Cancer 4: The cell cycle and its control

Question 1

Relevance of the appropriate regulation of the cell division

Answer 1

See slides

Question 2

Define the cell cycle

Answer 2

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

Duplication
Division
Co-ordination

Question 3

What are the two distinct phases of cell cycle?

Answer 3

M-phase: Mitosis (Division)

• Nuclear division
• Cell division (cytokinesis)

Interphase (duplication): Longest part of the cycle

• DNA
• Organelles
• Protein synethesis

Question 4

Which is the most vulnerable period of the cell cycle?

Answer 4

Mitosis

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

Question 5

Describe the eukaryotic cell cycle?

Answer 5

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

Question 6

Describe the S phase

Answer 6

Replication for division

• 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

Question 7

Describe the centrosome

Answer 7

Consists of two centrioles (barrels of nine triplet microtubules)

Functions: Microtubule organizing centre (MTOC) and mitotic spindle

They are called a mother and daughter centriole

See slides for normal duplication and life cycle.

Question 8

What are the six phases of mitosis?

Answer 8

Prophase, Prometaphase, Metaphase, Anaphase A, Anaphase B, Telophase

Question 9

What is prophase?

Answer 9

Condensation of chromatin.

DNA wraps around nucleosomes - chromatin. Chromatin packs further and further until it reaches a fully condensed chromosome.

Question 10

What is the centromere?

Answer 10

Belt of DNA surrounded by a kinetochore (protein complex)

Question 11

Describe prophase

Answer 11

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

• 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. (essential for proper mitosis)

Question 12

Describe spindle formation

Answer 12

1) Radial microtubule arrays (ASTERS) form around each centrosome (microtubule organizing centers - MTOC)
2) Radial arrays meet
3) Polar microtubules form

Microtubules are in a dynamic state

Question 13

Describe metaphase?

Answer 13

Chromosomes aligned at equator of the spindle.

Early prometaphase
Late prometaphase

Question 14

What happens in early prometaphase?

Answer 14

Breakdown of nuclear membrane

Spindle formation largely complete

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

See slides for diagram.

Question 15

What happens in late prometaphase?

Answer 15

Microtubule from opposite pole is captured by sister kinetochore

Chromosomes attached to each pole congress to the middle

Chromosome slides rapidly towards centre along microtubules

Question 16

Describe anaphase?

Answer 16

Paired chromatids separate to form two daughter chromosomes

Cohesin holds sister chromatids together. This is broken down so that the chromatids can move apart

Two phases: Anaphase A and B

Question 17

What happens in anaphase A?

Answer 17

• Breakdown cohesin
• Microtubules get shorter
• Daughter chromosomes pulled toward opposite spindle poles (start to move)

Question 18

What happens in anaphase B?

Answer 18

Two stages of movement

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

Question 19

Describe telophase?

Answer 19

• Daughter chromosomes arrive at spindle
• Nuclear envelope reassembles at each pole
• Assembly of contractile ring

Question 20

What is cytokinesis?

Answer 20

Actin-myosin contractilce ring contracts separating the cell into two independent cells.

There are traces of the spindle called the midbody.

Question 21

Where is the mitotic checkpoint

Answer 21

Metaphase is a key mitotic checkpoint

• Every single kinetochore needs to be attached to a microtubule.
• Unattached kinetochores will generate signals, signalling the cell not to continue with mitosis.

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

When all dissociated, anaphase proceeds.

Question 22

What is a monotelic attachment?

Answer 22

When only one one spindle is attached to one side of the chromosome. See slides

Question 23

what is a syntelic attachment?

Answer 23

If both chromatids are attached to a microtubule but from the same side. See slides
This is the only attachment where the kinetochores may or may not produce a signal.

Question 24

What is a merotelic attachment?

Answer 24

If both chromatids are attached to a microtubule from their appropriate poles but one chromatid has an extra attachment from the opposite pole. See slides

Question 25

What can causes aberrant centrosome/DNA duplication

Answer 25

Monotelic, syntelic an merotelic attachments If there is too much centrosome duplication. See slides

Question 26

Describe anti-cancer therapies by inducing gross chromsome mis-segregations?

Answer 26

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. Taxanes and vinca alkaloids (breast and ovarian cancers) - Alters microtubule dynamics - Produces unattached kinetochores - Causes long-term mitotic arrest.

Question 27

What happens if something does wrong during the cell cycle? Normal pathology

Answer 27

e.g. Cell is not big enough or DNA damage 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 1) Chromosomal abnormalities 2) Toxic agents Cell cycle progression aborted and cell destroyed

Question 28

What are the different cell cycle checkpoints?

Answer 28

``` Metaphase checkpoint (kintechores - sister chromatids alignment) G2 checkpoint (DNA damage) G1 checkpoint (growth factors - tumour target this checkpoint overproduction of GF) ```

Question 29

Describe the deregulation of cell cycle during tumorigensis?

Answer 29

Tumours can prevent the cell from exiting the cell cycle = there is no dismantling of cell cycle apparatus See slide 31

Question 30

Describe the signalling cascades?

Answer 30

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

Question 31

What happens to receptors in the presence of ligand?

Answer 31

Receptors form dimers and are activated by phosphorylation. See slides The phosphorylation of the receptors cause a kinase cascade binding of adapter proteins

Question 32

Describe phosphorylation, what happens?

Answer 32

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 Phosphate group usually added to OH group. Serine Threonine Tyrosine

Question 33

Describe the protein kinase cascade?

Answer 33

See slides. Phosphorlyation is reversed by phosphatases. Phosphorylation by kinases Leads to signal amplification, diversification and opportunity for regulation