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Canc > Cancer 4: The cell cycle and its regulation > Flashcards

Cancer 4: The cell cycle and its regulation Flashcards

1
Q

What might determine rate of differentiation

A

Embryonic vs adult cells (early frog embryo cells - 30 min)

Complexity of system (yeast cells - 1.5 - 3 h)

Necessity for renewal
(intestine vs
hepatocyte)

State of differentiation

Tumour

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2
Q

How often will intesintal and hepatocyte divide

A

(intestinal epithelial cells - ~20 h

hepatocytes - ~1 year)

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3
Q

What is terminally divided cell, give examples

A

Cells which don’t re-enter proliferation following differentiation (neurons and cardiomyocytes)

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4
Q

What is consequence of abberant mitosis

A

Cell death

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5
Q

What are the key genetic properties of solid tymour cells

A

In addition to mutations in oncogenes and tumour suppressor genes, most solid tumours are aneuploid (abnormal chromosome number and content).

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6
Q

Irregegular levels of which type of protein is found in tmours

A

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

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7
Q

What is contact inhibition

A

Cells stop dividing when they reach other cells

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8
Q

What has been a successful means of cance therapy relating to cell division

A

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

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9
Q

What are the 3 events in te cell cycle

A

Duplication

Division

Co-ordination

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10
Q

What are the 2 parts of the M phase

A

Mitosis (Division)

Nuclear division
Cell division (cytokinesis)
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11
Q

What is involved in the interphase

A

Duplication

DNA
organelles
protein synthesis

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12
Q

Why is mitosis the most vulnerable period of the cell cycle

A

Cells are more easily killed (irradiation, heat shock, chemicals)
DNA damage can not be repaired
Gene transcription silenced
Metabolism?

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13
Q

Outline the phases of the cell cycle

A

M phase - Mitosis

Interphase:

G0 - cell cycle machinery
dismantled

G1 phase (Gap) - Decision point

S phase - Synthesis of DNA/protein

G2 phase (Gap) - Decision point

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14
Q

What occurs in S phase

A

DNA replication

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

Replication of organelles (centrosomes, mitochondria, Golgi, etc)
in case of mitochondria, needs to coordinate with replication of mitochondrial DNA

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15
Q

What is the centrosome made up of

A

Consists of two centrioles (barrels of nine triplet microtubules), which are surrounded by an electron dense and protein dense amorphous cloud of pericentriolar material (PCM).

These 2 centrioles are at 90 degrees to each other… have interconnecting fibres…. mother and daughter

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16
Q

Outline the centrosome cycle

A

The centrosome cycle consists of four phases that are synchronized to cell cycle.

These include: centrosome duplication during the G1 phase and S Phase, centrosome maturation in the G2 phase, centrosome separation in the mitotic phase, and centrosome disorientation in the late mitotic phase—G1 phase.

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17
Q

How do microtubules get made from the centrosomes

A

Tubulin enters the nucleating sites in the PCM and forms tubulin ring complexes due to polymerisation of tubulin

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18
Q

What is the size of the naked DNA

A

2nm

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19
Q

Outline the condensation of chromatin…. when does this occur

A

PROPHASE:

2nm (naked)

11nm (beads on a string)

30nm (30nm chromatin fiber of packed nucleosomes)

Extented scaffhold associated form (300m)

Condensed scaffhold associated form (700nm)

Replicated (1400nm)

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20
Q

What are the chromosomes like in prophase

A

Condensed chromosomes - each consists of 2 sister chromatids, each with a kinetochore

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21
Q

When do the centrosomes replicate and divide into 2 poles

A

Late prophase

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22
Q

What occurs in 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

What are ASTERS

What happens next

A

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

send out microtubes in all directions

Then the radial arrays meet in the centre, forming polar microtubules (keep the MTOCs separated)

And some arrays meet the membrane, forming astral microtubuls, which anchor MTOCs to the membrane

they are in a dynamic state (constantly polymerising and depolymerising)

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24
Q

What occurs in metaphase

A

Chromosomes aligned at equator of the spindle.

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25
Q

What are the stages of prometaphase

A

Prometaphase: early prometaphase

late prometaphase

26
Q

What occurs in early prometaphase

A

Breakdown of nuclear membrane

Spindle formation largely complete

Attachment of chromosomes to
spindle

27
Q

How do chromsomes attach to the spindle

When does this occur

A

Attachment of chromosomes to
spindle via kinetochores (centromere region of chromosome)

in EARLY PROMETAPHASE

28
Q

What occurs 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 center along microtubules

29
Q

What is CENP-E

A

Senses the tension of the spindle attachment to the kinetochore

30
Q

What occurs in anaphase

A

Paired chromatids separate to form two daughter chromosomes

31
Q

What usually holds the sister chromatids together

A

Cohesin holds sister chromatids together

32
Q

What occurs in anaphase A

A

Breakdown cohesin

Microtubules get shorter

Daughter chromosomes pulled toward opposite spindle poles

33
Q

What happens in anaphase B

A

1-Daughter chromosomes migrate towards poles

2-Spindle poles (centrosomes) migrate apart

34
Q

T/F all spindle fibres are attached to the chromatids

A

F…. some remain interracted with microtubes from the other pole in the centre between the poles to stabilise the structure

35
Q

What occurs in telophase

A

Daughter chromosomes arrive at spindle

Nuclear envelope reassembles at each pole

Assembly of contractile ring

36
Q

What is the contractile ring in telophase composed of

A

Actin and myosin

37
Q

What is seen between the two daughter cells in cytokinesis. What else happens in this stage

A

A midbody (microtube remnant)

Also chromatin decondenses, nuclear substructured reform (not the envelope, which reforms in telophase), interphase microtubule array reassembles (not like the radial ones in mitosis)

38
Q

When is there a mitotic checkpoint active

A

Prometaphase and metaphase

because the cells need to know that all chromatids are attached to microtubule

39
Q

What does an unattached kinetochore signal to the cell

A

generating checkpoint signals

it tells the cell that the cell CANNOT yet proceed with mitosis

attached kinetochore then stops giving these signals

40
Q

Which proteins are involved with kinetochore spindle attachment checkpoint

A

Requires:
CENP-E
BUB protein kinases

BUBs dissociate from kinetochore when chromosomes are properly attached to the spindle

CENP-E senses the tension of the spindle attachment to the kinetochore

When all dissociated, anaphase proceeds.

41
Q

What is amphelic attachment

A

Each sister chromatid attached to a microtube from different pole (normal)

42
Q

What is monotelic attachment

A

Only one microtube attached to one sister chromatid…. the other sister chromatid does not have a microtubule

Kinetochore of the unattached chromosome will produce a checkpoint signal that prevents progression to mitosis

43
Q

What is syntelic attachment

A

When microtubules from the same pole attach to both sister chromatids (kinetochore may or may not produce checkpoint signal

44
Q

Which is worse, monotelic or syntelic attachment… and why

A

Syntelic because the kinetochores may stop producung checkpoint signal

However, with monotelic attachment, there will be one kinetchore (i.e. the one whose sister chromatid is not attached to a microtubule) which is generating checkpoint signals, and thus the cell will not be able to proceed.

45
Q

What is merotelic attachment

A

Attachments of 2 microtubles from opposite poles to the same sister chromatid

46
Q

What happpens in syntheluc and merotelic attachment

A

Synthetic…. both sister chromaitds might end up at the same pole

In merotelic attachent chromosome loss at cytokinese (chromosme pulled toward both poles)

47
Q

What are the two roads to aneupoidy

A

a) mis-attachment of microtubules to kinetochores (or no breakdown of cohesin, which holds the sister chromatids together)
b) aberrant centrosome/DNA duplication

48
Q

Outline abberant centrosome/DNA duplication

A

Instead of the usual 2 x centrosomes, you can get a double replication such that there are 4 centrosomes.

In this case, you get weird spindle formation, and some might not even form a spindle, you could end up with 4 cells

49
Q

What is the function of checkpoint kinase

A

Serine threonine kinase activation holds cells in G2 phase until all is ready–> inhibition leads to untimely cell transition to mitosis before the cell is ready to go into mitosis

(ps this is different from BUB protein kinases and CENP-E, which are checking for kinetochore attachment during metaphase. This is a separate checkpoint)

50
Q

How do checkpoint kinase inhibitors work

Give examples of checkpoint kinase inhibitors and how they work

In addition to checkpoint kinase inhibitors, you can use taxenes and vinca alkaloids. What cancers are they used for, and what do they do

A

Just as a summary, we have been introduced to 2 checkpoints here.

  1. Kinetochore during metaphase at mitosis
  2. G2 checkpoint kinases (CHKE1 and CHKE2), which actually prevents cell from getting into mitosis as long as they are present

Slide 27 is kind of messed up, but it basically shows that you can use checkpoint kinase inhibitors, for either of the two checkpoints
1. If you use checkpoint kinase inhibitor you can inhibit attachment-error correction mechanism (you inhibit the checkpoint signals, make the cell think it has aligned its chromosomes, and then it’ll go into anaphase early and you induce gross chromosome mis-segregations)

  1. If you inhibit the checkpoint kinase (CHKE1 and CHKE2), the cell will think it is ready to progress into mitosis from G2, so there is untimely entry into mitosis, and the cancer cells will die

Taxanes and vinca alkaloids (breast and ovarian cancers)

  1. Alters microtubule dynamics (taxanes prevent disassembly of MTs and vinca alkaloids prevent assembly)
  2. Produces unattached kinetochores
  3. Causes long-term mitotic arrest because there will not be attachment of microtubules so kinetchores will not stop producing checkpoint signals. Remember that if they are arrested in mitosis, they are vulnerable to damage
51
Q

What occurs if something goes wrong in the cell cycle,

when might each of these occur

A
  1. Cell cycle arrest
    - at check points (G1 and spindle check point)
    - can be temporary (i.e. following DNA repair)
  2. Programmed cell death (apoptosis)
    - DNA damage too great and cannot be repaired
    - Chromosomal abnormalities
    - Toxic agents

Cell cycle progression aborted and cell destroyed

52
Q

What are the usual checkpoints in the cell cycle

A

The first checkpoint is during G1 (tells the cell to acutally enter the cycle)

Then the next checkpoint is just before mitosis, to check for DNA damage before entering mitosis (G2)- checkpoint kinases (CHKE1 and CHKE2, need to be inhibited, to allow to move from G2 to mitosis )

Then there is also a metaphase checkpoint which tests the correct sister chromatid alignment- - kinetochore checkpoint signals (need to REMOVE to allow progression beyond metaphase of mitosis) .

Tumours develop means by which they can bypass these checkpoints

53
Q

How can tumours bypass the cell checkpoints

A

Tumours exploit the first checkpoint (i.e. G1) by hyper-activating growth factors.

G1 CHECKPOINT: The tumour cells over-express growth factors (EGF, PDGF), and the end result is induction of cells to overcome this checkpoint.

G2 CHECKPOINT: Tumours can also block the ability of the cell to sense DNA damage (e.g. p53 mutation), such that the cell bypasses this checkpoints, which can result in chromosome abnormalities.

METAPHASE CHECKPOINT: Tumour cells can also block the sister chromatid alignment checkpoint, such that the chromatids divide even when the chromosomes are not aligned

During tumorigenesis, tumours can also operate at the exit of the cell cycle. When the cells divide, they pause and enter the G0 phase (the place where they start functioning as normal cells). Tumour cells can BLOCK THIS. Once cells exit mitosis, the cycle is initiated AGAIN to continue cell division.

54
Q

What usually triggers a cell to enter the cell cycle

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

55
Q

How does exit from G0 occur

A

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

56
Q

What occurs in signalling cascades

A

Response to extracellular factors

Signal amplification

Signal integration

Modulation by other pathways

Regulation of divergent responses

57
Q

Give example of factors responsible for moving the cell out of G0. What is the normal structure

A

Epidermal growth factor (EGF); Platelet-derived growth factor (PDGF)…

DIMERIC ligand

58
Q

What are the receptors like for EGF and PDGF and what happens in the presence of a ligand

A

Respective receptors found as monomeric, inactive state

Receptor Protein Tyrosine Kinase (RPTK)

In presence of the dimeric ligand:

Receptors form dimers and they cross phosphorylate each other, and and are activated by phosphorylation.

(AA in the kinase domain at phosphorylated)

59
Q

Outline the phosphorylation of AA residues in receptors

Which AAs are commonly phosphorylated

Which part is phosphorylated

A

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

  • The serine is phosphorylated – this phosphorylation is a SIGNALLING TRIGGER
  • This is REVERSED by protein phosphatases (they remove phosphate groups to restore the OH group)
  • There are two types of kinase

o One type can phosphorylate serine and threonine residues

o The other type can phosphorylate tyrosine residues

60
Q

How does added phosphate group change protein function

A

Causing a change in shape (conformation) leading to change in activity (+ve or –ve)

AND

Creating a docking site for another protein

61
Q

Why are signalling cascades used

A

Leads to signal amplification, diversification and opportunity for regulation

Canc (16 decks)

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