Cancer 4: The cell cycle and its regulation

Question 1

define cell cycle

what are the 3 stages involved?

Answer 1

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

involves:
- Duplication
- Division
- Co-ordination

Question 2

Why is the mitosis phase the most vulnerable period of the cell cycle?

Answer 2

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

Question 3

Describe the process of M-phase

Answer 3

phase where cells undergo mitosis

Question 4

Describe what happens in interphase

Answer 4

longest time of cell life time = interphase

• where duplication occurs

Question 5

Give the order if the eukaryotic cell cycle

Answer 5

M phase = mitosis

Interphase:
G0 phase = cell cycle machinery dismantled

G1 phase = decision point (to divide/ or not)
S phase = DNA/Protein synthesis
G2 phase = Decision point
then M phase –> G0 again

Question 6

What happens in S phase ?

Answer 6

• DNA replication
• Protein synthesis occurs
• -> there is increase in initiation of translation + elongation of proteins
• replication of organelle

(for mito–> needs to coordinate w mitochondrial DNA)
–> because mitochondria has its own DNA

Question 7

Describe the structure of centrosome, and its function

Answer 7

structure:
- has 2 centrioles (barrels of 9 x triplet microtubules)

function:
- acts as Microtubule organizing centre ( MTOC) + mitotic spindle

Question 8

by __ phase, centrosomes are completely duplicated

Answer 8

by M phase they are completely duplicated

Question 9

What are the 6 phases of mitosis?

Answer 9

• prophase
• pro metaphase
• metaphase
• anaphase
• telophase
• cytokinesis

Question 10

What happens in prophase?

Answer 10

• condensation of chromatin (chromatin - has DNA wrapped in histones)
• becomes 30nm chromatin
• forms a chromosome scaffold
• condensed chromosome scaffold associated form
  then goes on to form condensed chromosomes

condense chr = has 2 sister chromatids

• has centromere (constriction of sister chromatin) = DNA core
• kinetochore (belt like) = allows segregation of chromosome to occur smoothly

Question 11

What happens between prophase pro metaphase ?

Answer 11

• Replicated chromosomes condense
• Duplicated centrosomes migrate –> to opposite sides of the nucleus + organize assembly of spindle microtubules
• Mitotic spindle forms outside nucleus (between the 2 centrosomes)

Question 12

Describe the process of spindle formation.

Answer 12

• Radial microtubule arrays (ASTERS) form around each centrosome (MTOC)
• ASTERS meet in the middle –> form stable interactions
• Polar microtubules form

note: microtubules polymerase + depolymerize all the time

Question 13

What is a characteristic of cell at metaphase?

Answer 13

Chromosomes = aligned at equator of spindle.

• centrosome = in opposite. poles
• microtubules = arranged in equator

Question 14

What happens in early pro metaphase?

Answer 14

• Breakdown of nuclear membrane
• Spindle formation = mostly complete
• polar microtubules/spindles capture chromosomes –> by their constrictions (kinetochore)

note: microtubules only attach to the kinetochore

Question 15

What happens in late pro metaphase?

Answer 15

• Microtubule from opposite pole = captured by sister kinetochore
• Chromosomes attached to each pole come to middle
• Chromosome slides rapidly towards center –> along microtubules

important factors involved:
CENP-E = centromere protein E
–> sense tension of cables

Question 16

What happens in Anaphase?

What are the 2 parts of Anaphase?

Answer 16

• Paired chromatids separate to form two daughter chromosomes
• Cohesin holds sister chromatids together

2 parts of anaphase

• A
• B

Question 17

What happens in Anaphase A ?

Answer 17

• cohesin= broken down
• Microtubules get shorter –>and pulls Daughter chromosomes
• toward opposite spindle poles

Question 18

What happens in Anaphase B ?

Answer 18

1-Daughter chromosomes migrate towards poles

2-Spindle poles (centrosomes) migrate apart
–> to allow space for cells to divide

Question 19

What happens in telophase of the cell cycle ?

Answer 19

• Daughter chromosomes arrive at spindle
• Nuclear envelope reassembles at each pole
• there is assembly of contractile ring (ring of actin –> squeezes 2 cells apart)

Question 20

What happens in cytokinesis?

Answer 20

• actomyosin (contractile) ring contracts
• squeezes 2 cells apart
  then when it is close enough, the memb fuses to form 2 distinct cells

Question 21

How does the cell cycle transition out of metaphase? (spindle assembly checkpoint)

what is required for this to occur?

Answer 21

• control = done by kinetochore
• depends on attachment/unattachment of microtubules to kinetochore
• unattached kinetochore –> sends signal (generates checkpoint signals)
• when kinetochore = attached = no signaling –> can go onto next anaphase of cell cycle

requires:
- CENP-E
- BUB protein kinases

Question 22

what are the 2 ways in which aneuploidy can occur?

Answer 22

1) mis-attachment of microtubules to kinetochores
a) defect of cohesion / synthetic attachment
- -> both sister chromatid will be at the same pole

b) merotelic attachement
- -> chromosome = lost at cytokinesis

2) aberrant centrosome/DNA duplication

Question 23

describe how induction of gross chromosome mis segregation can act as an anti cancer therapy

Answer 23

check point kinase inhibitor –> inhibits attachment error correction mechanism

• holds cells at G2 phase
• then make cell think all cells = aligned
• lose chromosome –> cancer cells die

Question 24

What happens if something goes wrong during the cell cycle?

Answer 24

a) cell cycle arrest
- -> at check points (G1 + Spindle check point)
- -> temporary (following DNA repair)

b) Apoptosis
- -> DNA damage = too great
- -> chromosomal abnormalities
- -> toxic agents

after a) + b) cells = aborted + destroyed

Question 25

Cell cycle checkpoints and tumour progression PCWT

Answer 25

``` at start = G1 check point (enter cell cycle) G2 checkpoint ( senses DNA damage) metaphase checkpoint (cells all align --> to see if sister chromatids are aligned) ``` tumours: - acts on G1 CKPT --> prevents exits via G0 phase - acts on G2 CKPT --> blocks sensing of DNA damage - acts on metaphase CKPT --> makes cell think chromatid are aligned --> can lead to aneuploidy/defects

Question 26

De-regulation of cell cycle during tumorigenesis

Answer 26

tumors: - blocks exit from cell cycles - -> doesn't go into G0 - -> goes back into cell cycle --> proliferates again

Question 27

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

Answer 27

- no stimulus = cell go into G0 (quiescent phase) | - Exit from G0 requires growth factors + intracellular signaling cascades

Question 28

what are the difference signalling cascade

Answer 28

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

Question 29

How does signalling occur by peptide growth factors? to trigger a cell to enter cell cycle what happen upon activation of receptors?

Answer 29

e. g EGF + PDGF - -> found in inactive state - with ligand: - -> receptors form dimers - -> receptors are activated by cross phosphorylation (when 2 kinase domains = close enough) - -> upon activation, - kinase cascade = triggered - triggers binding of adaptor proteins

Question 30

What happens in protein phosphorylation to trigger a cell to enter cell cycle

Answer 30

- there is transfer of phosphate from ATP to a hydroxyl groups - added Phosphate group - -> alters protein function: --> causes change in shape --> which causes change in acitivity --> OR creates a docking site for another protein (usually serine, threonine, tyrosine)

Question 31

What is the significance of protein kinase cascades in triggering cell cycle?

Answer 31

- Leads to signal amplification, diversification and opportunity for regulation - phosphorylation = occurs by kinase - phosphorylation = reversed by phophatases

Question 32

why is appropriate regulation of cell division important?

Answer 32

- 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). - 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

Question 33

what action does CENP-E have on late pro metaphase?

Answer 33

important factors involved: CENP-E = centromere protein E --> sense tension of cables