Cancer 4: The cell cycle and its control Flashcards
Relevance of the appropriate regulation of the cell division
See slides
Define the cell cycle
Orderly sequence of events in which a cell dupilcates its contents and divides into two.
Duplication
Division
Co-ordination
What are the two distinct phases of cell cycle?
M-phase: Mitosis (Division)
- Nuclear division
- Cell division (cytokinesis)
Interphase (duplication): Longest part of the cycle
- DNA
- Organelles
- Protein synethesis
Which is the most vulnerable period of the cell cycle?
Mitosis
Cells are more easily killed (irradiation, heat shock, chemicals)
DNA damage can not be repaired
Gene transcription silenced
Metabolism?
Describe the eukaryotic cell cycle?
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
Describe the S phase
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
Describe the centrosome
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.
What are the six phases of mitosis?
Prophase, Prometaphase, Metaphase, Anaphase A, Anaphase B, Telophase
What is prophase?
Condensation of chromatin.
DNA wraps around nucleosomes - chromatin. Chromatin packs further and further until it reaches a fully condensed chromosome.
What is the centromere?
Belt of DNA surrounded by a kinetochore (protein complex)
Describe prophase
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)
Describe spindle formation
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
Describe metaphase?
Chromosomes aligned at equator of the spindle.
Early prometaphase
Late prometaphase
What happens in early prometaphase?
Breakdown of nuclear membrane
Spindle formation largely complete
Attachment of chromosomes to
spindle via kinetochores (centromere region of chromosome)
See slides for diagram.
What happens in late prometaphase?
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
Describe anaphase?
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
What happens in anaphase A?
- Breakdown cohesin
- Microtubules get shorter
- Daughter chromosomes pulled toward opposite spindle poles (start to move)
What happens in anaphase B?
Two stages of movement
1) Daughter chromosomes migrate towards poles
2) Spindle poles (centrosomes) migrate apart
Describe telophase?
- Daughter chromosomes arrive at spindle
- Nuclear envelope reassembles at each pole
- Assembly of contractile ring
What is cytokinesis?
Actin-myosin contractilce ring contracts separating the cell into two independent cells.
There are traces of the spindle called the midbody.
Where is the mitotic checkpoint
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.
What is a monotelic attachment?
When only one one spindle is attached to one side of the chromosome. See slides
what is a syntelic attachment?
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.
What is a merotelic attachment?
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
What can causes aberrant centrosome/DNA duplication
Monotelic, syntelic an merotelic attachments
If there is too much centrosome duplication. See slides
Describe anti-cancer therapies by inducing gross chromsome mis-segregations?
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.
What happens if something does wrong during the cell cycle? Normal pathology
e.g. Cell is not big enough or DNA damage
- Cell cycle arrest
- at check points (G1 and spindle check point)
- can be temporary (i.e. following DNA repair) - 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
What are the different cell cycle checkpoints?
Metaphase checkpoint (kintechores - sister chromatids alignment) G2 checkpoint (DNA damage) G1 checkpoint (growth factors - tumour target this checkpoint overproduction of GF)
Describe the deregulation of cell cycle during tumorigensis?
Tumours can prevent the cell from exiting the cell cycle = there is no dismantling of cell cycle apparatus
See slide 31
Describe the signalling cascades?
Response to extracellular factors
Signal amplification
Signal integration
Modulation by other pathways
Regulation of divergent responses
What happens to receptors in the presence of ligand?
Receptors form dimers and are activated by phosphorylation.
See slides
The phosphorylation of the receptors cause a kinase cascade
binding of adapter proteins
Describe phosphorylation, what happens?
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
Describe the protein kinase cascade?
See slides.
Phosphorlyation is reversed by phosphatases.
Phosphorylation by kinases
Leads to signal amplification, diversification and opportunity for regulation
