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Cancer > The cell cycle and its regulation > Flashcards

The cell cycle and its regulation Flashcards

1
Q

Describe the reasons why different cells divide at different rates

A
  1. Embryonic vs adult cells (early frog embryo cells - 30 min)- embryonic cells divide much faster
  2. Complexity of system (yeast cells - 1.5 - 3 h)
  3. Necessity for renewal
    (intestinal epithelial cells - ~20 h
    hepatocytes - ~1 year)- however hepatocytes can proliferate much faster upon injury (liver lobules can re-grow)- shows how tightly regulated the system is
  4. State of differentiation (some cells never divide -
    i. e. neurons and cardiac myocytes)
  5. Tumour cells?- lose ability to control proliferation and differentiation- not regulated
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2
Q

Describe the antagonistic relationship between differentiation and division

A

When a cell is differentiating- it is not dividing
When a cell is dividing- it is not differentiating

This is why once a cell has differentiated- they never divide

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3
Q

Outline the relevance of appropiate regulation of cell division

A

Premature, aberrant mitosis results in cell death

In addition to mutations in oncogenes and tumour suppressor genes, most solid tumours are aneuploid (abnormal chromosome number and content).- due to dysregulaiton of cell cycle and mitosis

Various cancer cell lines show chromosome instability (loose and gain whole chromosomes during cell division)

Perturbation of protein levels of cell cycle regulators is found in different tumours - abnormal mitosis

Contact inhibition of growth

Attacking the machinery that regulates chromosome segregation is one of the most successful anti-cancer strategies in clinical use

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4
Q

What is meant by contact inhibition of growth

A

Cells grow normally by detecting neighbouring cells and know when to stop growing (spatial awareness) when there are enough cells to form a functional organ/tissue.

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5
Q

What is meant by the cell cycle

A

Orderly sequence of events in which a cell duplicates its contents
and divides in two.

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6
Q

Outline the 3 key events in the cell cycle

A

Duplication

Division

Co-ordination

Co-ordination is extremely important as if you divide before duplicaitng, the daughter cells will not have enough organelles or DNA to be viable

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7
Q

What is meant by the M-phase of the cell cycle

A

M-phase: Mitosis (Division)
Nuclear division
Cell division (cytokinesis)

need to divide both the nuclear and cytpolasmic contents

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8
Q

What is meant by interphase

A

Interphase (Duplication)
DNA
organelles
protein synthesis- to make new organelles

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9
Q

Why is the M-phase the most vulnerable part of the cell cycle

A

Mitosis - most vulnerable period of cell cycle:
Cells are more easily killed (irradiation, heat shock, chemicals)
DNA damage can not be repaired- so if a chromosome splits unevenly here- it will perpetuate into the daughter cells
Gene transcription silenced
Metabolism reduced

Everything is focussed into dividing the cell
This is why the M-phase is the shortest part of the cell cycle (1 hour)

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10
Q

What happens during the 3 stages of interphase

A

G1 – the cell makes sure that it has everything that is necessary for duplication
S – DNA replication, protein synthesis and replication of organelles
G2 – the cell checks that everything is ready to enter mitosis and that the DNA has been replicated without any errors (any errors are repaired here)

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11
Q

What is Go

A

G0 - cell cycle machinery
dismantled

Cell has left the cell cycle
Most cells are here
This is where they perform their function (regeneration, secretion, motility etc)

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12
Q

What happens during the S phase of the cell cycle

A

DNA replication

Protein synthesis: initiation of translation and elongation increased; capacity is also increased (increased ribosomes)

Replication of organelles (centrosomes, mitochondria, Golgi, etc)
in case of mitochondria, needs to coordinate with replication of mitochondrial DNA- need to replicate mtDNA too

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13
Q

Describe the structure of a centrosome

A

Consists of two centrioles ( mother and daugher centrioles)
Each centriole has barrels of nine triplet microtubules

The mother and daughter centrioles are held perpendicuarly to each other by inter-connecting fibres and a cloud of electro-dense material .

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14
Q

What is the function of a centrosome

A

Centrosomes are organelles near the nucleus of a cell, which contain centrioles (mother and daughter), and from which spindle fibres develop in cell division (to form the highways for chromosomal segregation)

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15
Q

Describe the life cycle of centrosomes during mitosis

A

The mother and daughter centrioles separate in G1

Then the mother produces another daughter and the daughter produces another mother, resulting in the formation of 2 centrosomes (the duplication takes place during S phase)
One centrosome will go to each daughter cell

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16
Q

Describe the role of the centrosomes during the M-pahse

A

Nucleation sites appear (gamma-tubulin ring complexes)

NOTE: nucleation is the assembly and polymerisation of microtubules which are needed for chromosomal segregation

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17
Q

List the different stages of mitosis

A

Prophase à prometaphase à metaphase à anaphase à telophase à cytokinesis.

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18
Q

Describe the condensation of chromatin during prophase and its importance

A

Short region of DNA double helix- 2nm

The double helices wrap around histones to form beads-on-a-string (11nm)

The beads then fold in on themselves to compact furher to form the 30nm fibre of packed nucleosome (each bead is a nucleosome)

It is then compacted to form a chromosome scaffold (300nm) and then further wrapped (700nm) until you get a chromosome (1400 nm)

Important as condensed chromatin is less likely to break off, easier to segregate and transport around the cell.

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19
Q

Describe the condensed chromosomes in prophase

A

Condensed chromosomes - each consists of 2 sister chromatids, each with a kinetochore attached to the centromere

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20
Q

What is a kinetochore

A

Protein complexes that are attached to each sister chromatid – they are important in detecting the attachment of microtubules in chromosomal segregation

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21
Q

What can be seen at the start of prophase

A 
Heterogenous nucleus (due to condensation of chromosomes)
Centrosome and formation of microtubles outside the nucleus
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22
Q

What can be seen by the end of late prophase

A

Replicated chromosomes condense
Duplicated centrosomes migrate to opposite sides of the nucleus and organize the assembly of spindle microtubules
Mitotic spindle forms outside nucleus between the 2 centrosomes

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23
Q

Describe spindle formation

A

Radial microtubule arrays (ASTERS) form around each centrosome (microtubule organizing centers - MTOC)

Radial arrays meet (from each centrosome)

Polar microtubules form (the ASTERS change properties)

N.B. Microtubules are in a DYNAMIC state- where the polar microtubules are constantly polymerising and depolymerising- so that there length and shape will continually be changed

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24
Q

What is the key feature of metaphase

A

Chromosomes aligned at equator of the spindle.

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25
Q

What are the two phases or prometaphase

A

Prometaphase: early prometaphase

late prometaphase

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26
Q

What happens during early prometaphase

A

Breakdown of nuclear membrane (important as we need to seperate the nuclear material in mitosis)

Spindle formation largely complete

Attachment of chromosomes to
spindle via kinetochores (centromere region of chromosome)- chromosomes captured by these microtubules (via kinetochores) once the nuclear membrane is broken down.

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27
Q

What happens during 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 center along microtubules

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28
Q

What is CENP-E

A

CENP-E = centromere protein E (kinetochore tension sensing

Senses the stretch on the chromosome from the microtubule

29
Q

Summarise anaphase

A

Paired chromatids separate to form two daughter chromosomes

Cohesin (multi-protein complex) holds sister chromatids together

Anaphase A and B

30
Q

What are the 3 main types of half-spindle

A

Kinetochore microtubule – attached to kinetochores

Polar microtubule – attached to a microtubule array from the other centrosome

Astral microtubule – microtubule originating from a centrosome that does not connect to a kinetochore

31
Q

What happens during anaphase A

A

Cohesin is broken down and the microtubules get shorter so the chromatids start moving towards their respective poles

32
Q

What happens in anaphase B

A

1-Daughter chromosomes migrate towards poles
2-Spindle poles (centrosomes) migrate apart

These two forces provide considerable segregation of the DNA in the cell- such that are large area is cleared for easy segreagation of the contents

33
Q

Are all the microtubules moves to each pole in anaphase

A

No, some remain in the centre- to maintain the highways for chromosomal segregation.

34
Q

What happens in telophase

A

Daughter chromatids arrive at the pole and the nuclear envelope reassembles

Assembly of a contractile ring of actin and myosin filaments where the cells are going to split

The contractile ring squeezes the cell so it divides into two daughter cells

NOTE: cleavage furrow = where the cell is going to be cleaved

35
Q

What is important to remember about telophase

A

Last phase of mitosis

36
Q

Describe what happens in cytokinesis

A

Cytoplasm cleaved in two (by contractile ring)
Chromatin recondenses
Nuclear substructures reform
Interphase microtubule array reassembles.

37
Q

What is the mid-body

A

The point where the actin-myosin contractile ring is formed- seen at the end of cytokinesis still- as a tail between the two daughter cells.

38
Q

Essentially, what is the spindle assembly checkpoint

A

Senses completion of chromosome alignment and spindle assembly
(monitors kinetochore activity)

Ensures that all the chromosomes are arranged in the middle of the cell and they each chromatid is attached to a mictorubule.

39
Q

How does the spindle assembly checkpoint monitor chromosomal attachment

A

The cell makes use of negative signals:unattached chromosomes send a stop signal to the cell-cycle control system.
The kinetochore has proteins that emit a signal when the kinetochore is NOT attached to microtubules

When a microtubule attaches to the kinetochore, it stops emitting the signal

At the end of metaphase, you want all the kinetochores to stop sending signals before you can proceed to anaphase

40
Q

Name two proteins that allow the kinetochores to detect spindle attachment

A

attachment.

CENP-E (monitors tension on chromosomes from microtubules).

BUB-protein kinase (this dissociates from the kinetochores when the chromatids are properly attached to the spindle – then they go on to signal progression to anaphase)

41
Q

Describe the importance of the spindle assembly checkpoint

A

Active during prometaphase and metaphase

If a dividing cell were to begin to segregate its chromosomes before all the chromosomes were properly attached to the spindle, one daughter cell would recieve an incomplete set of chromosomes, while the other would recieve a surplus. Both situations can be lethal, thus the cell ensures that every last chromosome is attached properly to the spindle before it completes mitosis.

42
Q

What can cause aneuploidy

A

Mitotic checkpoint defect

Mis-attachment of the spindles (so chromatids end up at different poles to the ones that they should be at)

Aberrant mitosis (production of an abnormal number of centrosomes leads to abnormal division of the chromatids, and abnormal cytokinesis)

43
Q

What are the four different types of spindle attachment

A

Amphitelic – normal spindle attachment

Syntelic – both kinetochores of the sister chromatids are attached to spindles from one centrosome

Merotelic – one kinetochore of one of the sister chromatids is attached to spindles from both centrosomes

Monotelic – one kinetochore of one of the sister chromatids is attached to a spindle, the other is unattached

44
Q

What is important to remember about syntellic attachment

A

The kinetochores may or may not be producing checkpoint signals.

45
Q

What are the consequences of syntellic attachment

A

Both sister chromatids at the same pole (duplicated chromosome)

46
Q

What is the consequence of merotellic attachment

A

Mulitple competition for the same chromatid
Chromatid stays in centre of the cell
Chromosome lost at cytokinesis.

47
Q

Describe how aberrant centrosome/DNA dupliation can lead to aneuploidy

A

 Aberrant centrosomes:
o DNA and centrosome duplication leading to too many centrosomes (often 4) and a multipolar spindle  aberrant cytokinesis.

48
Q

Broadly speaking, how can anti-cancer therapies work

A

Anti-cancer therapy by inducing gross chromosome mis-segregations

49
Q

Describe the use of checkpoint-kinase inhibitors as anti-cancer therapies

A

Checkpoint kinase (CHKE1 and CHKE2) – Serine threonine kinase
activation holds cells in G2 phase until all is ready
inhibition leads to untimely cell transition to mitosis

These inhibit the the attachment-error mechanism- leading to abnormal segregation of chromosomes in mitosis and thus early apoptotic cell death

50
Q

Describe the use of taxanes and vinca alkaloids as anti-cancer therapies

A

Taxanes and vinca alkaloids (breast and ovarian cancers)
Alters microtubule dynamics
Produces unattached kinetochores
Causes long-term mitotic arrest. (as cell cannot progress to anaphase without loss of these signals- don’t want cells to spend ages in mitosis as the cell is vulnerable during this time- so the cell is just killed off.

51
Q

Why don’t chemotherapies cause as much damage to normal cells

A

As cancer cells divide faster- so these will be targeted more.

52
Q

What can go wrong during the cell cycle

A

e.g. Cell is not big enough or DNA damage

53
Q

What happens when something goes wrong during the cell cycle

A

. Cell cycle arrest
at check points (G1 and spindle check point)
can be temporary (i.e. following DNA repair)

  1. Programmed cell death (apoptosis)
    DNA damage too great and cannot be repaired
    Chromosomal abnormalities
    Toxic agents

Cell cycle progression aborted and cell destroyed

54
Q

What are the main checkpoints of the cell cycle

A

During G1 (triggered by growth factors- ensure the cell has everything it needs to be able to duplicate and divide).

Just before mitosis to check for DNA damage

Metaphase-anaphase checkpoint (spindle assembly checkpoint)

55
Q

Describe the potential impact of tumours on the cell cycle checkpoints.

A

G1- Increased production of grwoth factors or growth factor receptors- to increase the frequency and speed f the cell cycle

G2- blocks checkpoint so all cells enter mitosis- even if they have unrepaired DNA damage

Spindle assembly- mitosis continues irrespective of whteher the chromosomes are properly alligned or not- this can lead to aneuploidy

These mechanisms are ultimately why tumour cells are so dysregulated.

56
Q

Describe the de-regulation of the cell cycle during tumorigenesis.

A

Tumours can prevent the cell from entering Go

and thus prevent the dismantling of the cell cycle apparatus- so the cell continually divides.

57
Q

What triggers the cell to enter Go

A

In the absence of stimulus, cells go into Go (quiescent phase)
Most cells in the body which are differentiated to perform specific functions
Cells are not dormant, but are non-dividing

58
Q

How can cells exit Go

A

Exit from G0 highly regulated - requires growth factors and intracellular signalling cascades

59
Q

Summarise signalling cascades

A

Response to extracellular factors

Signal amplification

Signal integration

Modulation by other pathways (during relay and amplification steps)

Regulation of divergent responses (for example metabolic, gene expression or cytoskeletal changes).

60
Q

Describe peptide growth factors

A

Epidermal growth factor (EGF); Platelet-derived growth factor (PDGF)
Respective receptors found as monomeric, inactive state
Receptor Protein Tyrosine Kinase (RPTK)- E.C binding domain and I.C tyrosine kinase domain.

61
Q

Describe signalling by peptide growth factors

A

Receptors are monomeric, ligands are dimeric

In the presence of a ligand:
Receptors form dimers
are activated by phosphorylation

62
Q

Which 3 amino acids can be phosphoylated

A

Tyrosine
Serine
Threnonine

63
Q

Describe what happens during protein phosphorylation

A

transfer of phosphate from ATP to a hydroxyl groups

64
Q

What are the consequences of protein phosphorylation

A

The added phosphate group (negatively charged) can alter protein function by:
causing a change in shape (conformation) leading to change in activity (+ve or –ve)
creating a docking site for another protein

65
Q

What does receptor activation trigger

A

Different phosphorylation events
kinase cascades ( to different sites other than the tyrosine kinase domain).
binding of adapter proteins (which allows control of divergent pathways)

66
Q

Summarise the protein kinase cascade

A

 The proteins regulated by the kinases are often other kinases and so activation of one kinase activates another to activate another.
Each kinase also has a corresponding phosphatase to turn the kinase off- allows for regulation.
 This leads to:
o Signal amplification.
o Signal diversification.
o Opportunity for regulation.

67
Q

What are the 3 actions of prophase

A

o Chromosomes condense.

o Duplicated centrosomes migrate to opposite sides of cell and become MTOC.

o Mitotic spindle forms between 2 centrosomes.

68
Q

What can a permanent activation of a cyclin lead to

A

Driving of a cell through a checkpoint.

Cancer (15 decks)

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