Download The Cell Cycle Control

The Cell Cycle Control
(Lecture 23)
The timing and rate of cell division differ between different organisms and also between different cells
of an organism.
Compare skin cells with muscle or nerve cells.
What is controlling the rate of cell division, how cells “know” that it is time to divide?
Why cancer cells do not stop dividing?
The cell cycle is regulated at the molecular level
Accumulating experimental evidences appearing since early seventies suggested that the cell cycle is
driven by specific chemical signals present in the cytoplasm.
Most of the experiments were conducted with cell cultures.
Many types of animal and plant cells can be removed from an organism and cultured in an artificial
environment.
Cell cycle is controlled !
Cultured mammalian cells can be induced to fuse, forming a single cell with two nuclei.
The results of fusing cells at two different phases of the cell cycle suggested that particular chemicals
control the progression of phases.
For example, when a cell in M phase was fused with one in any other phase, the nucleus from the
latter cell immediately began mitosis.
If the second cell was in G1, the condensed chromosomes that appeared had single chromatids.
Cell-cycle control system
These experiments suggested that events happening from one cell division to another are driven by
cell-cycle control system,
a cyclically operating set of molecules in the cell that triggers and coordinates key events in the cell
cycle
When and how is the cell cycle controlled?
Short summary of interphase
• Comprised by three (four) subphases: G1, (G0), S and G2 .
• Common feature of all (except G0) subphases: growth of the cell by producing proteins and
cytoplasmic organelles.
• G1 – “first gap”
• S phase – chromosome duplication
• G2 – “second gap”, DNA repair
Cell cycle is controlled !
G1 nucleus is competent to replicate. S-phase cells contain activator
G2 nuclei aren’t competent and do not re-replicate. G2 cells do not inhibit replication. S-phase nuclei
retard mitosis in G2 nuclei.
G2 cells do not suppress S-phase entry of G1-phase nuclei.
Cell cycle control
A checkpoint in the cell is a critical control point where stop and go signals can regulate the cycle
Animal cells have built-in “stop” signals that halt the cell cycle at checkpoints until overridden by
“go” signals
To function properly checkpoint signals have to percept “reports” from crucial cellular processes:
have it been completed correctly and should the cell cycle proceed.
Checkpoint also register signals from outside the cell
The most important decision to make is: to continue the cell division after the exit from M phase or
not.
Cells that do not receive the “go” signal at the G1 checkpoint, switch into a nondividing state called
the G0 phase.
A good example of quiescent cells are liver cells.
They can be called back to the cell cycle by growth factors released during injury.
Cyclins and cyclin-dependent kinases (Cdks)
Regulatory molecules of the cycle transition are proteins of two main types: protein kinases and
cyclins.
Protein kinases are proteins that regulate the activity of the others by phosphorylating them.
“Go” signal at the G1 and G2 checkpoints is regulated by particular protein kinases.
To be active, such a kinase must be attached to a cyclin, a protein that gets its name from its cyclically
fluctuating concentration in the cell
This kinases are called cyclin-dependent kinases – Cdks.
Control at the G2 checkpoint
The stepwise processes of the cell cycle are timed by
rhythmic fluctuations in the activity of protein kinases.
These enzymes are called cyclin-dependent kinases (Cdks) because they are active only when bound
to a cyclin, a protein whose concentration varies cyclically.
Cdk-cyclin complex called MPF, acts at the G2 checkpoint to trigger mitosis.
(a) The graph shows how MPF activity fluctuates with the level of cyclin in the cell.
The cyclin level rises throughout interphase (G1, S, and G2 phases),
then falls abruptly during mitosis (M phase).
The Cdk itself is present at a constant level.
(b)
1. By the G2 checkpoint (red bar), enough cyclin is available to produce many molecules of MPF.
2. MPF promotes mitosis by phosphorylating various proteins, including other enzymes.
3. One effect of MPF is the initiation of a sequence of events leading to the breakdown of its own
cyclin.
4. The Cdk component of MPF is recycled.
Its kinase activity will be restored by association with new cyclin that accumulates during interphase.
Internal regulation
Internal signals: messages from kinetochores.
Anaphase, the separation of sister chromatids, does not begin until all the chromosomes are properly
attached to the spindle at the metaphase plate.
Certain associated proteins trigger a signalling pathway that keeps an anaphase promoting complex
(APC) in an inactive state.
M-phase checkpoint is the gatekeeper.
Only when all the kinetochores are attached to the spindle does the “wait” signal cease.
External regulation
External signals: growth factors.
Most of mammalian cells divide in culture only if the growth medium includes specific growth
factors.
PDGF – platelet-derived growth factor – is required for the division of fibroblasts.
Density-dependent inhibition of cell division, a phenomenon in which crowded cells stop dividing.
Cultured cells normally divide until they form a single layer of cells on the inner surface of the
culture container.
Anchorage dependence: to divide, cells must be attached to a substratum (extracellular matrix of a
tissue).
Anchorage is signalled to the cell-cycle control system via plasma membrane proteins and elements
of the cytoskeleton linked to them.
Cancer cells
If the cell evades destruction, it may proliferate to form a tumor, a mass of abnormal cells.
Benign tumor is localised at original site, malignant tumor becomes invasive.
The spread of cancer cells beyond their original site is called metastasis.
The growth and metastasis of a malignant breast tumor
The cells of malignant (cancerous) tumors grow in an uncontrolled way and can spread to
neighboring tissues and, via the circulatory system, to other parts of the body.
The spread of cancer cells beyond their original site is called metastasis.
Summary
• Cell cycle regulation
– everything is under the control of CdkC:
association of the kinases with cyclines support unidirectional cell cycle progression
with the main influences at G1, G2 and M phases.
Reading
Ch. 12 pp.228-235.