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Year 2 MCD - Cancer > The Cell Cycle and its Regulation > Flashcards

The Cell Cycle and its Regulation Flashcards

1
Q

What affects the rates of division of different cells?

A
  1. Embryonic cells divide at a much faster rate than adult cells (early frog embryo cells: 30 min)
  2. Complexity of systems: a less complex system will divide more rapidly (yeast cells: 1.5-3 hours)
  3. Necessity for renewal: in the body, certain cell types must divide more rapidly to replenish lost cells
    - Intestinal epithelial cells are shed very often so need quick replenishment: 20 hours
    - Hepatocytes don’t need frequent renewal: 1 year
  4. State of differentiation: some cells NEVER divide – such as neurones and cardiac myocytes
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2
Q

What is the relevance of appropriate regulation of cell division?

A
  • Cell death –when there is premature/aberrant mitosis
  • Aneuploidy –due to mutations in oncogenes and tumour suppressor genes
  • Chromosome instability
  • Contact inhibition of growth
  • Anti-cancer strategies –aimed at attacking machinery that regulates chromosome segregation
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3
Q

What is mitosis?

A

nuclear division and cytokinesis

  • Mitosis is the most vulnerable period of the cell cycle
  • Cells more easily killed –e.g. heat shock
  • DNA damage not repaired
  • Gene transcription silenced
  • Metabolism
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4
Q

What happens in interphase?

A

duplication of DNA, organelles and protein synthesis

  • G0 PHASE: cell cycle machinery dismantled
  • G1 PHASE (GAP PHASE 1): decision point
  • S PHASE (SYNTHESIS): synthesis of DNA/protein
  • G2 PHASE (GAP PHASE 2): decision point.
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5
Q

What happens in the s phase?

A

Replication stage preparing for division in mitosis

  • DNA replication
  • Protein synthesis –initiation of synthesis is increased along with ability to do so (capacity)
  • Replication of organelles –e.g. golgi, mitochondria (will coordinate with mitochondrial DNA for this)
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6
Q

What is a centrosome?

A

an organelle near the nucleus of a cell which contains the centrioles

consists of two centrioles(barrels of 9 triplet microtubules)

  • matrix proteins hold the centrioles at 90 degree angles to each other - There is a mother and daughter centriole

Function –form the MTOC(Microtubule Organising Centre) and form the mitotic spindle

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7
Q

What are the stages of mitosis?

A
  • prophase
  • prometaphase
  • metaphase
  • anaphase
  • telophase
  • cytokinesis
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8
Q

What happens in prophase?

A

DNA needs to be condensed so that you can minimise DNA damage during mitosis

double helices are wrapped around histones to forms ‘beads-on-a-string’ form of chromatin (2 - 11 nm wide) -> further wrapped around itself to form 30 nm fibres -> extended as a scaffold forming a chromosome scaffold – 300 nm -> further wrapped until you end up with a chromosome

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9
Q

What is a kinetochore?

A

a complex of proteins. It’s a key regulator of the processes around chromosomes in the cell cycle

  • functional unit for segregation of the chromosomes
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10
Q

What happens in late prophase?

A

The centrosome has been duplicated by late prophase - the microtubules are radiating away from the centrosome

the nuclear envelope breaks down and by doing so, the chromosomes come out into the cytoplasm -> centrosomes migrate to opposite sides -> begin to organise the spindle

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11
Q

What are the types of microtubule arrays?

A

RADIAL MICROTUBULE ARRAYS (ASTERS)
- These form around each centrosome. As soon as the nucleus starts to break down, they start to form around the MTOC, the radial arrays still grow and they meet in the middle. They hook to each other in the opposite direction.

These are then called POLAR MICROTUBULES
- Polar microtubules form to stabilise structures

  • Aster microtubules continue to grow. Microtubules are in a dynamic state.
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12
Q

What happens in early prometaphase?

A
  • Breakdown of nuclear membrane is finalised
  • Spindle formation is largely complete
  • Attachment of chromosomes to spindle via kinetochores (centromere region of chromosome)
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13
Q

What happens in late prometaphase?

A
  • Microtubule from opposite pole is captured by sister kinetochore
  • Chromosomes attached to each pole congress to the middle
  • Chromosome slides rapidly towards centre along microtubules
  • the sister chromatids have been captured by the microtubule arrays -> the chromosomes slide rapidly towards the middle of the cell
  • In the kinetochores there are specialised proteins, which sense the attachment of microtubules e.g CENP-E is one of these proteins: it senses whether the kinetochore is attached to microtubules or not
  • CENP-E = centromere protein E (kinetochore tension sensing)
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14
Q

What happens in anaphase?

A

Paired chromatids separate to form 2 daughter chromosomes

  • Cohesin is a protein complex that holds the sister chromatids tightly bound together (cohesin acts as a glue)

Anaphase A

  • Cohesin is broken down and the microtubules get shorter
  • The chromatids start moving towards the centrosomes
  • The daughter chromatids are pulled towards opposite spindle poles

Anaphase B
- The daughter chromosomes can reach the opposite poles by two methods:
> Due to the shortening of the microtubules that form the spindles
> By the pulling apart of the spindle poles (spindle poles migrate apart)

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15
Q

What happens in telophase?

A
  • Daughter chromosomes arrive at the pole
  • Nuclear envelope reassembles at each pole
  • Centrosomes are moved apart and cells try to revert to their normal size
  • There is a condensation of material where the cells are going to split
  • You get the assembly of a contractile ring of actin and myosin filaments - squeezes the cell so that it divides into 2 daughter cells
  • The cleavage furrow is where the cells are going to be cleaved
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16
Q

What happens in cytokinesis?

A

This is the last phase of mitosis

  • This shows that when the cells divide, they usually round up
  • The contractile ring (mid-body) can be seen
  • Once the cells divide, we see the remaining component where the cells were once joined.
  • With time, membrane will be inserted here and the cells will become completely separated from each other.
  • You get insertion of the new membrane at the cleavage furrow
17
Q

What is a mitotic check point?

A

sense the completion of chromosome alignment and also checks for spindle assembly

  • The kinetochore has proteins that emit a signal when the kinetochore is NOT attached to microtubules
  • Once the kinetochore attaches to microtubules, it stops emitting the signal
  • At metaphase, when all the kinetochores will stop sending signals, the cell can proceed to anaphas
18
Q

What are some proteins involved in signalling?

A

CENP-E

BUB Protein Kinase

19
Q

What do BUB proteins do?

A

dissociate from the kinetochore when chromatids are properly attached to the spindle. When all dissociated, they go on to signal progression to anaphase

20
Q

What are the different types of attachment of microtubules to kinetochores?

A 
Amphelic attachment (normal)
- microtubule array of one centrosome is attached to the kinetochore of one sister chromatid, and the microtubule array of another centrosome is attached to the kinetochore of the other chromatid

Syntelic Attachment
- both the kinetochores are hooked by two microtubule arrays from the SAME centrosome

Merotelic Attachment
- there is more than one microtubule array attached to the same kinetochore – this means that one of the chromatids is being pulled in two different directions

Monotelic Attachment
- only one of the kinetochores of one chromatid is attached to a microtubule array, the other kinetochore is unattached

21
Q

When does a cohesion defect occur?

A

two sister chromatids attach to the same pole -> one cell having a duplication, and the other having one chromosome less

22
Q

What are the consequences of merotelic attachment?

A

more than one microtubule array attached to the same kinetochore

chromatid doesn’t know where to go, because its pulled from both sides -> a lost chromosome – both sister cells will have one chromosome less

23
Q

What are the consequences of aberrant centrosome?

A

If duplication of centromere is defective, there may be a situation in which you end up with 4 centrosomes -> can lead to very abnormal attachment of the microtubule arrays to the kinetochores leading to abnormal cytokinesis -> 4 daughter cells

24
Q

What are the consequences of over replication of DNA?

A

aberrant cytokinesis -> two normal daughter cells, two cells with a single chromosome, and one cell without ANY chromosome

25
Q

What can be used to induce gross chromosome mis-segregations?

A

taxanes and vinca alkaloids (breast and ovarian cancers) are used as treatment.

  • Alters microtubule dynamics
  • Produces unattached kinetochores
  • Causes long-term mitotic arrest
26
Q

How can exploiting checkpoint control be used to slow down cancer?

A

inhibit kinetichore signalling checkpoint - makes nucleus think its correctly attached to microtubules -> cells proceed to anaphase -> long-term mitotic arrest -> cells are more easily killed

27
Q

What causes cell cycle arrest?

A
  • usually happens at the checkpoints (G1 and spindle check point)
  • may be due to the detection of DNA damage
  • Can be temporary (i.e. following DNA repair)
28
Q

What causes apoptosis?

A

Programmed cell death

  • DNA damage is too great and cannot be repaired (or if damage is irreversible)
  • Chromosomal abnormalities
  • Toxic agents
29
Q

Where are the checkpints in the cell cycle?

A
  1. G1
  2. G2 - just before mitosis
  3. metaphase-anaphase checkpoint
30
Q

How do tumours take advantage of checkpoints?

A
  • exploit first checkpoint by hyper-activating growth factors -> induction of cells to overcome this checkpoint
  • block DNA damage machinery -> induces mitosis when it shouldn’t
  • block exit of cell cycle to G0 phase so they don’t function aas normal cells
31
Q

What triggers a cell to enter the cell cycle and divide?

A

Signalling cascades:

  • Response to extracellular factors
  • Signal amplification
  • Signal integration
  • Modulation by other pathways
  • Regulation of divergent responses

When growth factors bind to the receptors, signals are transmitted to the cytoplasmic portion of the cell that will modulate a number of different factors. Signals will diverge to reach multiple targets, in order to regulate the metabolic pathway, to regulate gene expression, and to regulate changes in cytoskeleton and proliferation.

32
Q

How can peptide growth factors be used for signalling?

A

IN PRESENCE OF LIGAND

  • The intracellular domain will be linked to a kinase domain
  • When the dimeric ligand binds, it induces dimerization of the monomeric receptors
  • This is the SIGNALLING UNIT – dimerization activates the kinase domain
  • There is cross-phosphorylation of receptors due to kinase domains being brought close together
  • We see phosphorylated amino acid residues in the kinase domain -> ACTIVATION -> kinase cascade and binding of adapter proteins
33
Q

What are some examples of peptide growth factors used for signalling?

A
  • Epidermal growth factor (EGF); Platelet-derived growth factor (PDGF)
  • Respective receptors are monomeric and found in the inactive state
  • Receptor Protein Tyrosine Kinase (RPTK)
34
Q

How does protein phosphorylation happen?

A

protein kinase picks up an ATP and transfers a phosphate group to the hydroxyl group (ATP -> ADP)

  • serine is phosphorylated – SIGNALLING TRIGGER
  • REVERSED by protein phosphatases (they remove phosphate groups to restore the OH group)
35
Q

What are the two types of kinase?

A
  • One type can phosphorylate serine and threonine residues

- The other type can phosphorylate tyrosine residues

36
Q

How does the added phosphate group alter protein function?

A
  • Causing a change in shape (conformation) leading to change in activity (+ve or –ve)
  • Creating a docking site for another protein
37
Q

What happens in a protein kinase cascade?

A

The first kinase is activated by phosphorylation, and then further kinases are activated by the activated kinases and so on

38
Q

Other than kinases, what else can be subject to phosphorylation?

A

other types of proteins can be phosphorylated -includes scaffolding proteins and transcription factors.

leads to signal amplification, diversification and opportunity for regulation

Year 2 MCD - Cancer (15 decks)

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