LESSON 2.2 WORKBOOK. How is a cell born? Workbook Lesson 2.2

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1 For a complete list of defined terms, see the Glossary. 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. LESSON 2.2 WORKBOOK How is a cell born? 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? 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 of mitosis allows a cell that has duplicated its DNA to separate that DNA into two identical cells. Figure 1: The basic steps of mitosis involve replication of DNA, then separation into two daughter 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 replace 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. 1. What happens once the cell cycle is completed? The cell dies. The cell is ready for mitosis. Two daughter cells are made. The cell has replicated its DNA. 50

2 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. 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 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. Gap 2 (G2) phase the cell prepares the materials it needs for the process of mitosis. Mitosis (M) phase the cell actually divides. 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, neede In fact mitosis is actually the shortest phase of the cell cycle and by the time phases, followed by the process of mitosis, Interphase is broken down into G1, S, and G2 the cell has reached the M phase, mitosis is which occurs in M phase. 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 2. Which of the following is the shortest phase of mitosis? Gap 1 phase; Synthesis phase; Gap 2 phase; or Mitosis phase. 3. Why would cells need mitogens to promote cell growth? (Circle all correct.) Surrounding cells are secreting anti-mitogens. There is a need for cells to replicate. There are too many cells in the tissue. Mitogens promote entry into cell 51

3 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 Cyclins the driver proteins that control the progression of the cell 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. 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 produce Progressing through the cell cycle: driver proteins 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 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. 4. How do cyclins promote progression of the cell cycle? (Circle all correct.) Repair DNA during replication. Activate expression of proteins necessary for next phase of cell Promote expression of R Promote expression of INK proteins. 5. Which of the following mitogens are activated by mitogen signals? Cyclin A. Cyclin B. Cyclin D. Cyclin E. 52

4 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 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 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 exerte 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. Figure 3: Levels of cyclin protein within the cell change as the cell progresses through the cell 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 The important checkpoint controls in the cell cycle occur at: The transition between G1» S aka the R point. The transition will not occur if the cell s DNA is damage The transition between S» G2. The transition will not occur if DNA has become damaged during replication or if replication has not been complete 6. Which is a way that cells regulate cell proliferation? (Circle all correct.) Responding to external growth and anti-growth signals. Sequential activity of cyclins. Limiting the speed of DNA replication. Activation of hyperproliferation. 7. True or False: Surrounding cells have no influence on whether a cell enters the cell cycle or not. True. False. 53

5 INK proteins a family of proteins that specifically inhibit the activity of cyclin proteins and prevent progression of the cell through the cell 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. The transition between G2» M. The transition will not occur If DNA replication has not been complete During mitosis. Mitosis will not occur if the chromosomes are not properly aligne 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 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 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 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 repaire 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). 8. Which of the following checkpoints are sensitive to external anti-growth signals? (Circle all correct.) G1» S S» G2 G2» M Mitosis 9. Which of the following is an outcome of DNA damage to the cell? (Circle all correct.) Activation of INK proteins. Activation of mitogen proteins. Activation of cyclins. Activation of DNA repair proteins. 54

6 STUDENT RESPONSES Give 2-3 changes to the control of cellular replication that could occur in a cell that results in hyperproliferation. Remember to identify your sources 55

7 TERMS For a complete list of defined terms, see the Glossary. TERM Anti-mitogen Cell cycle Checkpoints Cyclins DNA repair proteins Driver proteins Hyperproliferation INK proteins Interphase Mitogen Mitosis Retinoblastoma R point DEFINITION A chemical signal that tells the cell not to undergo mitosis. The progression of events that prepares a cell to replicate, and then leads to division into two daughter cells. The transition points between different phases of the cell cycle where the cell evaluates whether preparation for replication is occurring properly. A family of proteins that control the progression of the cell Proteins that are responsible for identifying and correcting damage that occurs to DNA. An intracellular protein that promotes the progression of the cell When cells proliferate at abnormally high levels. A family of proteins that specifically inhibit the activity of cyclin proteins and prevent progression of the cell through the cell 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. A chemical signal that tells the cell to undergo mitosis. The phase of the cell cycle in which one cell divides into two identical daughter cells. A protein that prevents entry into the cell cycle until the cell is ready to replicate and divide. The point in the G1 phase of the cell cycle after which a cell no longer needs an external signal to progress to mitosis. 56