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3013 > Cell Cycle > Flashcards

Cell Cycle Flashcards

1
Q

What cells are incapable of forming tumours?

A

Senescent cells. Cancer is a deregulation of the cell cycle, so the more quiescent a cell is the less likely it is to be transformed.

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2
Q

What are the stages of the cell cycle?

A
  1. Mitotic phase
  2. Gap1
  3. S phase
  4. Gap2
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3
Q

What occurs in G1?

A

Duplication of cellular contents (not chromosomes)

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4
Q

What occurs in S phase?

A

Chromosomal replication

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5
Q

What occurs in G2?

A

The cell checks the replicated chromosomes for errors and makes any necessary repairs.

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6
Q

How is the cell cycle controlled?

A

Various checkpoints prevent it from continuing and lead to cell cycle arrest in response to various signals such as DNA damage.

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7
Q

What are the cell cycle checkpoints?

A
  1. Anaphase – Spindle Assembly Checkpoint
  2. G1 - M Restriction point
    - Entrance to S is blocked if genome is damage
    - DNA replication is halted in S phase if DNA is damaged
  3. G2 – DNA Damage Checkpoint
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8
Q

Which checkpoint is arguably the most important and why?

A

The G1 checkpoint is also known as the restriction point. This is the ‘point of no return’ for the cell cycle, the vinegar strokes of proliferation. Having passed this carefully regulated signalling gate the replication cannot be stopped.

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9
Q

What are the primary signalling components that regulate the cell cycle?

A

Cyclins and cyclin dependent kinases. Cyclins are structurally related proteins with a cyclin box, allowing them to interact with and regulate CDKs to produce active kinases which comprise the checkpoints.

Deregulation of CDKs is therefore unsurprisingly a cornerstone to transformation.

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10
Q

How are CDKs complexes regulated?

A

Association with cyclins
Phosphorylation state
Interaction with specific inhibitory proteins
Turnover - their concentration oscillates in time with the cell cycle

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11
Q

How many CDKs and cyclins are there?

A

There are eight of each, the cyclins denoted as A-H and the CDKs as 1-8. These can exist in different combinations to produce different effects.

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12
Q

Describe the cyclin-CDK complexes which are prevalent at different points of the cell cycle.

A

Mid G1 - CycD + CDK4/6

Late G1 + S - CycE + CDK2

G1/S boundary (and throughout S) - CycA + CDK2

Late G2 - CycA + CDK1

G2/M boundary - CycB + CDK1

D 4/6
E 2
A 2
A 1
B 1
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13
Q

What is the Cyc-CDK complex which controls entry into M-phase?

A

CycB-CDK1. This is also known as maturation promoting factor, MPF.

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14
Q

How is MPF regulated?

A

MPF is inhibited during S + G2 by phosphorylation of CDK1 at Thr-14 and Tyr-15.

It is activated in late G2 by cdc phosphatase removing these groups.

CycB must be degraded for exit from M-phase.

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15
Q

How are cyclin-CDK complexes regulated in general?

A

CDK Activating Kinase (CAK) is a major regulatory complex formed of CycH + CDK7 (or alt CDK MO15). This phosphoactivates the CDK at Threonine 160/161.

Cdc phosphatase removes inhibitory phosphorylation of CDKs at Thr-14 and Tyr-15. Cdc phosphatase is inhibited by the 14-3-3 sigma protein, a downstream target of p53

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16
Q

What controls the speed of the cell cycle?

A

Entry into G1 from G0 - controlled by contact inhibition and growth factor exposure.

The speed of the cycle itself is largely dependent on the rate of G1 and G2. G1 progression is controlled by mitogens and antiproliferative agents with the R-point acting as the terminus point for them - exposure to more will have no effect on cell cycle rate.

17
Q

What is required to pass through the R point?

A

A CycD-CDK4/6 concentration above the required threshold.

18
Q

What factors affect CycD-CDK4/6?

A

Both intracellular and extrinsic signals can act on them via a large number of mediators.

19
Q

How is the cell cycle regulated after the R point?

A

It isn’t really. After that it’s all autonomous and inevitable up until the DNA damage checkpoint and doesn’t respond to mitogenic or growth supressor signalling.

20
Q

How does CycD-CDK4/6 control the R point?

A

When activated it allows for entry into S phase. It does this by phosphorylating pRb (retinoblastoma susceptibility protein), relieving its inhibition of a dimeric TF called E2F.

E2F activates the genes requires for replication.

21
Q

How does pRb repress E2F, and how is this undone?

A

pRb binds and inhibit E2F with its long c-terminal tail. Repression by pRb is undone by CycD-CDK4/6 which double phosphorylates the c-terminal domain of pRb, causing it to release the HDAC and lowers its affinity for E2F.

Three further phosphorylations by both the Cyclin D-CDK4/6 and CycE-CDK2 complexes causes total complex disruption leading to full activation of EF2.

22
Q

What proteins are members of the pRb family? What is their role?

A

p105, p107, p130. All are capable of inhibiting E2F, and respond to a huge number of signals including CycD-CDK4/6 making them the primary regulatory hub of the R point.

23
Q

Describe the life of E2F.

A

8 different types of E2F.

Upregulates genes such as dihydrofolate reductase, DNAP, histones, etc

Rapidly degraded once in S phase so’s not to overproduce the replication machinery.

24
Q

How does the action/regulation of CycE-CDK2 compare to CycD-CDK4/6?

A

CycE-CDK has a broader specificity than cycD-CDK. For example, cycE-CDK phosphorylates the CDK inhibitor, p27, causing its degradation.

The activity of cycE-CDK is inhibited by p21, p27, and p57.

In contrast, these CDK inhibitors, at least at low concentrations, co-activate cycD-CDKs. Another class of CDK inhibitors, p15, p16, and p18, specifically inhibit cyclin D-CDKs.

25
Q

How are CycD and CDK4 dysregulated in cancer?

A

CycD is OEd in many cancers. CDK4 is upregulated in sarcomas and gliomas.

26
Q

What varieties of CDK inhibitors are there?

A

There are two families of CKI;

CDK Interacting Proteins (Cip/Kip family) - p21^CIP, p27^KIP1, p57^KIP2.

INK4 family - named INK4alpha-gamma. These are more potent CDK4 regulators frequently mutated in cancer.

27
Q

What is interesting about p21 regulation of CDKs?

A

It is a Cyc-CDK assembly factor at low levels but an inhibitor when its concentration is higher.

Other than that nothing. Even that barely counts as interesting. I’m sorry for misleading you about there being something interesting in any of these cue cards. There isn’t.

28
Q

How does p21 regulate S phase other than via CDK regulation?

A

It complexes with and inhibits PCNA, a DNAP cofactor, to downregulate replication by preventing PCNA from rescuing arrested DNAP delta complexes.

p21 also regulates pRb directly, increasing its propensity to inhibit E2F and thus repressing the cell cycle.

29
Q

How is p21 regulated?

A

It is phosphoinhibited as a result of many signalling pathways including PI3K mitogenic signalling.

It is strongly activated by p53.

30
Q

What similarities are shared by p27^Kip1 and p57^Kip2?

A

Both have conserved N-terminal 60AA kinase inhibitor domains that inhibit CDKs.

Neither impact DNA replication directly like p21 does.

31
Q

Describe the role of p27^Kip1.

A

This CKI (also called CDKN1B) is highly expressed in G0 cells, being activated by contact inhibition, mitogen starvation, and the TGF-B pathway.

p27^Kip1 strongly inhibits CycE-CDK2 activity.

32
Q

What connects the INK4 family?

A

All contain 4 ankyrin motifs and specifically inhibit CycD and its partners.

33
Q

What is the role of p16-INK4a?

A

This specifically binds CDK4/6, and while this does repress it it cannot displace CycD once bound. It is activated by the stress response, but not by DNA damage pathways.

p16 null mutations are common in cancers which also lack pRb.

34
Q

What is p14-ARF?

A

This is transcribed from an alternative reading frame in the same gene as p16. It has a different 5’exon but they share exons 2 and 3.

p14-ARF is an E3 ubiquitin ligase that is normally expressed at a low level, but activated by DNA damage. It inhibits Mdm2 which relieves the Mdm2 inhibition of p53.

35
Q

What are the constituents of the DREAM complex?

A

p130, p107, E2F4, DP & MuvB

MuvB is composed of four LINs and RBBP4.

36
Q

What is the role of the DREAM complex?

A

It represses all cell cycle dependent genes during quiescence, maintaining G0 by repressing the cell cycle.

37
Q

How does DREAM repress cell cycle proteins?

A

MuvB - B - MYB recruits FOXOM1 to promoters. The B-MYB is degraded leaving FOXOM1 bound to MuvB. FOXOM1 inhibits the genes.

38
Q

How is the DREAM complex inhibited to allow entry into the cell cycle?

A

Upon cell cycle entry p130 dissociates from the complex at E2F dependent processes, allowing E2F to act.

3013 (16 decks)

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