Download LESSON 2.2 WORKBOOK How is a cell born?

LESSON 2.2 WORKBOOK
How is a cell born?
DEFINITIONS OF TERMS
For a complete list of defined
terms, see the Glossary.
During the process of mitosis a cell replicate its DNA to create an identical ‘sister’
cell. But cells spend very little of their life cycle in mitosis; most time is spent waiting
for signals from the outside to tell the cell mitosis is necessary either to replace a
dead cell or make the tissue larger. This lesson introduces the concept of the cell’s
life cycle, describes the different phases of the cell cycle and introduces the driver
proteins that respond to signals and control progression to mitosis. When these
driver proteins become mutated so cells hyperproliferate, a tumor may form.
Why should I care about cancer?
Cell cycle – the progression of
events that prepares a cell to
replicate, and then leads to division into two daughter cells.
Mitosis – the phase of the cell
cycle in which one cell divides
into two identical daughter cells.
Wo r k b o o k
Lesson 2.2
How are cells born? Rudolph
Virchow, who we learned about in
Unit 1, put it most succinctly when
he stated, “Every cell comes from
another cell”. This means that
each cell contains a mechanism
that allows it to give birth to an
identical sibling. You have probably
learned about how the process
Figure 1: The basic steps of mitosis involve replicaof mitosis allows a cell that has
tion of DNA, then separation into two daughter cells.
duplicated its DNA to separate
that DNA into two identical cells.
But there is more to giving birth than simply the process of mitosis. Cells usually only divide when there
is a reason to do so – either because the tissue of as a whole is growing, or because a cell has died and
needs to be replaced. When a cell divides is so tightly controlled that cells spend most of their time waiting
for and responding to signals from the environment that tell them mitosis is necessary, than in the process
of mitosis itself.
MC Questions:
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1. What happens once the cell cycle is
completed?
aa. The cell dies.
bb. The cell is ready for mitosis.
cc. Two daughter cells are made.
dd. The cell has replicated its DNA.
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LESSON READINGS
We can think of the cycle of waiting and then responding to signals followed by mitosis followed by waiting
and responding again as analogous to the circle of life, and indeed it is called the cell cycle. As each cell
progresses through the cell cycle, it changes to reflect which stage of the cycle it is in. These stages can
be grouped into 4 major phases of development, which each cell must pass through before it is ready to
produce offspring during mitosis. These stages (or phases) of the cell cycle are:
■■ Gap 1 (G1) phase – the receives information from the environment that mitosis is required, and
begins to prepare
■■ Synthesis (S) phase – the cell duplicates its DNA (called its genome) in preparation for replication.
DEFINITIONS OF TERMS
■■ Gap 2 (G2) phase – the cell prepares the materials it needs for the process of mitosis.
■■ Mitosis (M) phase – the cell actually divides.
Interphase – The phases of
the cell cycle in which the cell is
preparing to undergo mitosis by
replicating its DNA and making
the proteins necessary to make
another cell.
Mitosis – the phase of the cell
cycle in which one cell divides
into two identical daughter cells.
Wo r k b o o k
Lesson 2.2
The first three phases of the cell cycle (G1,
S and G2) are collectively called interphase, which is a general term to indicate
that the cell is preparing for mitosis but not
actually dividing yet. Mitosis (also called M
phase) is when the cell actually divides. First
level biology courses tend to focus on the
process of mitosis and ignore what happens
during interphase, but interphase is critically
important because it ensures that mitosis
only takes place when and where it is
Figure 2: Cartoon depiction of the cell cycle,
needed. In fact mitosis is actually the shortInterphase is broken down into G1, S, and G2
est phase of the cell cycle and by the time
phases, followed by the process of mitosis,
which occurs in M phase.
the cell has reached the M phase, mitosis is
practically inevitable. Here we will be focusing on what happens during interphase
because losing the ability to regulate when mitosis takes place is one of the key hallmarks of cancer.
In the last lesson we emphasized that tissue is a community of cells that are sensitive to external events
such as infection and damage. Cells in the tissue community are in constant communication (we will learn
how in the next lesson) telling each other how to respond to these events to preserve tissue function.
Not surprisingly, one event that needs a quick response is when a cell gets damaged or dies, because
another cell needs to be generated to take its place. If we think back to the epithelia we studied yesterday,
if one epithelium cell dies it is crucial to replace it quickly so the lining of the tube doesn’t leak. In this case
MC Questions:
2. Which of the following is the shortest
phase of mitosis?
aa. Gap 1 phase;
bb. Synthesis phase;
cc. Gap 2 phase; or
dd. Mitosis phase.
3. Why would cells need mitogens
to promote cell growth? (Circle all
correct.)
aa. Surrounding cells are secreting
anti-mitogens.
bb. There is a need for cells to
replicate.
cc. There are too many cells in the
tissue.
dd. Mitogens promote entry into cell
cycle.
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LESSON READINGS
surrounding cells send each other signals that they need to replicate, and once the hole is plugged, they
send other signals to stop replication carrying on. Signals that promote replication (pro-growth signals)
are called mitogens. Mitogens tell cells that they should prepare for mitosis. Signals that stop replication
(anti-growth signals) are called anti-mitogens. In a mature normal tissue there will be more anti-mitogens
than mitogens. When mitosis is needed, more mitogens will be produced.
Progressing through the cell cycle: driver proteins
DEFINITIONS OF TERMS
Mitogen – a chemical signal that
tells the cell to undergo mitosis.
Anti-mitogen – a chemical
signal that tells the cell not to
undergo mitosis
Driver proteins – an intracellular protein that promotes the
progression of the cell cycle.
Cyclins – the driver proteins that
control the progression of the cell
cycle.
R point – the point in the G1
phase of the cell cycle after which
a cell no longer needs an external
signal to progress to mitosis.
Wo r k b o o k
Lesson 2.2
Another way to think of the cell cycle like a clock with gears that make the hands move. The roles of
moving gears in the cell are played by a family of proteins called the cyclins. The cyclins act as driver
proteins, because like a driver drives a car, cyclin proteins drive the cell cycle forward like gears in a
clock. Each phase of the cell cycle has its own cyclin proteins that act as gears to drive the cell through
that phase and onto the next.
■■ The G1 phase driver is called Cyclin D. Mitogens cause the cell to make cyclin D. Once enough
Cyclin D has been made the cell starts making the proteins necessary for S phase, including the first
S phase driver.
■■ The first S phase driver is called Cyclin E. Cyclin E tells the cell to make the proteins it needs to
replicate DNA as well as the second S phase driver.
■■ The second S phase driver is called Cyclin A. Cyclin A responds to successful completion of DNA
replication by telling the cells to make the proteins it needs for th G2 phase.
■■ The G2 phase and the mitosis driver is called Cyclin B. Cyclin B tells the cell to make the proteins it
needs to complete mitosis and responds to signals that mitosis has been successful.
Where do mitogens and anti-mitogens come in? Cells are responsive to mitogens and anti-mitogens at
the G1 phase of the cell cycle. At the end of the G1 phase the restriction point (or R point) marks the end
of the cell’s sensitivity to these signals. When the cell cycle reaches the R point the cell’s DNA is checked
for damage. If the DNA is undamaged the first S phase driver will be made and then the cell can progress
through the rest of the cell cycle irrespective of what signals are present in the environment. If the cell’s
DNA is damaged, the cell will spend time repairing it before passing through the R point and only start
making the first S phase driver once repair is complete. If the DNA is too damaged to repair, the cell will
essentially commit suicide (we will learn how later). The R point is like a ‘point of no return.
MC Questions:
4. How do cyclins promote progression
of the cell cycle? (Circle all correct.)
aa. Repair DNA during replication.
bb. Activate expression of proteins
necessary for next phase of cell
cycle.
cc. Promote expression of Rb.
dd. Promote expression of INK
proteins.
5. Which of the following mitogens are
activated by mitogen signals?
aa. Cyclin A.
bb. Cyclin B.
cc. Cyclin D.
dd. Cyclin E.
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LESSON READINGS
DEFINITIONS OF TERMS
Hyperproliferation – when cells
proliferate at abnormally high
levels.
Checkpoints – the transition
points between different phases
of the cell cycle where the cell
evaluates whether preparation for
replication is occurring properly.
In Figure 3 we have cut the circle seen
in Figure 2 after the mitosis phase so we
can more easily see how the amount
(level) of each driver rises and falls as the
cell moves round the cell cycle. As we
can see it is like a relay race: as the level
of one driver falls, another driver rises to
take over and drive the next phase of the
cell cycle.
Figure 3: Levels of cyclin protein within the cell
change as the cell progresses through the cell
cycle.
You may wonder – why does the cell
need so many proteins to move it through
the cell cycle? Why not just have cyclin D
do everything? Well, the more steps the cell cycle is broken down into, the more different kinds of control
can be exerted. For instance, the cell won’t want to replicate if its DNA is damaged, so having the first
S phase driver (Cyclin E) only made once the DNA has been repaired in G1 means that the cell won’t
produce damaged offspring.
Conversely, if the levels of the cyclins aren’t regulated properly so they are high all the time, the cell
would replicate constantly. Normally cells in the tissue community release anti-mitogen signals once
their numbers are at the correct levels. Cells that don’t respond to those signals and continue to replicate
irrespective of whether their DNA is damaged are said to be hyperproliferating as we saw yesterday.
Hyperproliferation is a hallmark of tumor formation.
Preventing errors in cell replication.
We have learned how dividing the cell cycle into different phases provides more opportunities for control,
We also learned that the cell cycle is like a relay race in which the levels of the driver proteins determine
the ‘hand off’ to the next phase. These hand-off points are critically important because they act as
checkpoints – where decisions are made about whether the cell is in good enough shape to move on to
the next phase of the cell cycle. The important checkpoint controls in the cell cycle occur at:
Wo r k b o o k
Lesson 2.2
■■ The transition between G1 » S aka the R point. The transition will not occur if the cell’s DNA is
damaged.
■■ The transition between S » G2. The transition will not occur if DNA has become damaged during
replication or if replication has not been completed.
MC Questions:
6. Which is a way that cells regulate cell
proliferation? (Circle all correct.)
aa. Responding to external growth
and anti-growth signals.
bb. Sequential activity of cyclins.
cc. Limiting the speed of DNA
replication.
dd. Activation of hyperproliferation.
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7. True or False: Surrounding cells
have no influence on whether a cell
enters the cell cycle or not.
aa. True.
bb. False.
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LESSON READINGS
DEFINITIONS OF TERMS
INK proteins – a family of
proteins that specifically inhibit
the activity of cyclin proteins and
prevent progression of the cell
through the cell cycle.
Retinoblastoma – a protein that
prevents entry into the cell cycle
until the cell is ready to replicate
and divide.
DNA repair proteins – proteins
that are responsible for identifying and correcting damage that
occurs to DNA.
Wo r k b o o k
Lesson 2.2
■■ The transition between G2 » M. The transition will not occur If DNA replication has not been
completed.
MC Questions:
■■ During mitosis. Mitosis will not occur if the chromosomes are not properly aligned.
8. Which of the following checkpoints
are sensitive to external anti-growth
signals? (Circle all correct.)
aa. G1 » S
bb. S » G2
cc. G2 » M
dd. Mitosis
These checkpoints are enforced by specific checkpoint proteins, which act like brakes on the drivers and
prevent progression to the next step of the cell cycle. There are two major types of checkpoint proteins
that work slightly differently INK proteins work at all the checkpoints whereas the retinoblastoma
protein (Rb) works specifically at the R point. The checkpoint proteins play an important role in preventing hyperproliferation and controlling the progression of the cell cycle. If cyclins are driver proteins, these
proteins are the brakes.
The brake proteins at each checkpoint are called INKs. The INK proteins at each checkpoint are different,
but they work in the same way: They recognize DNA damage stop the cell progressing to the next phase
of the cell cyclin by inhibiting the hand-off to the next cyclin. Once the hand-off is blocked, proteins responsible for repairing DNA damage, called DNA repair proteins, can do their maintenance work. Then the
successful repair is sensed and the INKs go away.
The R point brake protein is called Retinoblastoma (Rb). Rb is often called the ‘Gatekeeper’ of the cell
cycle because the R point is like a gate – any cell that enters the gate will go straight through the cell
cycle. At the beginning of this lesson we noted that in mature normal tissues cells the gate is shut - cells
aren’t dividing. Rb is like the latch on the gate and the signals that keep the latch down are anti-mitogens.
High enough levels of mitogens can overcome the effects of the anti-mitogens and allow the latch to open.
But if DNA is damaged, INKs will prevent the cell passing through the R point gate until DNA is repaired.
DNA repair proteins are not completely successful but only a few random mutations escape control when
a cell divides (~75 mutations out of 6.4 billion nucleotides at each cell duplication). On the other hand, if
DNA damage is irreparable, this will lead to cell death (more on that later in this Unit).
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9. Which of the following is an outcome
of DNA damage to the cell? (Circle all
correct.)
aa. Activation of INK proteins.
bb. Activation of mitogen proteins.
cc. Activation of cyclins.
dd. Activation of DNA repair
proteins.
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STUDENT RESPONSES
Give 2-3 changes to the control of cellular replication that could occur in a cell that results in hyperproliferation.
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Remember to identify your
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Wo r k b o o k
Lesson 2.2
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TERMS
TERM
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 2.2
DEFINITION
Anti-mitogen
A chemical signal that tells the cell not to undergo mitosis.
Cell cycle
The progression of events that prepares a cell to replicate, and then leads to division into two daughter cells.
Checkpoints
The transition points between different phases of the cell cycle where the cell evaluates whether preparation
for replication is occurring properly.
Cyclins
A family of proteins that control the progression of the cell cycle.
DNA repair proteins
Proteins that are responsible for identifying and correcting damage that occurs to DNA.
Driver proteins
An intracellular protein that promotes the progression of the cell cycle.
Hyperproliferation
When cells proliferate at abnormally high levels.
INK proteins
A family of proteins that specifically inhibit the activity of cyclin proteins and prevent progression of the cell
through the cell cycle.
Interphase
The phases of the cell cycle in which the cell is preparing to undergo mitosis by replicating its DNA and
making the proteins necessary to make another cell.
Mitogen
A chemical signal that tells the cell to undergo mitosis.
Mitosis
The phase of the cell cycle in which one cell divides into two identical daughter cells.
Retinoblastoma
A protein that prevents entry into the cell cycle until the cell is ready to replicate and divide.
R point
The point in the G1 phase of the cell cycle after which a cell no longer needs an external signal to progress
to mitosis.
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