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MCD Cancer > The cell cycle and its control > Flashcards

The cell cycle and its control Flashcards

1
Q

what factors affect the rate at which cells divide?

A

o Adult vs. embryonic cells
– e.g. embryo cells divide much faster.

o Complexity
– e.g. yeast cells ~1.5-3.0h.

o Necessity for self-renewal – e.g. intestinal epithelial cells ~20h.

o State of differentiation
– e.g. neurones never divide.

o Tumour cells.

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2
Q

what are the reasons for appropriate regulation of cell division?

A

o Cell death
– when there is premature/aberrant mitosis.
o Aneuploidy
– due to mutations in oncogenes and tumour suppressor genes.
o Chromosome instability.
o Contact inhibition of growth.
o Anti-cancer strategies
– aimed at attacking machinery that regulates chromosome segregation.

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3
Q

what is mitosis?

A

nuclear divisions and cytokinesis

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4
Q

what is interphase?

A

duplication of DNA, organelles and protein synthesis

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5
Q

which stage of the cell cycle is most vulnerable to insult? why?

A

mitosis
o Cells more easily killed – e.g. heat shock.
o DNA damage not repaired therefore appears in the daughter cell
o Gene transcription silenced.
o Metabolism.

mitosis is therefore the quickest phase to avoid being vulnerable for a long time

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6
Q

what is the S phase?

A

the stage of DNA replication prepping for mitosis

organelles made and DNA doubled

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7
Q

what occurs in the S phase?

A

o DNA replication.
o Protein synthesis – initiation of synthesis is increased along with ability to do so (capacity).
o Replication of organelles – e.g. golgi, mitochondria (will coordinate with mitochondrial DNA)

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8
Q

what is a centrosome made of?

A

two centrioles (barrels of 9 triplet microtubules)

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9
Q

what is the function of the centrosome?

A

forms the Microtubule Organising Centre (MTOC) and forms the mitotic spindle enabling the movement of the chromosomes

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10
Q

what are the stages of mitosis?

A 
Prophase 
prometaphase
metaphase
anaphase
telophase
cytokinesis.
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11
Q

what occurs in prophase?

A

early:

  • condensation of chromatin
  • sister chromatids have attached kinetochores connected via centromere using cohesin

late:
- duplicated centrosomes migrate to opposite sides of cell
- MTOC forms where mitotic spindle forms between 2 centrosomes
- polar microtubules made
- nuclear envelope breakdown

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12
Q

what is the function the kinetochore?

A

site of attachment for the spindles via centromere using cohesin

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13
Q

what are the changes in DNA width during the condensation of chromatin?

A 
2nm DNA
11nm chromatin string 
30nm chromatin fibre 
300-700nm scaffold-associated form
1400nm chromosome.
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14
Q

how are the spindles formed?

A
  1. Radial microtubule arrays (ASTERS) form around each centrosome to form the MTOC.
  2. Radial arrays meet.
  3. Polar microtubules form.
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15
Q

how is metaphase split up?

A

early prometaphase
late prometaphase
metaphase

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16
Q

what occurs at early prometaphase?

A
  • Chromosomes align at the equator of the spindle.
  • Breakdown of nuclear membrane.
  • Spindle formation largely complete.
  • Chromosome attachment via spindles to kinetochores.
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17
Q

what occurs at late prometaphase?

A
  • Microtubule from opposite pole is captured by sister kinetochore.
  • Chromosomes attached at each pole come to middle
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18
Q

what occurs at anaphase?

A

 Paired chromatids separate into daughter chromosomes

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19
Q

what holds the sister chromatids together?

A

cohesin, a multiprotein complex

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20
Q

how is anaphase split?

A

Anaphase A and Anaphase B

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21
Q

what happens in Anaphase A?

A

o Cohesin is broken down.

o Microtubules shorten and sister chromatids pulled towards poles.

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22
Q

what happens in Anaphase B?

A

two movements occur:
o Daughter chromosomes migrate towards the poles.
o Centrosomes migrate apart further (these are at the poles)

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23
Q

what happens at telophase?

A
  • Daughter chromosomes arrive at spindle.
  • Nuclear envelope reforms.
  • cell reverts to normal size
  • Contractile ring (myosin and actin filaments) forms and produced cleavage furrow
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24
Q

what is the contractile ring made of?

A

actin and myosin

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25
Q

what is left over when the contractile ring contracts?

A

two separate bodies attached by a mid body

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26
Q

when does the mitotic checkpoint take place?

A

from prometaphase beginning to the end of metaphase

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27
Q

what is the purpose of the mitotic checkpoint/ spindle assembly checkpoint?

A

1) check spindle alignment:
monitors chromosome alignment and the spindle assembly

2) check that the chromosome is attached:
An unattached kinetochore will generate a checkpoint signal so will not let the system advance into anaphase

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28
Q

what is required for the mitotic checkpoint to function?

A

CENP-E (centromere protein E- kinetochore tension sensing protein)

BUB protein kinases (disconnect from the kinetochore when the chromosome properly attaches)

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29
Q

what are the 4 types of attachments during spindle attachment?

A

1) amphelic- normal
2) Monotelic – only one kinetochore bound
3) Merotelic – both centrosomes/ two+ microtubules to same kinetochores
4) Syntelic – same centrosome/ microtubules to both kinetochores.

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30
Q

what is the effect of merotelic attachment?

A

sister chromosome is lost during cytokinesis

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31
Q

what is the effect of syntelic attachment?

A

both sister chromatids end up on the same pole

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32
Q

what causes aberrant cytokinesis?

A

When centrosome duplication is aberrant leading to too many centromeres (often 4) leading to a multiple polar spindle

33
Q

how is spindle attachment targetted in anti-cancer therapy?

A

induce chromosome miss-segregation by inhibiting kinetochore attachment
leading to the formation of inviable cells post-anaphase that eventually will die after mitotic arrest

34
Q

what drugs induce chromosome miss-segregation by targeting spindle attachments?

what is the role of the target BUB?

A

checkpoint kinase inhibitors e.g. BUB protein kinase inhibitors.

  • BUB proteins normally dissociate to indicate that the cell is ready to move from metaphase to anaphase
  • these drugs prevent dislocation of BUB, so the cell thinks that it is ready for anaphase despite being not, leading to an inviable cell that will be killed by apoptosis
35
Q

what drugs are used to target chromosome segregation but not specifically the mitotic checkpoint?

what conditions are they used for?

A

taxanes (breast cancer)

alkaloids (ovarian cancer)

36
Q

what do taxanes and vinca alkaloids do?

A

o Alter the microtubule dynamics.
o Produce unattached kinetochores.
o Cause long-term mitotic arrest –> apoptosis.

37
Q

what can a cell do when things go wrong in the cell cycle?

A

1) cycle arrest (can be temporary after DNA repair)

2) apoptosis

38
Q

at which stages can cycle arrest occur?

A

G1 and spindle check

39
Q

when does apoptosis occur?

A

a. DNA damage is too great (p53 said so)
b. Chromosomal abnormalities.
c. Toxic agents.

40
Q

where are the 3 checkpoints in the cell cycle?

A

1) G1 (start, check for sufficient GF to stimulate cell cycle)
2) G2 (entering mitosis checking for DNA damage)
3) metaphase checkpoint (going into anaphase)

41
Q

what is checked for in the G1 checkpoint?

A

growth factors

42
Q

what is checked for in the G2 checkpoint?

A

DNA damage

43
Q

what is checked for in the metaphase checkpoint?

A

sister chromatid alignment

44
Q

what effect to tumours have on a cell’s cell cycle?

A

blocks exit from cell cycle:
normally in the absence of a stimulus, the cells goes into G0 (quiescent phase)

a tumour may block the cell exiting into G0, keeping it in the cycle of division, so the cell keep dividing

45
Q

what is required for a cell to exit G0 into the cell cycle?

A

growth factors

lead to intracellular cascades –> MAPK/ERK

46
Q

what is involved in a signalling cascade?

A 
o	Response to extracellular factors.
o	Signal amplification.
o	Signal integration.
o	Modulation (via other pathways).
o	Regulation of responses.
47
Q

G0

A

quiescent phase

the cell is not dormant, just carrying out its regular functions

48
Q

examples of extracellular factors that can trigger a signalling cascade?

A

EGF (Epidermal Growth Factor)

PDGF

49
Q

how are the structures of the receptor and ligand significant when it comes to starting the signalling pathway?

A

the receptor is monomeric in an inactive state

the ligand i.e. GF, is dimeric

50
Q

what happens when the growth factor binds to the receptor?

A

the receptors become dimers and intiate the kinase cascades

the tyrosine kinase domains of the two receptors are cross linked and phosphorylated (when adaptor proteins bind)

51
Q

what happens during phosphorylation of the tyrosine kinase domains?

A

Phosphate transfer from ATP –> a hydroxyl group

side chains that are phosphorylated:
Serine.
Threonine.
Tyrosine.

52
Q

how effect does phosphorylation have?

A

alters the protein function by change in conformation and therefore change in activity

a docking site is create for another protein

can be activating or deactivating in its effect

53
Q

how is the protein kinase cascade self enhancing?

A

proteins regulated by the kinases are often other kinases and so activation of one kinase activates another to activate another

54
Q

what is the effect of protein kinase cascade?

A

o Signal amplification.
o Signal diversification.
o Opportunity for regulation.

55
Q

if kinases cause phosphorylation, what causes the reversal of phosphorylation for the inactivation of the protein kinase cascade?

A

phosphatases

56
Q

what happens when a kinetochore is not attached to chromatid? what happens as a result

A

it emits a signal to say it is not attached

when attached the BUB protein kinase dissociated from the kinetochore (sensed by CENP-E)

57
Q

when only can anaphase occur?

A

when all the BUB protein kinases attached to the kinetochores have dissociated

58
Q

what are the types of microtubule (according to their attached state)?

A

1- astral microtubule
:comes from centrosome but no bound to anything

2- kinetochore microtubule
: bound to kinetochore

3- polar microtubule
: connected to microtubules from the other centrosome

59
Q

what is aneuploidy?

A

having an abnormal number of chromosomes

60
Q

what occurs in cytokinesis?

A

insertion of new membrane at the cleavage furrow creating a mid- body between the two cells

61
Q

simple outline of tyrosine-kinase mediated signal triggering cell cycle entry from G0 in mammalian cycles?

A
  • GF
  • kinase domains dimerise
  • phosphorylation of tyrosine
  • conformational changes
  • active kinases
  • MAPK (Ras- Raf-MEK-ERK)
  • c-Myc expression
  • activation of cyclin D production
  • complex with cdk4/6
  • entry into G1
62
Q

what enables cyclic activation of cdks?

A

pRb proteins

  • inactivated by phosphorylation by cdk/cyclin
  • release of e2F (needed for TFs of cell cycle regulation)
  • Rb as negative regulator of cell cycle (halts it)
63
Q

what is the e2f protein?

A

transcription factor that stimulates S-phase gene transcription and production of new cyclins

held hostage by UNphosphorylated pRB

64
Q

Cdk for cyclin D?

stage?

A

4/6

entry into G1

65
Q

Cdk for cyclin E?

A

2

entry into S

66
Q

Cdk for cyclin A?

A

2

entry into G2

67
Q

Cdk for cyclin B?

A

1

entry into mitosis

68
Q

what is the function of PI3k?

A

conversion of PIP2 to PIP3 so it can bind to PKB (Akt)

69
Q

which proteins does PKB have its effects on?

A

wants to prevent apoptosis therefore:

  • inhibit caspase 9
  • inhibit Bad (BH3 pro-apoptotic)
  • inhibit p27KIP (Cdk inhibitor)
  • stimulate FOXO genes
70
Q

how is the PI-3K pathway activated?

what is the role of Akt?

A

1) GF recruits PI-3K
2) PI3K enables PIP2–> PIP3 (reversed by PTEN)
3) PIP3 mediates Akt/PKB-PDK1 recruitment to the plasma membrane
4) PDK1 phosphorylates threonine on Akt to partially activated Akt
- mTOR phosphorylates Serine on partially activated Akt to fully activated Akt

5) PIP3 dissociates from Akt

PKB/Akt goes into nucleus/cytosol to phosphorylate other proteins to have anti-apoptotic effects

71
Q

what effect does FOXO have on the cell cycle?

A

prevents apoptosis i.e promotes cell longevity
–>blocks transcription of p27KIP and apoptotic Fas Ligand

and therefore their expression so allow cell-cycle progression

stimulated by Akt (phosphorylates it)

72
Q

what do INK4 inhibit?

A

cdk4/6 in G1

p15INK4b
p16INK4a
p18INK4c, p19INK4d.

73
Q

what do CIP/KIP inhibit?

A

all Cdks made in S phase

p21CIP1/WAF1
p27KIP1
p57KIP2.

74
Q

what checks DNA for damage?

A

p53

75
Q

how does p53 become involved in cell cycle control?

A

production of Cdk inhibitors so it can do its repair ting:
1) p53 is phosphorylated (extrinsic pathway of apoptosis)

2) MDM2 unbinds from p53
- p53 binds to p21 region of a regulatory gene

3) This promotes transcription and translation of p21 (a KIP Cdk inhibitor)
4) inhibits all Cdks until the cell can fix the DNA damage or apoptose.

76
Q

list of proto-oncogenes involved in cell cycle

A
  • EGFR/HER2 (breast cancer)
  • Ras
  • Cyclin D1
  • B-raf
  • c-Myc

all enable cell cycle progression

77
Q

list of tumour suppressor genes involved in the cell cycle

A 
- p53 
(DNA damage and repair) 
- PTEN 
(prevent PKB/Akt activation  by dephos of PIP3 so apoptosis is not cancelled)
- pRB 
(takes hold of E2F)
- p27KIP 
(Cdk inhibitor)
78
Q

Grb2

A

SH2 binds to tyrosine domain of receptor

SH3 binds to SOS protein

MCD Cancer (17 decks)

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