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Chapter 8—Cell Division Lecture Outline I. All Cells Come from Preexisting Cells via Cell Division A. Meiosis is cell division that occurs only in reproductive cells. 1. The nuclei of cells generated by meiosis have half the chromosomes of the parent cell. 2. Daughter cells generated by meiosis are genetically different than the parent cells. B. Mitosis is cell division that happens in all cells. 1. Mitosis generates daughter cells that are genetically identical to the parent cell. 2. Mitosis is responsible for growth and repair in multicellular organisms. II. Most Cells Experience a Cell Cycle Including Several Phases Leading Up to Cell Division A. How do cells pass on their genetic information during cell division? 1. Walther Flemming discovered that thread-like structures (chromosomes) in the nucleus change and move during cell division. (Fig. 8.1) a. He found that the threads paired before cell division. b. He found that the pairs split during division and were isolated into new cells. 2. Edouard van Beneden found that chromosome number ultimately remained constant during a sequence of cell divisions. 3. W. Waldeyer called the threads chromosomes. (Fig. 8.2) B. Cells do not divide constantly, but cycle through several preparatory phases (the cell cycle). 1. M phase, or mitosis, is the phase of cell cycle in which cell division occurs. 2. Interphase is the time of the cell cycle during which the cell is not dividing. C. When does DNA replication occur during the cell cycle? (Fig. 8.3) 1. Alma Howard and Stephen Pelc used radioactively labeled nucleotides to study DNA replication. a. Experimental Design (1) They gave cultured mammalian cells radioactive thymidine and nonradioactive adenosine, guanosine, and cytidine for 30 minutes. (2) Then they washed out the radioactive thymidine and exposed the cells to nonradioactive nucleotides. (3) At various time periods after exposure to radioactive thymidine, the researchers removed a sample of cells from the culture and exposed them to x-ray film. (4) Black dots appeared where there were chromosomes that had radioactive thymidine incorporated. (5) Any chromosome with radioactive thymidine could be considered a “newly synthesized” chromosome. b. Results (Fig. 8.4) (1) Immediately after exposure, all of the radioactive thymidine was incorporated into cells that were in interphase, not mitosis. (2) M-phase cells appeared 4 to 5 hours after the radioactive thymidine exposure. (3) Cells undergoing mitosis were seen for 6 to 8 hours after the radioactive thymidine exposure. c. Conclusions (1) Because the radioactive thymidine would be incorporated only during the replication phase, the researchers concluded that DNA replication occurs during interphase. (2) They called the time when DNA is synthesized the S phase. (3) Because there was a 4- to 5-hour lag time between when they exposed the cells to the radioactive thymidine and they observed mitosis, they concluded that there is an intervening phase, which they called G 2. (4) Because they observed M-phase cells for 4 to 5 hours after the radioactive thymidine exposure, they concluded that was the duration of mitosis. (5) Because the entire cell cycle lasted about 18 to 24 hours, they concluded that the length of time between the end of mitosis and the next synthesis phase was 7 to 9 hours. They called this G1. (Fig. 8.5) III. During Mitosis, Chromosome Copies Are Separated and Packaged into Two New Cells A. Chromosome Structure—Packaged for Movement (Fig. 8.6) 1. DNA is complexed with proteins into chromatin. 2. At the beginning of mitosis, chromatin condenses to form a compact, mobile structure. a. Each replicated chromosome is called a chromatid. b. Each set of chromatids is joined at a centromere. c. Chromatids from the same chromosome are called sister chromatids. 3. During mitosis, sister chromatids separate to form independent chromosomes. B. Prophase—The Preparation Phase (Fig. 8.8) 1. DNA condenses. 2. The mitotic spindle is built. a. Mitotic spindles are built from microtubules. b. In animals, mitotic spindles arise from centrosomes. c. Mitotic spindles extend into the center of the cell toward the nucleus. 3. The nuclear envelope breaks down. 4. Spindle fibers from each centrosome attach to one of a pair of sister chromatids at the kinetochore. 5. The centrosomes begin moving to opposite poles of the cells. C. Metaphase—The Organizing Phase (Fig. 8.8) 1. The centrosomes complete their migration and reach the opposite poles. 2. This results in all of the chromosomes becoming lined up with their kinetochores at the metaphase plate. D. Anaphase—Separating DNA Copies (Fig. 8.8) 1. Spindles attached to kinetochores begin to shorten. 2. This exerts a force on the sister chromatids that pulls them apart. 3. Spindle fibers continue to shorten, pulling chromatids to opposite poles. 4. This ensures that each daughter cell gets identical sets of chromosomes. E. Telophase and Cytokinesis—Finishing the Task (Fig. 8.8) 1. Telophase a. Nuclear envelope re-forms around the two new nuclei. b. The spindle fibers break down. 2. Cytokinesis (Fig. 8.9) a. In animals a cleavage furrow forms between the two new nuclei. (1) This is made from a ring of actin and myosin microfibrils that surround the inside circumference of the cell. (2) The microfilaments contract, causing the cell membrane to constrict and pinch the cell in two. b. In plants, a cell plate forms. (1) Vesicles from the Golgi apparatus carrying cell-wall material migrate to the middle of the cell between the two new nuclei. (2) The vesicles build up and fuse, forming a new cell membrane and cell wall dividing the two new nuclei. IV. Chromosome Separation Is the Key Event of Mitosis A. Mitotic spindle fibers are the railroad tracks for chromosome movement. 1. Spindle fibers are made of microtubules. a. Microtubules are lengthened and shortened by the addition and loss of tubulin subunits. b. Mitotic spindle shortening during anaphase is a result of the loss of tubulin subunits. (1) Gary Borisy and colleagues studied this process using fluorescently labeled tubulin subunits to visualize spindle fibers. (2) They found that spindle fibers were shortening at the end connected to the kinetochore. B. A kinetochore motor is the engine that drives chromosome movement. 1. Multiple studies have shown that the kinetochore contains motor proteins that can “walk” along the spindle fiber during anaphase. 2. These proteins presumably remove tubulin subunits, shortening spindle fibers and facilitating the chromosome movement. V. The Cell Cycle Is Regulated at Several Points A. Cell types differ in the length of time they are in the G1 phase. 1. Nondividing cells stay in G1-like phase called G0 indefinitely. 2. Other cells divide only when triggered by external cues. B. What is the signal that switches the cell from one cell cycle phase to the next? (Fig. 8.10) 1. Potu Rao and Robert Johnson used cell fusion experiments to identify the existence of a molecular cell cycle switch in cells. (Fig. 8.12) a. Experimental Design: (1) Rao and Johnson fused two cells from different mammalian species to form a heterokaryon. (2) They fused two cells that were in different stages of the cell cycle. b. Results (1) When a cell in mitosis was fused with a cell in interphase, the nucleus of the interphase cell began to enter M phase. (2) When an S-phase cell was fused with a cell in G1, the cell in G1 began replicating its DNA. c. Conclusions—These experiments suggested that something in the cells that were undergoing M and S phases was able to initiate those phases in other cells. 2. Masui and Markert used frog eggs to further these experiments. a. Experimental Design (1) The researchers extracted cytoplasm from frog eggs going through various stages of the cell cycle and injected it into cells at various stages of the cell cycle. (Fig. 8.13) b. Results (1) When they injected cytoplasm from an egg in M phase into a cell in G2, the G2-phase eggs entered M phase. (2) The cytoplasm from an interphase cell could not remove the G 2-phase cells from their current phase. c. Conclusions—These experiments demonstrated that there was some molecular signal in the cytoplasm that initiated mitosis. d. This factor came to be known as M phase-promoting factor (MPF). (1) MPF is comprised of two polypeptide subunits. (2) One polypeptide functions as a protein kinase that can activate and inactivate other proteins by phosphorylation. (Fig. 8.14) This subunit is expressed at constant levels throughout the cell cycle. (3) The other subunit is a cyclin whose concentration fluctuates throughout the cell cycle. (4) When cyclin levels are high, it binds with the kinase (cyclin-dependent protein kinase, or Cdk) to form active MPF. (Fig. 8.15) C. Cell-cycle regulatory molecules form cell-cycle checkpoints. (Fig. 8.16) 1. Different sets of cyclins and Cdks are involved at each phase shift during the cell cycle. 2. Three main switches occur during the cell cycle, and they are called cell-cycle checkpoints. a. The G1 checkpoint ensures that the cell is large enough to divide, and that enough nutrients are available to support the resulting daughter cells. b. The G2 checkpoint ensures that DNA replication in S phase has been completed successfully. c. The metaphase checkpoint ensures that all of the chromosomes are attached to the mitotic spindle by a kinetochore. VI. When the Cell Cycle Is Not Regulated, Cancer Results A. All cancers have some common properties. 1. All cancers involve uncontrolled cell growth that results in the formation of a mass of cells called a tumor. 2. Cancerous cells not only form tumors, but actually leave the original site of growth and invade other organs. This movement is called metastasis. (Fig. 8.17) B. Cancer is a result of failing cell-cycle checkpoints. 1. Understanding the normal cell cycle is crucial to understanding the failure that occurs during cancer. (Fig. 8.18) a. Most cells leave the G1 phase because they receive a signal from neighboring cells. Researchers have termed this social control. b. Growth factors are intercellular signals that can trigger cells to pass the G 1 checkpoint. (1) Growth factors trigger an increase in expression of the cyclin that is involved in the G1 checkpoint. (2) When the concentration of this cyclin increases, the cyclin molecules bind with the appropriate Cdk; the cell then moves into S-phase, thus becoming committed to divide. 2. In certain cancers, the G1 checkpoint does not work properly. a. This causes the cell to move through G1 too quickly and divide too often. b. Retinoblastoma is an example of this. (1) The cyclin/Cdk complex involved in the G1 checkpoint is an active kinase that activates and inactivates target proteins by phosphorylation. (2) In the retina, one of the target proteins is the Rb protein that normally serves as a brake to the cell cycle. (3) Rb is inactivated when phosphorylated, thus allowing the cell cycle to continue. (4) In retinoblastoma, the Rb protein is dysfunctional, so that the cell never experiences a G1 checkpoint and cell division is constant. C. Cancers arise only after many defects have accumulated. 1. Inherited cancers involve mutated genes acquired from one parent. 2. But one undamaged copy of a gene is often enough to provide adequate cell cycle control. 3. Additional mutations or mitotic errors must result in a cell receiving two copies of the damaged allele. (Fig. 8.19)