CONTROL OF THE CELL CYCLE
If it wasn't controlled, your cells would continue to grow
and divide...over and over again!
A number of proteins regulate and control the cell cycle.
Tell the cell when is the proper time to grow and divide,
Stop the cell when the time's not right.
Clinically, cancer can be described as uncontrolled cell growth
and proliferation
Understanding cell cycle control has many implications for
cancer, especially for the development of therapeutics.
http://cancerquest.org/index.cfm?page=2463#
If it wasn't controlled, your cells would continue to grow
and divide...over and over again!
A number of proteins regulate and control the cell cycle.
Tell the cell when is the proper time to grow and divide,
Stop the cell when the time's not right.
Clinically, cancer can be described as uncontrolled cell growth
and proliferation
Understanding cell cycle control has many implications for
cancer, especially for the development of therapeutics.
Control of the cell cycle
CONTROL OF THE CELL CYCLE
Three checkpoints:
The G1/S cell cycle checkpoint
G2/M DNA damage checkpoint
Mitosis checkpoint
Animation
G1/S cell cycle checkpoint
controls the passage of eukaryotic cells from the first 'gap'
phase (G1) into the DNA synthesis phase (S).
Checks:
That the size is CORRECT
That the environment is CORRECT
External agents regulate progression
Kinases – add a phosphate group (phosphorylate)
G1/S cell cycle checkpoint
How do they do that?
Major proteins involved:
Cyclins (proteins) - level fluctuate in the cell cycle.
&
Cyclin dependent KINASES* (Cdks)
They add phosphate groups to proteins that control processes in
the cell cycle.
They only do this when the cyclins are present.
*Kinases – add a phosphate group (phosphorylate)
FLICKING THE SWITCH ON
External Controls?
Many different stimuli exert G1 checkpoint control including
DNA damage, contact inhibition and growth factor withdrawal.
They act to inhibit kinases (in a mechanism similar to Jacob
Monod).
Growth factors, promoting cell division, stimulate transcription
of Cyclins
A key characteristic of stem cells is that they can divide for long periods
of time in an environment where most other cells are quiescent,
prompting the question of how they overcome the G1/S checkpoint of
the cell cycle. Hatfield et al. used fruit fly germline stem cells carrying a
mutation in dicer-1, a gene essential for miRNA biogenesis, to show
that miRNAs are required for stem cells to bypass the G1/S checkpoint.
This suggests that miRNAs may be involved in the mechanism that
makes stem cells insensitive to environmental stimuli that would
normally halt most cells at the G1/S checkpoint. The implication is that
the mechanism used by stem cells to overcome this checkpoint could
possibly be usurped by tumor cells.
G2/M DNA damage checkpoint
The G2/M DNA damage checkpoint prevents the cell
from entering mitosis (M phase) if the genome is damaged.
It also checks if the cell is big enough (i.e. has the resources to
undergo mitosis)
Almost exclusively, internally controlled
Kinases – add a phosphate group (phosphorylate)
M checkpoint
The M checkpoint is where the attachment of the spindle
fibres to the centromeres is assessed.
Only if this is correct can mitosis proceed.
Failure to attach spindle fibres correctly would lead to failure to
separate chromosomes
Kinases – add a phosphate group (phosphorylate)
MITOSIS PROMOTING FACTOR
Fusion of mitotic cell with cells in other stages of the cell-cycle
causes chromosomes of the other cell to condense and the nucleus
to breakdown.
Mitotic cells must contain a mitosis -promoting factor (MPF) –
produced at the end of G2?
MPF may:
• phosphorylate histone protein H1 to condense chromatin.
• phosphorylate nuclear lamins to break nuclear envelope.
•phosphorylate MAPs (microtubule-associated proteins)
resulting in the formation of spindle
Summary of Controls:
Three checkpoints,
G1 – assesses cell size, environment (contact inhibition)
G2 – assesses success of DNA replication
M – assesses have spindle fibres attached correctly to
the chromosomes
Mitosis promoting factor - a protein (or number of
proteins) which causes chromosomes to condense,
nuclear membrane to disappear and so cells to
enter mitosis
http://science.education.nih.gov/supplements/nih1/cancer/activities/activity2_animations.htm
http://nobelprize.org/educational_games/medicine/2001/index.htmll
http://cancerquest.org/index.cfm?page=193#
http://www.biology.arizona.edu/cell_bio/tutorials/cell_cycle/main.html
http://nobelprize.org/medicine/educational/2001/index.html