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eMCD - Can > Cancer 4: The cell cycle and its regulation > Flashcards

Cancer 4: The cell cycle and its regulation Flashcards

1
Q

define cell cycle

what are the 3 stages involved?

A

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

involves:
- Duplication
- Division
- Co-ordination

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2
Q

Why is the mitosis phase 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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3
Q

Describe the process of M-phase

A

phase where cells undergo mitosis

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4
Q

Describe what happens in interphase

A

longest time of cell life time = interphase

  • where duplication occurs
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5
Q

Give the order if the eukaryotic cell cycle

A

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

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6
Q

What happens in S phase ?

A
  • 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

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7
Q

Describe the structure of centrosome, and its function

A

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

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

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8
Q

by __ phase, centrosomes are completely duplicated

A

by M phase they are completely duplicated

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9
Q

What are the 6 phases of mitosis?

A
  • prophase
  • pro metaphase
  • metaphase
  • anaphase
  • telophase
  • cytokinesis
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10
Q

What happens in prophase?

A
  • 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
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11
Q

What happens between prophase pro metaphase ?

A
  • 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)
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12
Q

Describe the process of spindle formation.

A
  • 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

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13
Q

What is a characteristic of cell at metaphase?

A

Chromosomes = aligned at equator of spindle.

  • centrosome = in opposite. poles
  • microtubules = arranged in equator
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14
Q

What happens in early pro metaphase?

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

note: microtubules only attach to the kinetochore

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15
Q

What happens in late pro metaphase?

A
  • 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

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16
Q

What happens in Anaphase?

What are the 2 parts of Anaphase?

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

2 parts of anaphase

  • A
  • B
17
Q

What happens in Anaphase A ?

A
  • cohesin= broken down
  • Microtubules get shorter –>and pulls Daughter chromosomes
  • toward opposite spindle poles
18
Q

What happens in Anaphase B ?

A

1-Daughter chromosomes migrate towards poles

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

19
Q

What happens in telophase of the cell cycle ?

A
  • Daughter chromosomes arrive at spindle
  • Nuclear envelope reassembles at each pole
  • there is assembly of contractile ring (ring of actin –> squeezes 2 cells apart)
20
Q

What happens in cytokinesis?

A
  • actomyosin (contractile) ring contracts
  • squeezes 2 cells apart
    then when it is close enough, the memb fuses to form 2 distinct cells
21
Q

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

what is required for this to occur?

A
  • 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

22
Q

what are the 2 ways in which aneuploidy can occur?

A

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

23
Q

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

A

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
24
Q

What happens if something goes wrong during the cell cycle?

A

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

25
Q

Cell cycle checkpoints and tumour progression

PCWT

A 
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

26
Q

De-regulation of cell cycle during tumorigenesis

A

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

27
Q

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

A
  • no stimulus = cell go into G0 (quiescent phase)

- Exit from G0 requires growth factors + intracellular signaling cascades

28
Q

what are the difference signalling cascade

A

Response to extracellular factors

Signal amplification

Signal integration

Modulation by other pathways

Regulation of divergent responses

29
Q

How does signalling occur by peptide growth factors?
to trigger a cell to enter cell cycle

what happen upon activation of receptors?

A

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
30
Q

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

A
  • 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)

31
Q

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

A
  • Leads to signal amplification, diversification and opportunity for regulation
  • phosphorylation = occurs by kinase
  • phosphorylation = reversed by phophatases
32
Q

why is appropriate regulation of cell division important?

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).
  • 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

33
Q

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

A

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

eMCD - Can (15 decks)

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