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BIOM 3500 - Midterm 3: The Cell Cycle > Lecture 18 - S-Phase ad the Regulation of Growth and Cell Division > Flashcards

Lecture 18 - S-Phase ad the Regulation of Growth and Cell Division Flashcards

1
Q

What is BrdU?

A

Bromo-deoxyUridine
- Analogue of dTTP

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2
Q

What does the incubation of cells/tissues in BrdU result in?

A

Its incorporation into DNA during S-phase so that the BrdU of the fixed cells can then be detected with anti-BrdU antibodies followed by a fluorescent secondary antibody

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3
Q

What is the order in which Cdks are activated in sequence to allow S-phase to occur?

A
  • G1: Cdk4/cyclin D (inhibited by INK4)
  • G1/S: Cdk2/cyclin E (inhibited by p27, p21)
  • S: Cdk2/cyclin A (inhibited by p27, p21)
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4
Q

What is the cdk-cyclin complex for G2/M?

A

Cdk1/cyclin B

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5
Q

What APC complexes are seen in mitosis and G1?

A

APC/C-Cdc20 and APC/C-Cdh1

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6
Q

How and when is APC/C-Cdc20 activated and inactivated?

A
  • Activated in mitosis by Cdk1
  • Inactivated in late anaphase when Cdk activity drops
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7
Q

How and when is APC/C-Cdh1 activated and inactivated?

A
  • Activated from late anaphase to S-phase due to low Cdk activity (keeps Cdk activity low in G1)
  • Inactivated by Cdk1 activity in S-phase, G2, and M-phase
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8
Q

What kind of Cdk activity is seen in G1?

A

Low Cdk activity

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9
Q

Why is low Cdk activity seen in G1?

A
  • APC/C-Cdc20 inactivated after anaphase
  • APC/C-Cdh1 becomes active
  • Cyclin transcription is low and Cdk inhibitors are present
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10
Q

After completion of cytokinesis, what are the two daughter cells in?

A

G1

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11
Q

What allows preRC assembly?

A

Active APC/C-Cdh1 due to absence of Cdk1 activity and Cdk inhibitors

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12
Q

What occurs for preRC to be assembled?

A

1) APC/C-Cdh1 ubiquitinates cyclins (A and B) –> degraded
2) p21 and p27 bind and inhibit Cdk2/cyclin A and Cdk2/cyclin E
3) INK4 binds and inhibits Cdk4/cyclin D
4) Low levels of cyclin transcription

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13
Q

What cells arrest permanently in a G1-like state (G0)?

A

Cells that are terminally differentiated (most cells in our body)

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14
Q

What mechanism do all cells have?

A

Some mechanism of coupling cell division and growth

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15
Q

What is the main determinant of the rate of division in unicellular organisms?

A

Nutrient availability for the cell

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16
Q

What is the main determinant of the rate of division in multicellular organisms?

A

Extracellular signals, typically from neighbouring cells
(Extracellular signals also control the rate of growth)

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17
Q

In most cells, what does G1 of the cell cycle decide?

A

When and if the cells divide

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18
Q

In multicellular organisms what is highly regulated?

A
  • Growth
  • Cell cycle
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19
Q

What are mitogens?

A

Extracellular regulators of the cell cycle
*Many mitogens are also growth factors

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20
Q

What are growth factors?

A

Extracellular regulators of growth

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21
Q

What are survival factors?

A

Extracellular regulators of survival

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22
Q

What does the effect of a given extracellular signal depend on?

A

The cell receiving it

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23
Q

What do the PDGF and EGF mitogens do?

A

Activate the Ras/MAPK pathway

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24
Q

What happens during the Ras/MAPK pathway?

A

1) Receptor binding - transphosphorylation
2) Grb2-SH2 domain protein recruited to the receptor by RTK activation
3) Grb2 recruits and binds Sos (GEF for Ras)
4) Ras-GTP binds to Raf
5) Raf phosphorylates and activates MEK
6) MEK phosphorylates MAPK
7) MAPK enters the nucleus and phosphorylates 8) and activates transcription factors
9) Transcription factors promote the expression of the transcription factors, myc and fos (promote cell division and growth)
10) myc and fos promote cyclin D transcription and repress INK4 transcription
11) Accumulation of cyclin D and reduction of INK4 leads to activation of Cdk4-cyclin D

25
Q

Where is the Ras/MAPK pathway activated?

A

Downstream of many RTKs

26
Q

What were ras, raf, fos, and myc all discovered as?

A

Viral oncogenes

27
Q

What helps to relieve the inhibition of Cdk2/cyclin E?

A

Mitogens and Cdk4/cyclin D which inhibit p27

28
Q

How do mitogens and Cdk4/cyclin D relieve inhibition of Cdk2/cyclin E?

A

1) In G0/G1, when cyclin E levels are low, Cdk2-cyclin E complexes are inhibited by p27 or p21 binding
- Cdk4/cyclin D sequesters p27 and allows low level activation of Cdk2-cyclin E and Cdk2-cyclin E phosphorylates p27, which is recognized by SCF ubiquitin ligase and targeted for destruction
2) Cyclin D levels increase in response to mitogens

29
Q

How does G1-Cdk activity promote G1/S?

A

Cdk4-cyclin D and Cdk2-cyclin E phosphorylate Rb to inactivate it, thus activation E2F1

30
Q

What does E2F1 do?

A

Drives high level expression of cyclin A and cyclin E (and other S-phase genes)

31
Q

What is Rb named after?

A

The type of cancer it typically causes - retinoblastoma

32
Q

What is responsible for a rapid increase in G1/S and S-cyclin levels?

A

E2F1 and other activator E2Fs

33
Q

When is E2F1 inactive?

A

G0 and G1 by binding to Rb

34
Q

What promotes the activation of the E2F1 transcription factor?

35
Q

How do mitogens eventually promote S-phase?

A

1) Mitogens promote Cdk4-cyclin D activity and low levels of Cdk2-cyclin E activity by sequestering p27
2) Cdk4-Cyclin D and Cdk2-cyclin E phosphorylate Rb
3) Phosphorylated Rb causes it’s dissociation from E2F1
4) E2F1 associates with promoters and activates high-level transcription of G1/S: Cdk2/cyclin E and S:Cdk2/cyclin A, and man other genes required for S-phase, including DNA replication factors
5) E2F1 levels of transcription are promoted by E2F1
6) Active G1/S-Cdks further promote E2F1 activation by further phosphorylation Rb

36
Q

How is cyclin A activated?

A

1) E2F1 promotes high-level transcription of itself, cyclin E, and cyclin A
2) Cdk2-A and Cdk2-E phosphorylates p27
3) Phosphorylated p27 is recognized by SCF ubiquitin ligase that targets them for destruction leading to further activation of Cdk2-E and Cdk2-A complexes
4) Cdk2-E and Cdk2-A phosphorylate and inactivate APC/C-Cdh1
*Cyclin A is thereby stabilized

37
Q

What occurs during the G1 to S transition in higher eukaryotes?

A

1) Mitogens activate ras/MAPK pathway leading to myc and fos transcription
2) myc and fos promote cyclin D transcription and INK4 repression
3) Cdk4/cyclin D sequesters p27, leading to activation of the small amounts of Cdk2/cyclin E
4) Cdk4-D and Cdk2-E phosphorylates Rb, leading to E2F1activation
5) E2F1 promotes high-level transcription of itself, cyclin E, and cyclin A
6) Cdk2-A and Cdk2-E promote the destruction of p27
7) Cdk2/E and Cdk2/A phosphorylate and inactivate APC/C-Cdh1 so cyclin A is thereby stabilized
8) Cdk2/cyclin A promotes S-phase by phosphorylation multiple targets

38
Q

What makes up the pre-replication complex?

A
  • ORC
  • Cdc6
  • Cdt1
  • Mcm helicase
39
Q

How is the pre-replication complex formed?

A

1) ORC recruits Cdc6 and Cdt1
2) Cdc6 and Cdt1 recruit Mcm helicase

40
Q

When does PreRC remain “licensed”?

A

Throughout G1

41
Q

What triggers the replication at origins in S-phase?

A

Activity of two kinases, Cdk2-cyclin A and DDK1

42
Q

What does DDK1 do?

A

Phosphorylates MCM helicase

43
Q

When is the pre-replication complex (preRC) formed and when is it inhibited?

A

Formed in G1 and inhibited from forming until the next G1

44
Q

Why is the assembly of preRD inhibited after S-phase?

A

To ensure that re-replication does not occur since it would result in tetraploidy, which is frequently the first step in cancer development

45
Q

What ordered sequence of events after mitosis does S-phase initiation require?

A

1) Anaphase/early G1 (low Cdk activity due to APC/C-Cdh1)
2) Early S (high Cdk activity)
3) G2/M (medium to high Cdk activity)
4) Anaphase (low Cdk activity)

46
Q

What happens when Cdk activity is low due to APC/C-Cdh1?

A

preRC forms on origins of replication (licensing)

47
Q

What happens when there is high Cdk activity?

A
  • Pre-initiation (DNA replication) complex assembles on preRC and initiates DNA unwinding and loads DNA polymerases onto DNA
  • DNA replication begins
  • preRC dismantled
48
Q

What happens when there is medium to high Cdk activity?

A

preRC formation inhibited

49
Q

What is the G1 preRC assembly (licensing) inhibited by?

A

Cdk activity (APC/C-Cdh1 is active in G1)

50
Q

What contributes to the inhibition of preRC formation?

51
Q

What are the steps that occur for DNA replication to occur?

A

1) preRC: ORC recruits Cdc6 and Cdt1 which recruit Mcm helicase
2) At S-phase, Cdk2 phosphorylates and activates a number of proteins to promote origin firing
3) Cdk2 phosphorylates Cdc6, leading to its destruction via Ubiquitination
4) Cdk2 phosphorylates ORC components, inactivating them
5) Geminin binds and inactivates Cdk1
- DNA replication continues but as long as Cdk activity is maintained, it only initiates once per origin

52
Q

What does APC target geminin and cyclins at anaphase for?

A

Destruction

53
Q

What allows Cdc6 accumulation and ORC dephosphorylation and activation?

A

Low Cdk activity

54
Q

The cell cycle summary: G1

A
  • Low Cdk activity
  • preRCs assemble
55
Q

The cell cycle summary: Late G1

A

Transcriptional activation of G1/S cyclins and other S-phase regulators, increasing Cdk activity

56
Q

The cell cycle summary: S-phase

A
  • High Cdk activity
  • Replication firing
  • preRC dissassembly
57
Q

The cell cycle summary: G2

A
  • Moderate Cdk activity
  • preRCs not able to assemble
58
Q

The cell cycle summary: Prophase to metaphase

A
  • Increasing Cdk1 activity
  • Nuclear envelope breakdown
  • Chromosome condensation
  • Spindle formation
59
Q

The cell cycle summary: Anaphase to cytokinesis

A
  • Low Cdk activity
  • APC/C-Cdc20 destroys cyclins, securin, and geminin
  • Loss of sister chromatid cohesion
  • Chromosome segregation
  • Contractile ring formation

BIOM 3500 - Midterm 3: The Cell Cycle (7 decks)

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