ready to replicate)

29
Q

What is meant by the phrase “The origin is no longer licensed”

A

The pre-RC has fallen off and the origin is no longer ready to replicate

30
Q

Once an origin has become ‘unlicensed’, how long will it take for the pre-RC to become re-assembled?

A

Once the cell is back in G1, the pre-RC will assemble and the origin will be ‘licensed’

31
Q

What is the importance of origins becoming ‘unlicensed’?

A

This means that only one round of replication can take place per cell cycle: each origin only fires once, then it loses its pre-RC and can’t get it back again until the next G1 phase

32
Q

What class of enzyme controls replication?

A

Cyclin dependent kinases (Cdks)

33
Q

Which enzyme catalyses:

1) formation of the preinitiation complex and initiation (from the prereplicative complexes) during S phase
2) chromosome segregation during M phase
3) assembly of new prereplicative complexes at origins (during the transition from M phase to G1 phase)

A

1) S-Cdk activation
2) M-Cdk activation
3) APC/C activation (and Cdk inactivation)

34
Q

What does the pre-replication complex consist of? (4)

A

Origin recognition complexes (ORCs), Cdc6, Cdt1 and Mcm (helicase)

35
Q

Name an S-phase Cdk

A

Cdk2

36
Q

Which components of the pre-RC does Cdk2 phosphorylate? What does this cause?

A

ORC - triggers recruitment of DNA polymerase

Cdc6 - triggers its destruction, preventing reassembly of Pre-RC

37
Q

How is the pre-RC activated?

A

Phosphorylation of components of the pre-RC by Cdk2

38
Q

How is re-replication of DNA before mitosis prevented?

A

1) Generation of the pre-RC can only occur in the ABSENCE of Cdk activity (i.e. in G1)
- Firing of replication at origins absolutely requires Cdk2 activity

2) In G2, when Cdk activity is high, pre-RCs cannot assemble onto replicated DNA

39
Q

At what stage of the cell cycle is there no Cdk activity at all?

A

G1

40
Q

What is the importance of there being no Cdk activity during G1?

A

This allows pre-RCs to assemble because Cdc6 can re-accumulate

41
Q

Why can pre-RCs re-assemble only when there is no Cdk activity?

A

1) Cdk phosporylates Cdc6, which promotes its destruction.
Therefore, when Cdk activity is absent, Cdc6 can re-accumulate, and the pre-RC can form (Cdc6 is one of the core components of the pre-RC)

2) Cdt1 is inhibited by geminin which accumulates in the S-phase

42
Q

What activates Cdk2?

A

Cyclin E (and Cyclin A, but Cyclin E is present earlier in the cell cycle)

43
Q

Why can pre-RCs only assemble in G1?

A

They require:
1) Cdc6, which is triggered for destruction by Cdk2 (which is only absent during G1)

2) Cdt1, which is inhibited by geminin which accumulates in S-phase

44
Q

Cyclin E activates Cdk2. What controls Cyclin E expression?

A

Cyclin E expression is controlled by the Retinoblastoma protein

Cancer and The Cell Cycle (2 decks)

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