The Cell Cycle & Its Control Flashcards

1
Q

Cells divide at different rates depending on various factors - what are these?

A
  1. Adult vs. embryonic cells
    • embryo cells divides much FASTER
  2. Complexity of system
    • e.g. yeast cells ~1.5-3hrs
  3. Necessity for self-renewal
    • e.g. intestinal epithelial cells ~20hrs
  4. State of differentiation
    • e.g. neurones & cardiac myocytes never divide
  5. Tumour cells?
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2
Q

Relevance of the appropriate regulation of cell division?

A

• Cell death
- premature, aberrant mitosis leads to this

• Aneuploidy (abnormal chr no. & content)
- in solid tumours due to mutations in oncogenes and TSGs

• Chromosome instability
- as loose & gain chr. during cell division

• Contact inhibition of growth

• Perturbation of protein levels of cell cycle regulations
- due to abnormal mitosis

• Anti-cancer strategies
- aimed at attacking machinery that regulates chr. segregation

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3
Q

What is the cell cycle?

A

Orderly sequence of events in which a cell duplicates its contents and divides in two
• duplication
• division
• co-ordination

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4
Q

What is involved in the M-phase?

A

Mitosis (division)
• nuclear division
• cytokinesis

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5
Q

What is involved in interphase?

A

Duplication
• DNA
• organelles
• protein synthesis

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6
Q

Which stage of the cell cycle is the most vulnerable and why?

A
MITOSIS
 • cells more easily killed (irradiation, heat shock, chemicals)
 • DNA damage can NOT be repaired
 • Gene transcription is silenced
 • Metabolism?
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7
Q

What are the vague stages of the eukaryotic cell cycle?

A

M phase - mitosis

Interphase:
 • Go - cell cycle machinery dismantled
 • G1 - decision point
 • S - synthesis of DNA/protein
 • G2 - decision point
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8
Q

Describe 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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9
Q

Define centrosomes

A

Consists of two CENTRIOLES

• barrels of 9 triplet microtubules

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10
Q

What is the function of centrosomes

A

Form the
• MTOC (microtubule organising centre)
AND
• the MITOTIC SPINDLE

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11
Q

6 different phases of mitosis?

A
Prophase
Prometaphase
Metaphase
Anaphase
Telophase

Cytokinesis
(technically not mitosis)

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12
Q

Main actions in prophase?

A

• Chromosones condense

• Duplicated centrosomes migrate to opposite sides of cell
- and become MTOC

• Mitotic spindles form between 2 centrosomes

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13
Q

Describe the condensed chromosomes formed in prophase?

A

Consist of 2 sister chromatids
• each have a KINETOCHORE
• provides site of attachments for spindles

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14
Q

Explain how the chromosomes condense in prophase?

A
  1. 2nm DNA
  2. 11nm chromatin string
  3. 30nm chromatin fibre
  4. 300-700nm sacffold-associated form
  5. 1400nm chromosome
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15
Q

Describe the spindle formation during prophase?

A
  1. Radial microtubule arrays (ASTERS) form around each centrosome
    • go on to form MTOC
  2. Radial arrays meet
  3. Polar microtubules meet

This is a DYNAMIC ENVIRON. with polar microtubules constantly forming & breaking

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16
Q

What occurs during metaphase?

A

Chromosomes align at the equator of the spindle

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17
Q

What in unique about metaphase to the other stages?

A

Split into 2 phases:
• early prometaphase
• late prometaphase

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18
Q

What happens during early prometaphase?

A
  • Breakdown of nuclear membrane
  • Spindle formation completion
  • Chromosome attachment via. spindles to kinetochores
19
Q

What happens during late prometaphase?

A
  • Microtubule from opposite pole is captures by sister kinetochore
  • Chromosomes attached to each pole come to the middle
  • Chromosomes slides rapidly towards center along microtubules
20
Q

What is CENP-E?

A

Centromere Protein E

• kinetochore tension sensing protein

21
Q

What happens during anaphase?

A

Paired chromatids separate into daughter chromosomes

• with cohesin holding sister chromatids together

22
Q

What in unique about anaphase compared to the other stages?

A

Separated into 2 phases
• anaphase A
• anaphase B

23
Q

What occurs during anaphase A?

A

• Cohesin is broken down

  • Microtubules shorten
  • Daughter chromosomes pulled towards opposite spindle poles
24
Q

What occurs during anaphase B?

A
  • Daughter chromsomes migrate towards poles

* Centrosomes migrate further apart

25
What happens during telophase?
* Daughter chromsomes arrive at spindle * Nuclear envelope reassembles at each pole • Contractile ring forms - made up of actin & myosin
26
What happens during cytokinesis?
The contractile ring forms | • it contracts, leaving behind a mid-body
27
What is the spindle assembly checkpoint?
Transition out of metaphase - monitors: • chromosome alignment AND • the spindle assembly HENCE monitors kinetochore activity • an unattached kinetochore generates a checkpoint signal = will NOT let system advance into anaphase
28
What is required for the spindle assembly checkpoint?
CENP-E BUB protein kinases • these dissociate from the kinetochore when the chromosome properly attaches to the spindle (when all dissociated, anaphase proceeds)
29
What two things can lead to aneuploidy?
(a) mis-attachment of microtubules to kinetochores (b) aberrant centrosome/DNA duplication
30
Explain how (a) leads to aneuploidy
Amphelic • normal Monotelic • only ONE kinetochore bound Merotelic • BOTH centrosomes to same kinetochores • sister chromosome lost during cytokinesis Syntelic • same centrosome to both kinetochores • will put BOTH sister chromosomes to one side (ONENOTE for picture!!)
31
How does (b) lead to aneuploidy?
DNA and centrosome duplication ``` • leads to too many centrosomes (often 4) AND • a multipolar spindle = • aberrant cytokinesis ```
32
Main principle anti-cancer therapy is based on?
Induces gross chromosome mis-segregations Inhibits attachment • error-correction mechanism
33
How does inhibiting attachment help in anti-cancer therapy?
Chekpoint kinase (CHKE1 & CHKE2) * serine theronine kinase activation holds cells in G2 phase until all is ready * inhibition leads to untimely cell transition to mitosis
34
What can be used for breast & ovarian cancer?
Taxanes & vinca alkaloids • alters microtubule dynamics • produces unattached kinetochores • causes long-term mitotic arrest
35
If something goes wrong during the cell cycle, what are the 2 things the cell can do?
1. Cell Cycle ARREST • at check points (G1 & spindle check) • can be temporary (i.e. following DNA repair) 2. APOPTOSIS • DNA damage too great so cannot be repaired • Chromosomal abnormalities • Toxic agents
36
What are the 3 checkpoints in the cell cycle and at which points?
1. During G1 • GFs required to exit G0 and into G1 2. BEFORE mitosis (G2 checkpoint) • to check for DNA damage 3. Metaphase checkpoint • check for sister chromatid alignment
37
What triggers a cell to enter the cell cycle and divide?
In the absence of stimulus: • cells go into the G0 stage (quiescent phase) • cells are NOT dormant but are NON-dividing Exit from G0 is highly regulated • requires GFs & IC signalling cascades
38
How to tumours affect the cell cycle and de-regulate it?
Tumours ignore ALL the checkpoints ALSO Tumours block the ability of the cell to exit the cycle into G0 • thus cell CONTINUES to DIVIDE
39
What does the signalling cascade in the cell involve?
* Response to EC factors * Signal amplification * Signal integration * Modulation (via. other pathways) * Regulation of divergent responses (look at ONENOTE picture!!)
40
Explain signalling by peptide GFs
Ligand binds and activates the receptor! e.g. EGF (epidermal) & PDGF (platelet-derived) Receptors are MONOMERIC in their INACTIVE state - when ligand binds • receptors form dimers = kinase cascade • kinases are PHOSPHOSRYLATED = binding of adapted proteins
41
Explain the role of phosphorylation in the signalling cascade
``` • Phosphate transfer from ATP - to a hydroxyl group - examples of side chains that can be phosphorylated include • serine • THREONINE • tyrosine ``` The added phosphate can alter the protein function by: • change in conformation --> change in activity • creating a docking site for another protein
42
Overall: what happens in the presence of ligands AND what does receptor activation trigger?
In presence of ligands (a) receptors form dimers (b) are activated by phosphorylation Receptor activation triggers: (a) kinase cascades (b) binding of adapted proteins
43
Describe the protein kinase cascase
Normally, the protein regulated by a kinase is ANOTHER kinase (and so on)...... i.e. activation of one kinase activates another to activate another This leads to • signal amplification • signal diversification • opportunity for regulation
44
What is phosphorylation reversed by?
Phosphates