Cell cycle Flashcards
What is the cell cycle?
Orderly sequence of events in which a cell duplicates its contents and divides in two.
Duplication, division, coordination.
What is the most vulnerable period of the cell cycle and why?
Mitosis.
Cells are more easily killed (irradiation, heat shock, chemicals).
DNA damage cannot be repaired.
Gene transcription silenced.
Why is appropriate regulation of cell division important?
Premature, aberrant mitosis results in cell death.
Most solid tumours are aneuploid.
Cancer cell lines may show chromosome instability.
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 on elf the most successful anti-cancer strategies in clinical use.
Why do different cells divide at different rates?
Embryonic vs. adult cells
Complexity of system
Necessity for renewal varies
State of differentiation (some cells never divide, i.e. neurons and cardiac myocytes)
What happens during M-phase (mitosis) of the cell cycle?
Division: nuclear division and cell division (cytokinesis).
What happens during interphase of the cell cycle?
Duplication of DNA, organelles, and protein synthesis.
What are the 4 stages within interphase of the cell cycle?
G0: cell cycle machinery dismantled
G1 phase (Gap): decision point
S phase: synthesis of DNA/protein
G2 phase (Gap): decision point
What happens in S phase of interphase (cell cycle)?
Replication for division.
DNA replication
Protein synthesis: initiation of translation and elongation increases; capacity is also increased.
Replication of organelles (centrosomes, mitochondria, Golgi, etc.)
What is the centrosome?
An organelle consisting of 2 centrioles (barrels of 9 triplet microtubules).
What are the functions of the centrosome?
Microtubule organising centre (MTOC)
Mitotic spindle
What are the different phases of mitosis in the cell cycle?
(Interphase) Prophase Prometaphase Metaphase (Metaphase-to-anaphase transition) Anaphase Telophase (Cytokinesis) (Interphase)
What happens in prophase of mitosis (cell cycle)?
Condensation of chromatin.
Condensed chromosomes- each consists of 2 sister chromatids, with a kinetochore.
Replicated chromosomes condense.
Duplicated centrosomes migrate to opposite sides of the nucleus and organise the assembly of spindle microtubules.
Mitotic spindle forms outside nucleus between the 2 centrosomes.
How does spindle formation occur?
Radial microtubule arrays (ASTERS) form around each centrosome (microtubule organising centres, MTOCs).
Radial arrays meet.
Polar microtubules form.
Microtubules are in a dynamic state.
What happens in metaphase of mitosis (cell cycle)?
Chromosomes aligned at equator of the spindle.
What happens in early pro metaphase of mitosis (cell cycle)?
Breakdown of nuclear membrane.
Spindle formation largely complete.
Attachment of chromosomes to spindle via kinetochores (central region of chromosome).
What happens in late pro metaphase of mitosis (cell cycle)?
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.
What happens in anaphase of mitosis (cell cycle)?
Paired chromatids separate to form 2 daughter chromosomes.
Cohesin holds sister chromatids together.
2 parts: A and B.
What happens in anaphase A of mitosis (cell cycle)?
Breakdown of cohesion.
Microtubules get shorter.
Daughter chromosomes pulled towards opposite spindle poles.
What happens in anaphase B of mitosis (cell cycle)?
Daughter chromosomes migrate towards poles. Spindle poles (centrosomes) migrate apart.
What happens in telophase of mitosis (cell cycle)?
Daughter chromosomes arrive at spindle.
Nuclear envelope reassembles at each pole.
Assembly of contractile ring.
What happens in cytokinesis of the cell cycle?
Last phase of mitosis.
New membrane inserted at cleavage furrow.
Acto-myosin ring contracts.
Midbody begins to form.
Chromatin decondenses.
Nuclear substructures reform.
Interphase microtubule array reassembles.
What is the significance of the spindle assembly checkpoint after metaphase of the cell cycle?
Senses completion of chromosome alignment and spindle assembly (monitors kinetochore activity).
What does the spindle assembly checkpoint require?
CENP-E.
BUB protein kinases- BUBs dissociate from kinetochore when chromosomes are properly attached to the spindle.
When all dissociated, anaphase proceeds.
How may aneuploidy arise?
Mis-attachment of microtubules to kinetochores.
Aberrant centrosome/DNA duplication.
Happens if anaphase initiates before spindles attach properly.
What happens if something goes wrong in the cell cycle?
Cell cycle arrest: at checkpoints (G1 and spindle checkpoint); can be temporary (i.e. following DNA repair).
Programmed cell death (apoptosis): DNA damage too great and cannot be repaired; chromosomal abnormalities; toxic agents.
Cell cycle progression aborted and cell destroyed.
What triggers a cell to enter the cell cycle and divide?
In the absence of a stimulus, cells go into G0 (quiescent phase).
Most cells in the body which are differentiated to perform specific functions.
Cells are not dormant, but are non-dividing.
Exit from G0 is highly regulated- requires growth factors and intracellular signalling cascades.
What is the role of signalling cascades in the cell cycle?
Response toe extracellular factors Signal amplification Signal integration Modulation by other pathways Regulation of divergent responses.
How may an added phosphate group alter protein function?
Phosphate (negatively charged) is transferred from ATP to hydroxyl group.
Causing a change in shape (conformation) leading to change in activity (positive or negative).
Creating a docking site for another protein.
Name 2 peptide growth factors involved in signalling in the cell cycle.
Epidermal growth factor (EGF)
Platelet-derived growth factor (PDGF)
What happens in the presence of a ligand in signalling by peptide growth factors in the cell cycle?
Receptors form dimers and are activated by phosphorylation.
What does receptor activation trigger in signalling by peptide growth factors in the cell cycle?
Kinase cascades
Binding of adaptor proteins
What do protein kinase cascades lead to?
Signal amplification
Diversification
Opportunity for regulation
What is a kinetochore?
A complex of proteins that is a key regulator of the processes around chromosomes in the cell cycle. Contains specialised proteins that sense the attachment of microtubule (CENP-E) in late prometaphase.
What are the 3 types of half-spindle?
Kinetochore microtubule- bound to the kinetochore.
Polar microtubule- a microtubule that has met and connected with a microtubule from the other centrosome.
Astral microtubule- a microtubule that is originating from the centrosome and does not connect to a kinetochore.
What is syntelic attachment?
Both the kinetochores are hooked by 2 microtubule arrays from the same centrosome.
What is merotelic attachment?
There is more than one microtubule array attached to the same kinetochore- this means that one of the chromatids is being pulled in 2 different directions.
What is monotelic attachment?
Only one of the kinetochores of one chromatid is attached to a microtubule array, the other kinetochore is unattached.
How do taxanes and vinca alkaloids work as anti-cancer therapy?
Induce gross chromosome mis-segregations.
Alter microtubule dynamics.
Produce unattached kinetochores.
Cause long-term mitotic arrest- disorganised and vulnerable position for a prolonged period, tumour cells more easily killed.
What are the checkpoints in the cell cycle that tumours may bypass?
During G1.
Just before mitosis, to check for DNA damage.
Metaphase-anaphase checkpoint.
How is the cell cycle deregulated during tumorigenesis?
Tumours block the ability of the cells to leave the cell cycle and enter G0- once they finish mitosis, they enter another cell cycle instead.
