Download Cell Cycle 1

Cell Cycle 1 – The Cell Cycle
Anil Chopra
1. Describe the cell cycle in terms of the named phases (G0, G1, G2, S, M) and
explain what these mean in terms of protein and DNA synthesis.
2. Identify (or sketch or describe) the named stages of mitosis.
3. Explain the importance of checkpoints in controlling progression through the cell
cycle, and give examples of external factors which provide signals allowing cells
to pass these checkpoints and enter cell division.
4. Give examples of the different rates of cell division found for cells in different
tissues and under different physiological and pathological conditions.
5. Describe the way the cell cycle allows decision making about
whether a cell divides, differentiates or undergoes programmed cell
death (apoptosis).
Cells divide at different rates depending on:
- Whether they are embryonic or adult cells
- How complex the system is
- The necessity for renewal
- State of differentiation
- If they are tumour cells
The Cell Cycle Process
2 main phases:
Interphase – the cell is metabolising, duplicating its organelles, and synthesising
proteins.
M-Phase / Mitosis – where the nucleus divides and the cell divides by cytokinesis. It
is also the most vulnerable period in the cell cycle as cells are most easily killed by
heat/radiation, DNA damage cannot be repaired and gene transcription is unable to
take place.
Mitosis is essential because:
- premature mitosis results in cell death
- most tumours are aneuploid (abnormal chromosome numbers) and
chromosomal instability
- changes in the regulators of the cell cycle are found in tumour cells
- attacking the machinery that regulates chromosome segregation is one of the
most successful anti-cancer strategies in clinical use.
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
S Phase
 Where replication of DNA and organelles occurs.
 The time of protein synthesis – initiation of translation and elongation increased,
capacity is also increased.
Mitosis
Prophase
 The replicated chromosomes condense.
 They migrate to opposite sides of the nucleus.
 The mitotic fibres form between then 2 centrosomes
o Consists of two centrioles (barrels of nine triplet microtubules)
o Is the primary microtubule organizing centre (MTOC)
kinetochore
centromere
Sister chromatids
 Condensed chromosomes form: 2 sister chromatids, each
with a kinetochore
 Spindle fibers form:
o Radial microtubule arrays from around the
centrosome.
o These arrays meet up.
o Polar microtubules form between them.
o These are all in a dynamic state.
Metaphase
 The chromosomes align along the equator of the spindle.
Early Prometaphase
 Break down of the nuclear membrane.
 Microtubules grow and shrink in aster (the spindles around the
centrosomes).
 The chromosomes attach to the spindles via the kinetochore – at the
centromere part of the chromosome
Late Prometaphase
 Microtubules from opposite poles are captured by sister kinetochores
causing the chromosomes attached to each pole to congress to the middle.
 Chromosomes slide rapidly towards the centre along microtubules.
The microtubules are in a DYNAMIC state.
Anaphase
 The paired chromatids are separated forming two daughter chromosomes.
 This is done by the breakdown of “cohesion” – a molecule that holds the chromatids
together.
 The daughter chromatids are pulled to the opposite spindle poles by a process called
“treadmilling”.
o Tubulin monomers are added to
the plus + end of the
microtubule.
o The same number of monomers
is lost at the minus – end.
o This results in the movement of
the kinetochore attached to the
microtubules.
Telophase
 Daughter
chromosomes
arrive at the
spindle.
 Nuclear envelope
reassembles at each pole.
 Contractile ring of actin and myosin filaments forms.
Mitotic Checkpoints
At various stages in the cell cycle – the chromosomes are checked for abnormalities:
Spindle Assembly Checkpoint: Senses completion of chromosome alignment and
spindle assembly (monitors kinetochore activity) and takes place during
Prometaphase and metaphase. It requires centromere protein E (CENP-E) and BUB
protein kinases. They dissociate from the kinetochore when they attach to the spindle.
If this checkpoint fails, aneuploidy can result. This is because, one of the
chromosomes will fail to dissociate.
Aneuploidy can also result from mis-attachment of microtubules to kinetochores.
This can result in one of three kinds of attachment:
Amphelic: normal attachment, each microtubule to a kinetochore from different
centromeres.
Syntelic: both kinetochores are attached to microtubules from the same centromere,
which results in both sister chromatids going to the same pole.
Merotelic: more than one microtubule attaches to the same kinetochore. This results
in chromosome loss during cytokinesis.
Aneuploidy can also result form aberrant mitosis:
This is where the cell cycle, either at the point of spindle fibre
attachment, or during cytokinesis.
Anti-Cancer Therapy can involve Inducing Gross Chromosome
Mis-segregations
Taxanes & Vinca Alkaloids: mitotic inhibitors. Essentially they
“freeze” mitosis because they alter the dynamics of microtubules to
produce un-attached kinetochores.
At the end of mitosis cells can either enter G0 or G1 depending on whether or not
growth factors are present.
In G0 the cell is not dormant, it continues to perform its role.
In G1, the longest and most variable phase of the cell cycle, the cell literally grows,
protein and organelle synthesis occurs whilst growth factors are present (they have to
be continually present). There is a check-point at the end of G1.
In G2 there is a gap between DNA replication and mitosis. If the cell is not big
enough, then the phases are delayed i.e. mitotic arrest. When DNA is slightly
damaged cell cycle arrest can occur (i.e. G2 is longer), but if it is severely damaged,
then apoptosis occurs.