The Cell Cycle PDF

Superset The Cell Cycle 12 Figure 12.1 How do dividing cells distribute chromosomes to daughter cells? Key Concepts The Key Roles of Cell Division...

Superset The Cell Cycle 12 Figure 12.1 How do dividing cells distribute chromosomes to daughter cells? Key Concepts The Key Roles of Cell Division The ability of organisms to produce more of their own kind is the one characteristic 12.1 Most cell division results in genetically identical daughter cells that best distinguishes living things from nonliving matter. This unique capacity to procreate, like all biological functions, has a cellular basis. In 1855, Rudolf Virchow, 12.2 The mitotic phase alternates a German physician, put it this way: “Where a cell exists, there must have been a pre- with interphase in the cell cycle existing cell, just as the animal arises only from an animal and the plant only from 12.3 The eukaryotic cell cycle is a plant.” He summarized this concept with the Latin saying “Omnis cellula e cellula,” regulated by a molecular meaning “Every cell from a cell.” The continuity of life is based on the reproduction of control system cells, or cell division. The series of confocal fluorescence micrographs in Figure 12.1, starting at the upper left and reading from left to right, follows the events of cell divi- Chromosomes (blue) are attached by specific proteins (green) to cell machinery sion as the cells of a two-celled marine worm embryo become four. (red) and are moved during division of a Cell division plays several important roles in life. When a prokaryotic cell rat kangaroo cell. divides, it is actually reproducing, since the process gives rise to a new organism (another cell). The same is true of any unicellular eukaryote, such as the amoeba shown in Figure 12.2a. As for multicellular eukaryotes, cell division enables each of these organisms to develop from a single cell—the fertilized egg. A two-celled embryo, the first stage in this process, is shown in Figure 12.2b. And cell division continues to function in renewal and repair in fully grown multicellular eukaryotes, replacing cells that die from accidents or normal wear and tear. For example, divid- ing cells in your bone marrow continuously make new blood cells (Figure 12.2c). When you see this blue icon, log in to MasteringBiology Get Ready for This Chapter and go to the Study Area for digital resources. 234  Figure 12.2 The functions of cell division. is passed from one generation of cells to the next. A dividing ◀ (a) Asexual reproduction. cell replicates its DNA, distributes the two copies to opposite 100 μm An amoeba, a single-celled ends of the cell, and then splits into daughter cells. eukaryote, is dividing into two cells. Each new cell will be an individual Cellular Organization of the Genetic Material organism (LM). A cell’s DNA, its genetic information, is called its genome. Although a prokaryotic genome is often a single DNA mol­ 50 μm ecule, eukaryotic genomes usually consist of a number of DNA molecules. The overall length of DNA in a eukaryotic ▶ (b) Growth and develop- cell is enormous. A typical human cell, for example, has about ment. This micrograph shows a sand dollar 2 m of DNA—a length about 250,000 times greater than the embryo shortly after the cell’s diameter. Before the cell can divide to form genetically fertilized egg divided, forming two cells (LM). identical daughter cells, all of this DNA must be copied, or replicated, and then the two copies must be separated so that each daughter cell ends up with a complete genome. The replication and distribution of so much DNA are man- ageable because the DNA molecules are packaged into struc- tures called chromosomes (from the Greek chroma, color, and soma, body), so named because they take up certain dyes ◀ (c) Tissue renewal. These used in microscopy (Figure 12.3). Each eukaryotic chromo- dividing bone marrow cells 20 μm will give rise to new blood some consists of one very long, linear DNA molecule associ- cells (LM). ated with many proteins (see Figure 6.9). The DNA molecule Cell Division in a Sea Urchin Embryo carries several hundred to a few thousand genes, the units of information that specify an organism’s inherited traits. The associated proteins maintain the structure of the chromo- The cell division process is an integral part of the cell some and help control the activity of the genes. Together, cycle, the life of a cell from the time it is first formed during the entire complex of DNA and proteins that is the building division of a parent cell until its own division into two daugh- material of chromosomes is referred to as chromatin. As ter cells. (Biologists use the words daughter or sister in relation you will soon see, the chromatin of a chromosome varies in to cells, but this is not meant to imply gender.) Passing identi- its degree of condensation during the process of cell division. cal genetic material to cellular offspring is a crucial function Every eukaryotic species has a characteristic number of of cell division. In this chapter, you will learn how this process chromosomes in each cell’s nucleus. For example, the nuclei occurs in the context of the cell cycle. After studying the cellu- of human somatic cells (all body cells except the reproduc- lar mechanics of cell division in eukaryotes and bacteria, you tive cells) each contain 46 chromosomes, made up of two sets will learn about the molecular control system that regulates progress through the eukaryotic cell cycle and what happens Figure 12.3 Eukaryotic chromosomes. Chromosomes (stained when the control system malfunctions. Because a breakdown purple) are visible within the nucleus of this cell from an African blood in cell cycle control plays a major role in the development of lily. The thinner red threads in the surrounding cytoplasm are the cytoskeleton. The cell is preparing to divide (LM). cancer, this aspect of cell biology is an active area of research. Concept 12.1 Most cell division results in genetically identical daughter cells The reproduction of a cell, with all of its complexity, cannot occur by a mere pinching in half; a cell is not like a soap bub- ble that simply enlarges and splits in two. In both prokaryotes and eukaryotes, most cell division involves the distribution of identical genetic material—DNA—to two daughter cells. (The exception is meiosis, the special type of eukaryotic cell divi- sion that can produce sperm and eggs.) What is most remark- able about cell division is the accuracy with which the DNA 20 μm chapter 12 The Cell Cycle 235 of 23, one set inherited from each parent. Reproductive cells, Figure 12.4 A highly condensed, duplicated human or gametes—such as sperm and eggs—have half as many chromosome (SEM). chromosomes as somatic cells; in our example, human gam- etes have one set of 23 chromosomes. The number of chro- mosomes in somatic cells varies widely among species: 18 in Sister chromatids cabbage plants, 48 in chimpanzees, 56 in elephants, 90 in hedgehogs, and 148 in one species of alga. We’ll now con- sider how these chromosomes behave during cell division. Centromeres, one on each sister chromatid 0.5 μm Distribution of Chromosomes During DRAW IT Circle one sister chromatid of the chromosome in this micrograph. Eukaryotic Cell Division When a cell is not dividing, and even as it replicates its DNA chromosomes identical to that of the parent cell (Figure 12.5). in preparation for cell division, each chromosome is in the Mitosis, the division of the genetic material in the nucleus, form of a long, thin chromatin fiber. After DNA replication, is usually followed immediately by cytokinesis, the division however, the chromosomes condense as a part of cell divi- of the cytoplasm. One cell has become two, each the genetic sion: Each chromatin fiber becomes densely coiled and folded, equivalent of the parent cell. making the chromosomes much shorter and so thick that we From a fertilized egg, mitosis and cytokinesis produced can see them with a light microscope. the 200 trillion somatic cells that now make up your body, Each duplicated chromosome consists of and the same processes continue to generate new cells to two ­sister chromatids, which are joined copies of the original chromo- Figure 12.5 Chromosome duplication and distribution during cell division. some (Figure 12.4). The two chroma- Chromosomal tids, each containing an identical DNA Chromosomes DNA molecules molecule, are typically attached all along their lengths by protein complexes 1 One of the multiple chromosomes Centromere called cohesins; this attachment is known in a eukaryotic cell is represented here, not yet duplicated. Normally as sister chromatid cohesion. Each sister it would be a long, thin chromatin chromatid has a centromere, a region fiber containing one DNA molecule and associated proteins; here its Chromosome made up of repetitive sequences in the condensed form is shown for arm chromosomal DNA where the chromatid illustration purposes only. is attached most closely to its sister chro- Chromosome duplication (including DNA replication) matid. This attachment is mediated by and condensation proteins that recognize and bind to the centromeric DNA; other bound proteins condense the DNA, giving the dupli- 2 Once duplicated, a chromosome consists of two sister chroma- cated chromosome a narrow “waist.” tids connected along their entire The portion of a chromatid to either side lengths by sister chromatid cohesion. Each chromatid contains of the centromere is referred to as an a copy of the DNA molecule. arm of the chromatid. (An unduplicated Sister chromosome has a single centromere, chromatids distinguished by the proteins that bind Separation of sister there, and two arms.) chromatids into Later in the cell division process, the two chromosomes two sister chromatids of each duplicated chromosome separate and move into 3 Molecular and mechanical processes separate the sister two new nuclei, one forming at each chromatids into two chromosomes end of the cell. Once the sister chroma- and distribute them to two tids separate, they are no longer called daughter cells. sister chromatids but are considered individual chromosomes; this is the step ? How many chromatid arms does the chromosome in 2 have? Identify the point in the figure where one that essentially doubles the number of chromosome becomes two. chromosomes during cell division. Thus, BioFlix® Animation: Chromosome Duplication each new nucleus receives a collection of 236 Unit two The Cell replace dead and damaged ones. In contrast, you produce Figure 12.6 The cell cycle. In a dividing cell, the mitotic (M) phase gametes—eggs or sperm—by a variation of cell division called alternates with interphase, a growth period. The first part of interphase (G1) is followed by the S phase, when the chromosomes duplicate; meiosis, which yields daughter cells with only one set of G2 is the last part of interphase. In the M phase, mitosis distributes chromosomes, half as many chromosomes as the parent cell. the daughter chromosomes to daughter nuclei, and cytokinesis divides Meiosis in humans occurs only in special cells in the ovaries the cytoplasm, producing two daughter cells. or testes (the gonads). Generating gametes, meiosis reduces INTERPHASE the chromosome number from 46 (two sets) to 23 (one set). Fertilization fuses two gametes together and returns the chro- mosome number to 46 (two sets). Mitosis then conserves that number in every somatic cell nucleus of the new human indi- S G1 (DNA synthesis) vidual. In Chapter 13, we will examine the role of meiosis in reproduction and inheritance in more detail. In the remain- der of this chapter, we focus on mitosis and the rest of the cell sis cycle in eukaryotes. kine G2 sis yto ito M C M (M) ITOTIC Concept Check 12.1 PHA SE 1. How many chromosomes are drawn in each part of Figure 12.5? (Ignore the micrograph in step 2.) 2. WHAT IF? A chicken has 78 chromosomes in its somatic cells. How many chromosomes did the chicken inherit from each parent? How many chromosomes are in each Animation: The Cell Cycle of the chicken’s gametes? How many chromosomes will be in each somatic cell of the chicken’s offspring? For suggested answers, see Appendix A. the chromosomes, crucial for eventual division of the cell, occurs entirely during the S phase. (We will discuss syn- Concept 12.2 thesis, or replication, of DNA in Concept 16.2.) Thus, a cell grows (G1), continues to grow as it copies its chromosomes The mitotic phase alternates (S), grows more as it completes preparations for cell division (G2), and divides (M). The daughter cells may then repeat with interphase in the cell cycle the cycle. In 1882, a German anatomist named Walther Flemming A particular human cell might undergo one division in developed dyes that allowed him to observe, for the first time, 24 hours. Of this time, the M phase would occupy less than the behavior of chromosomes during mitosis and cytokinesis. 1 hour, while the S phase might occupy 10–12 hours, or (In fact, Flemming coined the terms mitosis and chromatin.) about half the cycle. The rest of the time would be appor- During the period between one cell division and the next, it tioned between the G1 and G2 phases. The G2 phase usually appeared to Flemming that the cell was simply growing larger. takes 4–6 hours; in our example, G1 would occupy about But we now know that many critical events occur during this 5–6 hours. G1 is the most variable in length in different stage in the life of a cell. types of cells. Some cells in a multicellular organism divide very infrequently or not at all. These cells spend their time Phases of the Cell Cycle in G1 (or a related phase called G0, to be discussed later in the ­chapter) doing their job in the organism—a cell of the Mitosis is just one part of the cell cycle (Figure 12.6). In pancreas secretes digestive enzymes, for example. fact, the mitotic (M) phase, which includes both mito- Mitosis is conventionally broken down into five stages: sis and cytokinesis, is usually the shortest part of the cell prophase, prometaphase, metaphase, anaphase, and cycle. The mitotic phase alternates with a much longer stage telophase. Overlapping with the latter stages of mitosis, called interphase, which often accounts for about 90% of cytokinesis completes the mitotic phase. Figure 12.7 describes the cycle. Interphase can be divided into three phases: the these stages in an animal cell. Study this figure thoroughly G1 phase (“first gap”), the S phase (“synthesis”), and the before progressing to the next two sections, which examine G2 phase (“second gap”). The G phases were misnamed mitosis and cytokinesis more closely. as “gaps” when they were first observed because the cells appeared inactive, but we now know that intense meta- bolic activity and growth occur throughout interphase. The Mitotic Spindle: A Closer Look During all three phases of interphase, in fact, a cell grows Many of the events of mitosis depend on the mitotic spindle, by producing proteins and cytoplasmic organelles such as which begins to form in the cytoplasm during prophase. This mitochondria and endoplasmic reticulum. Duplication of structure consists of fibers made of microtubules and associated chapter 12 The Cell Cycle 237  Figure 12.7   Exploring Mitosis in an Animal Cell G2 of Interphase Prophase Prometaphase Chromosomes Centrosomes (duplicated, Early mitotic Aster Centromere Fragments Nonkinetochore (with centriole pairs) uncondensed) spindle of nuclear microtubules envelope Nucleolus Nuclear Plasma Two sister chromatids Kinetochore Kinetochore envelope membrane of one chromosome microtubules G2 of Interphase Prophase Prometaphase A nuclear envelope encloses the nucleus. The chromatin fibers become more tightly The nuclear envelope fragments. coiled, condensing into discrete chromosomes The nucleus contains one or more nucleoli The microtubules extending from each centro- observable with a light microscope. (singular, nucleolus). some can now invade the nuclear area. The nucleoli disappear. Two centrosomes have formed by The chromosomes have become even more duplication of a single centrosome. Each duplicated chromosome appears as two condensed. Centrosomes are regions in animal cells identical sister chromatids joined at their cen- A kinetochore, a specialized protein structure, that organize the microtubules of the tromeres and, in some species, all along their has now formed at the centromere of each spindle. Each centrosome contains two arms by cohesins (sister chromatid cohesion). chromatid (thus, two per chromosome). centrioles. The mitotic spindle (named for its shape) Some of the microtubules attach to the kineto- Chromosomes, duplicated during S phase, begins to form. It is composed of the centro- chores, becoming “kinetochore microtubules,” cannot be seen individually because they somes and the microtubules that extend from which jerk the chromosomes back and forth. have not yet condensed. them. The radial arrays of shorter microtubules that extend from the centrosomes are called Nonkinetochore microtubules interact with asters (“stars”). those from the opposite pole of the spindle, lengthening the cell. The centrosomes move away from each other, The fluorescence micrographs show dividing propelled partly by the lengthening micro- lung cells from a newt; this species has 22 tubules between them. chromosomes. Chromosomes appear blue, ?  ow many molecules of DNA are in the H microtubules green, and intermediate prometaphase drawing? How many molecules filaments red. For simplicity, the drawings per chromosome? How many double helices show only 6 chromosomes. are there per chromosome? Per chromatid? 238 Unit two The Cell  10 μm Metaphase Anaphase Telophase and Cytokinesis Metaphase Cleavage Nucleolus plate furrow forming Daughter chromosomes Nuclear Spindle Centrosome at envelope one spindle pole forming Metaphase Anaphase Telophase The centrosomes are now at opposite poles of Anaphase is the shortest stage of mitosis, often Two daughter nuclei form in the cell. the cell. lasting only a few minutes. Nuclear envelopes arise from the fragments of the parent cell’s nuclear envelope and The chromosomes have all arrived at the Anaphase begins when the cohesin proteins are other portions of the endomembrane metaphase plate, a plane that is equidistant cleaved. This allows the two sister chromatids system. between the spindle’s two poles. The chromo- of each pair to part suddenly. Each chromatid somes’ centromeres lie at the metaphase plate. thus becomes an independent chromosome. Nucleoli reappear. For each chromosome, the kinetochores of the The two new daughter chromosomes begin The chromosomes become less condensed. sister chromatids are attached to kinetochore moving toward opposite ends of the cell Any remaining spindle microtubules are microtubules coming from opposite poles. as their kinetochore microtubules shorten. depolymerized. Because these microtubules are attached at the centromere region, the centromeres are pulled Mitosis, the division of one nucleus into ahead of the arms, moving at a rate of about two genetically identical nuclei, is now 1 µm/min. complete. The cell elongates as the nonkinetochore Cytokinesis microtubules lengthen. By the end of anaphase, the two ends of The division of the cytoplasm is usually well the cell have equivalent—and complete— under way by late telophase, so the two collections of chromosomes. daughter cells appear shortly after the end of mitosis. BioFlix® Animation: Mitosis In animal cells, cytokinesis involves the Video: Animal Mitosis formation of a cleavage furrow, which (time-lapse) pinches the cell in two. chapter 12 The Cell Cycle 239 proteins. While the mitotic spindle assembles, the other micro- Figure 12.8 The mitotic spindle at metaphase. The kinetochores tubules of the cytoskeleton partially disassemble, providing the of each chromosome’s two sister chromatids face in opposite directions. Here, each kinetochore is attached to a cluster of kinetochore microtubules material used to construct the spindle. The spindle microtu- extending from the nearest centrosome. Nonkinetochore microtubules bules elongate (polymerize) by incorporating more subunits of overlap at the metaphase plate (TEMs). the protein tubulin (see Table 6.1) and shorten (depolymerize) by losing subunits. Sister Aster In animal cells, the assembly of spindle microtubules starts chromatids Centrosome at the centrosome, a subcellular region containing material that functions throughout the cell cycle to organize the cell’s Metaphase microtubules. (It is also a type of microtubule-organizing center.) plate (imaginary) A pair of centrioles is located at the center of the centrosome, but they are not essential for cell division: If the centrioles are destroyed with a laser microbeam, a spindle nevertheless forms during mitosis. In fact, centrioles are not even present in plant cells, which do form mitotic spindles. During interphase in animal cells, the single centrosome duplicates, forming two centrosomes, which remain near the nucleus. The two centrosomes move apart during prophase Kineto- and prometaphase of mitosis as spindle microtubules grow chores out from them. By the end of prometaphase, the two centro- somes, one at each pole of the spindle, are at opposite ends of the cell. An aster, a radial array of short microtubules, extends from each centrosome. The spindle includes the centrosomes, the spindle microtubules, and the asters. Each of the two sister chromatids of a duplicated chro- Overlapping mosome has a kinetochore, a structure made up of pro- nonkinetochore Kinetochore teins that have assembled on specific sections of DNA at microtubules microtubules each centromere. The chromosome’s two kinetochores face Microtubules in opposite directions. During prometaphase, some of the spindle microtubules attach to the kinetochores; these are called kinetochore microtubules. (The number of microtu- bules attached to a kinetochore varies among species, from one microtubule in yeast cells to 40 or so in some mam- 0.5 μm malian cells.) When one of a chromosome’s kinetochores Chromosomes is “captured” by microtubules, the chromosome begins to move toward the pole from which those microtubules extend. However, this movement comes to a halt as soon as Centrosome microtubules from the opposite pole attach to the kineto- chore on the other chromatid. What happens next is like 1 μm a tug-of-war that ends in a draw. The chromosome moves first in one direction and then in the other, back and forth, DRAW IT On the lower micrograph, draw a line indicating the position finally settling midway between the two ends of the cell. of the metaphase plate. Circle an aster. Draw arrows indicating the directions At metaphase, the centromeres of all the duplicated chro- of chromosome movement once anaphase begins. mosomes are on a plane midway between the spindle’s Video: Spindle Formation During Mitosis two poles. This plane is called the metaphase plate, Animation: Mitosis which is an imaginary plate rather than an actual cellular structure (Figure 12.8). Meanwhile, microtubules that do The structure of the spindle correlates well with its not attach to kinetochores have been elongating, and by f­ unction during anaphase. Anaphase begins suddenly metaphase they overlap and interact with other nonkinetochore when the cohesins holding together the sister chromatids microtubules from the opposite pole of the spindle. By meta- of each chromosome are cleaved by an enzyme called phase, the microtubules of the asters have also grown and separase. Once separated, the chromatids become individ- are in contact with the plasma membrane. The spindle is ual chromosomes that move toward opposite ends now complete. of the cell. 240 Unit two The Cell  How do the kinetochore microtubules function in this Figure 12.9 poleward movement of chromosomes? Apparently, two Inquiry At which end do kinetochore microtubules mechanisms are in play, both involving motor proteins. (To shorten during anaphase? review how motor proteins move an object along a microtu- bule, see Figure 6.21.) Results of a cleverly designed experi- Experiment Gary Borisy and colleagues at the University of Wisconsin wanted to determine whether kinetochore microtubules ment suggested that motor proteins on the kinetochores depolymerize at the kinetochore end or the pole end as chromo- “walk” the chromosomes along the microtubules, which somes move toward the poles during mitosis. First they labeled the depolymerize at their kinetochore ends after the motor pro- microtubules of a pig kidney cell in early anaphase with a yellow teins have passed (Figure 12.9). (This is referred to as the fluorescent dye. (Nonkinetochore microtubules are not shown.) “Pac-man” mechanism because of its resemblance to the Kinetochore arcade game character that moves by eating all the dots in its path.) However, other researchers, working with different Spindle cell types or cells from other species, have shown that chro- pole mosomes are “reeled in” by motor proteins at the spindle poles and that the microtubules depolymerize after they pass by these motor proteins at the poles. The general consensus Then they marked a region of the kinetochore microtubules between now is that both mechanisms are used and that their relative one spindle pole and the chromosomes by using a laser to eliminate the fluorescence from that region, while leaving the microtubules intact contributions vary among cell types. (see below). As anaphase proceeded, they monitored the changes in In a dividing animal cell, the nonkinetochore microtubules microtubule length on either side of the mark. are responsible for elongating the whole cell during anaphase. Nonkinetochore microtubules from opposite poles overlap Mark each other extensively during metaphase (see Figure 12.8). During anaphase, the region of overlap is reduced as motor pro- teins attached to the microtubules walk them away from one another, using energy from ATP. As the microtubules push apart from each other, their spindle poles are pushed apart, elongat- Results As the chromosomes moved poleward, the microtubule ing the cell. At the same time, the microtubules lengthen some- segments on the kinetochore side of the mark shortened, while those what by the addition of tubulin subunits to their overlapping on the spindle pole side stayed the same length. ends. As a result, the microtubules continue to overlap. At the end of anaphase, duplicate groups of chromo- somes have arrived at opposite ends of the elongated parent cell. Nuclei re-form during telophase. Cytokinesis generally begins during anaphase or telophase, and the spindle even- tually disassembles by depolymerization of microtubules. Conclusion During anaphase in this cell type, chromosome Cytokinesis: A Closer Look movement is correlated with kinetochore microtubules shortening In animal cells, cytokinesis occurs by a process known as at their kinetochore ends and not at their spindle pole ends. This experiment supports the hypothesis that during anaphase, cleavage. The first sign of cleavage is the appearance of a a chromosome is walked along a microtubule as the microtubule cleavage furrow, a shallow groove in the cell surface near depolymerizes at its kinetochore end, releasing tubulin subunits. the old metaphase plate (Figure 12.10a). On the cytoplasmic side of the furrow is a contractile ring of actin microfilaments Chromosome movement associated with molecules of the protein myosin. The actin Kinetochore microfilaments interact with the myosin molecules, causing the ring to contract. The contraction of the dividing cell’s Motor Tubulin ring of microfilaments is like the pulling of a drawstring. Microtubule protein subunits The cleavage furrow deepens until the parent cell is pinched Chromosome in two, producing two completely separated cells, each with Data from G. J. Gorbsky, P. J. Sammak, and G. G. Borisy, Chromosomes move its own nucleus and its own share of cytosol, organelles, poleward in anaphase along stationary microtubules that coordinately disassemble and other subcellular structures. from their kinetochore ends, Journal of Cell Biology 104:9–18 (1987). Cytokinesis in plant cells, which have cell walls, is mark- WHAT IF? If this experiment had been done on a cell type in which edly different. There is no cleavage furrow. Instead, dur- “reeling in” at the poles was the main cause of chromosome movement, how would the mark have moved relative to the poles? How would the ing telophase, vesicles derived from the Golgi apparatus microtubule portions on either side of the mark have changed? move along microtubules to the middle of the cell, where Animation: Microtubule Depolymerization they coalesce, producing a cell plate. Cell wall materials chapter 12 The Cell Cycle 241  Figure 12.10 Cytokinesis in animal and plant cells. carried in the vesicles collect inside the cell plate as it grows (Figure 12.10b). The cell plate enlarges until its surrounding (a) Cleavage of an animal cell (SEM) membrane fuses with the plasma membrane along the perim- eter of the cell. Two daughter cells result, each with its own plasma membrane. Meanwhile, a new cell wall arising from the contents of the cell plate forms between the daughter cells. Figure 12.11 is a series of micrographs of a dividing plant cell. Examining this figure will help you review mitosis and cytokinesis. Binary Fission in Bacteria Prokaryotes (bacteria and archaea) can undergo a type of reproduction in which the cell grows to roughly double its size and then divides to form two cells. The term binary fission, meaning “division in half,” refers to this process and to the 100 μm asexual reproduction of single-celled eukaryotes, such as the Cleavage furrow amoeba in Figure 12.2a. However, the process in eukaryotes involves mitosis, while that in prokaryotes does not. In bacteria, most genes are carried on a single bacterial chromosome that consists of a circular DNA molecule and associated proteins. Although bacteria are smaller and sim- pler than eukaryotic cells, the challenge of replicating their genomes in an orderly fashion and distributing the copies Contractile ring of Daughter cells equally to two daughter cells is still formidable. For example, microfilaments when it is fully stretched out, the chromosome of the bac- terium Escherichia coli is about 500 times as long as the cell. (b) Cell plate formation in a plant cell (TEM) For such a long chromosome to fit within the cell, it must be highly coiled and folded. In some bacteria, the process of cell division is initiated when the DNA of the bacterial chromosome begins to repli- cate at a specific place on the chromosome called the origin of replication, producing two origins. As the chromosome continues to replicate, one origin moves rapidly toward the opposite end of the cell (Figure 12.12). While the chromo- some is replicating, the cell elongates. When replication is complete and the bacterium has reached about twice its initial size, proteins cause its plasma membrane to pinch inward, dividing the parent bacterial cell into two daughter cells. In this way, each cell inherits a complete genome. Using the techniques of modern DNA technology to tag Vesicles Wall of 1 μm the origins of replication with molecules that glow green in forming parent cell fluorescence microscopy (see Figure 6.3), researchers have cell plate Cell plate New cell wall directly observed the movement of bacterial chromosomes. This movement is reminiscent of the poleward movements of the centromere regions of eukaryotic chromosomes during anaphase of mitosis, but bacteria don’t have visible mitotic spindles or even microtubules. In most bacterial species studied, the two origins of replication end up at opposite ends of the cell or in some other very specific location, pos- sibly anchored there by one or more proteins. How bacterial chromosomes move and how their specific location is estab- Daughter cells lished and maintained are active areas of research. Several Animation: Cytokinesis proteins that play important roles have been identified. Video: Cytokinesis in an Animal Cell Polymerization of one protein resembling eukaryotic actin 242 Unit two The Cell  Figure 12.11 Mitosis in a plant cell. These light micrographs show mitosis in cells of an onion root. Nucleus Chromosomes 10 μm Nucleolus condensing Chromosomes Cell plate 1 Prophase. The chromo- 2 Prometaphase. Discrete 3 Metaphase. The spindle 4 Anaphase. The 5 Telophase. Daughter somes are condensing chromosomes are now is complete, and the chromatids of each nuclei are forming. and the nucleolus is visible; each consists of chromosomes, attached chromosome have Meanwhile, cytokinesis beginning to disappear. two aligned, identical to microtubules at their separated, and the has started: The cell Although not yet visible sister chromatids. Later kinetochores, are all at daughter chromosomes plate, which will divide in the micrograph, the in prometaphase, the the metaphase plate. are moving to the ends the cytoplasm in two, is mitotic spindle is starting nuclear envelope will of the cell as their growing toward the to form. fragment. kinetochore micro- perimeter of the parent tubules shorten. cell. Figure 12.12 Bacterial cell division by binary fission. The apparently functions in bacterial chromosome movement bacterium shown here has a single, circular chromosome. during cell division, and another protein that is related to Cell wall tubulin helps pinch the plasma membrane inward, separating Origin of replication the two bacterial daughter cells. Plasma membrane The Evolution of Mitosis Bacterial cell Bacterial chromosome Evolution Given that prokaryotes preceded eukaryotes on 1 Chromosome Two copies replication begins. Earth by more than a billion years, we might hypothesize that of origin Soon after, one copy mitosis evolved from simpler prokaryotic mechanisms of cell of the origin moves rapidly toward the reproduction. The fact that some of the proteins involved in other end of the cell by bacterial binary fission are related to eukaryotic proteins that a mechanism involving function in mitosis supports that hypothesis. an actin-like protein. As eukaryotes with nuclear envelopes and larger genomes evolved, the ancestral process of binary fission, seen today Origin Origin in bacteria, somehow gave rise to mitosis. Variations on cell 2 Replication continues. One copy of the origin division exist in different groups of organisms. These variant is now at each end of processes may be similar to mechanisms used by ancestral the cell. Meanwhile, species and thus may resemble steps in the evolution of the cell elongates. mitosis from a binary fission-like process presumably carried out by very early bacteria. Possible intermediate stages are 3 Replication finishes. suggested by two unusual types of nuclear division found The plasma membrane is pinched inward by today in certain unicellular eukaryotes—dinoflagellates, a tubulin-like protein, diatoms, and some yeasts (Figure 12.13). These two modes and a new cell wall is deposited. of nuclear division are thought to be cases where ancestral mechanisms have remained relatively unchanged over evo- lutionary time. In both types, the nuclear envelope remains intact, in contrast to what happens in most eukaryotic cells. Keep in mind, however, that we can’t observe cell division 4 Two daughter cells result. in cells of extinct species. This hypothesis uses only cur- rently existing species as examples and must ignore any potential intermediate mechanisms used by species that Animation: Cell Division in Bacteria disappeared long ago. chapter 12 The Cell Cycle 243  Figure 12.13 Mechanisms of cell division in several Concept Check 12.2 groups of organisms. Some unicellular eukaryotes existing today have mechanisms of cell division that may resemble intermediate steps 1. How many chromosomes are shown in the illustration in in the evolution of mitosis. Except for (a), cell walls are not shown. Figure 12.8? Are they duplicated? How many chromatids are shown? 2. Compare cytokinesis in animal cells and plant cells. 3. During which stages of the cell cycle does a chromosome consist of two identical chromatids? Bacterial 4. Compare the roles of tubulin and actin during eukaryotic chromosome cell division with the roles of tubulin-like and actin-like (a) Bacteria. During binary fission in bacteria, the origins of the proteins during bacterial binary fission. daughter chromosomes move to opposite ends of the cell. The 5. A kinetochore has been compared to a coupling device mechanism involves polymerization of actin-like molecules, and that connects a motor to the cargo that it moves. Explain. possibly proteins that may anchor the daughter chromosomes to 6. MAKE CONNECTIONS What other functions do actin specific sites on the plasma membrane. and tubulin carry out? Name the proteins they interact with to do so. (Review Figures 6.21a and 6.26a.) Chromosomes For suggested answers, see Appendix A. Microtubules Concept 12.3 The eukaryotic cell cycle is regulated Intact nuclear by a molecular control system envelope The timing and rate of cell division in different parts of a plant (b) Dinoflagellates. In unicellular protists called dinoflagellates, the chromosomes attach to the nuclear envelope, which remains or animal are crucial to normal growth, development, and intact during cell division. Microtubules pass through the nucleus maintenance. The frequency of cell division varies with the inside cytoplasmic tunnels, reinforcing the spatial orientation of type of cell. For example, human skin cells divide frequently the nucleus, which then divides in a process reminiscent of bacterial binary fission. throughout life, whereas liver cells maintain the ability to divide but keep it in reserve until an appropriate need arises— say, to repair a wound. Some of the most specialized cells, such Kinetochore as fully formed nerve cells and muscle cells, do not divide at microtubule all in a mature human. These cell cycle differences result from regulation at the molecular level. The mechanisms of this regulation are of great interest, not only to understand the life Intact nuclear cycles of normal cells but also to learn how cancer cells man- envelope age to escape the usual controls. The Cell Cycle Control System (c) Diatoms and some yeasts. In these two other groups of unicellular eukaryotes, the nuclear envelope also remains intact What controls the cell cycle? In the early 1970s, a variety of during cell division. In these organisms, the microtubules form a experiments led to the hypothesis that the cell cycle is driven by spindle within the nucleus. Microtubules separate the specific signaling molecules present in the cytoplasm. Some of chromosomes, and the nucleus splits into two daughter nuclei. the first strong evidence for this hypothesis came from experi- Kinetochore ments with mammalian cells grown in culture. In these experi- microtubule ments, two cells in different phases of the cell cycle were fused to form a single cell with two nuclei (Figure 12.14). If one of the original cells was in the S phase and the other was in G1, the G1 nucleus immediately entered the S phase, as though stimulated by signaling molecules present in the cytoplasm of the first cell. Fragments of Similarly, if a cell undergoing mitosis (M phase) was fused with nuclear envelope another cell in any stage of its cell cycle, even G1, the second (d) Most eukaryotes. In most other eukaryotes, including plants and nucleus immediately entered mitosis, with condensation of the animals, the spindle forms outside the nucleus, and the nuclear chromatin and formation of a mitotic spindle. envelope breaks down during mitosis. Microtubules separate the The experiment shown in Figure 12.14 and other experi- chromosomes, and two nuclear envelopes then form. ments on animal cells and yeasts demonstrated that the Video: Nuclear Envelope Breakdown and Formation During sequential events of the cell cycle are directed by a distinct Mitosis in C. elegans, a Eukaryote cell cycle control system, a cyclically operating set of 244 Unit two The Cell  Figure 12.14 Figure 12.15 Mechanical analogy for the cell cycle control system. In this diagram, the flat “stepping stones” around the perimeter Inquiry Do molecular signals in the cytoplasm represent sequential events. Like the control device of a washing machine, regulate the cell cycle? the cell cycle control system proceeds on its own, driven by a built-in clock. However, the system is subject to internal and external regulation Experiment Researchers at the University of Colorado wondered at various checkpoints; three important checkpoints are shown (red). whether a cell’s progression through the cell cycle is controlled by cytoplasmic molecules. They induced cultured mammalian cells G1 checkpoint at different phases of the cell cycle to fuse. Two experiments are shown. Experiment 1 Experiment 2 Control system S G1 S G1 M G1 M G2 M checkpoint G2 checkpoint S S M M When a cell in the When a cell in the M phase was Animation: Control of the Cell Cycle S phase was fused with fused with a cell in G1, the G1 a cell in G1, the G1 nucleus immediately began nucleus immediately mitosis—a spindle formed and the cycle. We’ll then consider the internal and external entered the S the chromosomes condensed, phase—DNA was even though the chromosomes checkpoint signals that can make the clock either pause synthesized. had not been duplicated. or continue. Conclusion The results of fusing a G1 cell with a cell in the S or M phase of the cell cycle suggest that molecules present in the cytoplasm The Cell Cycle Clock: Cyclins during the S or M phase control the progression to those phases. and Cyclin-Dependent Kinases Data from R. T. Johnson and P. N. Rao, Mammalian cell fusion: Induction of premature chromosome condensation in interphase nuclei, Nature 226:717–722 (1970). Rhythmic fluctuations in the abundance and activity of cell cycle control molecules pace the sequential events of the WHAT IF? If the progression of phases did not depend on cytoplasmic molecules and, instead, each phase automatically began when the previous cell cycle. These regulatory molecules are mainly proteins one was complete, how would the results have differed? of two types: protein kinases and cyclins. Protein kinases are enzymes that activate or inactivate other proteins by phosphorylating them (see Concept 11.3). Many of the kinases that drive the cell cycle are actually molecules in the cell that both triggers and coordinates key present at a constant concentration in the growing cell, but events in the cell cycle (Figure 12.15). The cell cycle control much of the time they are in an inactive form. To be active, system has been compared to the control device of a washing such a kinase must be attached to a cyclin, a protein that machine. Like the washer’s timing device, the cell cycle con- gets its name from its cyclically fluctuating concentration in trol system proceeds on its own, according to a built-in clock. the cell. Because of this requirement, these kinases are called However, just as a washer’s cycle is subject to both internal cyclin-dependent kinases, or Cdks. The activity of a Cdk control (such as the sensor that detects when the tub is filled rises and falls with changes in the concentration of its cyclin with water) and external adjustment (such as starting or stop- partner. Figure 12.16a shows the fluctuating activity of MPF, ping the machine), the cell cycle is regulated at certain check- the cyclin-Cdk complex that was discovered first (in frog points by both internal and external signals. A checkpoint eggs). Note that the peaks of MPF activity correspond to the in the cell cycle is a control point where stop and go-ahead peaks of cyclin concentration. The cyclin level rises during signals can regulate the cycle. Three important checkpoints the S and G2 phases and then falls abruptly during M phase. are found in the G1, G2, and M phases (red gates in Figure 12.15), The initials MPF stand for “maturation-promoting factor,” which will be discussed shortly. but we can think of MPF as “M-phase-promoting factor” To understand how cell cycle checkpoints work, we’ll because it triggers the cell’s passage into the M phase, past first identify some of the molecules that make up the cell the G2 checkpoint. When cyclins that accumulate during cycle control system (the molecular basis for the cell G2 associate with Cdk molecules, the resulting MPF complex cycle clock) and describe how a cell progresses through is active—it phosphorylates a variety of proteins, initiating chapter 12 The Cell Cycle 245 ­ itosis (Figure 12.16b). MPF acts both directly as a kinase and m During anaphase, MPF helps switch itself off by initiating indirectly by activating other kinases. For example, MPF causes a process that leads to the destruction of its own cyclin. The phosphorylation of various proteins of the nuclear lamina (see noncyclin part of MPF, the Cdk, persists in the cell, inactive Figure 6.9), which promotes fragmentation of the nuclear enve- until it becomes part of MPF again by associating with new lope during prometaphase of mitosis. There is also evidence that cyclin molecules synthesized during the S and G2 phases of MPF contributes to molecular events required for chromosome the next round of the cycle. condensation and spindle formation during prophase. The fluctuating activities of different cyclin-Cdk com- plexes are of major importance in controlling all the stages Figure 12.16 Molecular control of the cell cycle at the of the cell cycle; they also give the go-ahead signals at some G2 checkpoint. The steps of the cell cycle are timed by rhythmic fluctuations in the activity of cyclin-dependent kinases (Cdks). Here we checkpoints. As mentioned above, MPF controls the cell’s focus on a cyclin-Cdk complex in animal cells called MPF, which acts at passage through the G2 checkpoint. Cell behavior at the the G2 checkpoint as a go-ahead signal, triggering the events of mitosis. G1 checkpoint is also regulated by the activity of cyclin-Cdk protein complexes. Animal cells appear to have at least three M G1 S G2 M G1 S G2 M G1 Cdk proteins and several different cyclins that operate at this MPF activity checkpoint. Next, let’s consider checkpoints in more detail. Cyclin Stop and Go Signs: Internal and External concentration Signals at the Checkpoints Animal cells generally have built-in stop signals that halt the cell cycle at checkpoints until overridden by go-ahead signals. Time (The signals are transmitted within the cell by the kinds (a) Fluctuation of MPF activity and cyclin concentration during of signal transduction pathways discussed in Chapter 11.) the cell cycle Many signals registered at checkpoints come from cellular 1 Synthesis of cyclin surveillance mechanisms inside the cell. These signals report begins in late S phase whether crucial cellular processes that should have occurred and continues through by that point have in fact been completed correctly and thus G2. Because cyclin is protected from degra- whether or not the cell cycle should proceed. Checkpoints 5 During G1, the degradation dation during this stage, also register signals from outside the cell. of cyclin continues, and it accumulates. Three important checkpoints are those in the G1, G2, and the Cdk component of MPF is recycled. M phases (see Figure 12.15). For many cells, the G1 check- point seems to be the most important. If a cell receives a go- ahead signal at the G1 checkpoint, it will usually complete the G1, S, G2, and M phases and divide. If it does not receive a 1 S Cyclin accumulatio G go-ahead signal at that point, it may exit the cycle, switching Cdk into a nondividing state called the G0 phase (Figure 12.17a). M Most cells of the human body are actually in the G0 phase. As Degraded G2 cyclin mentioned earlier, mature nerve cells and muscle cells never G2 Cdk divide. Other cells, such as liver cells, can be “called back” checkpoint n Cyclin is degraded from the G0 phase to the cell cycle by external cues, such as growth factors released during injury. Cyclin MPF Biologists are currently working out the pathways that link signals originating inside and outside the cell with 4 During 3 MPF promotes 2 Cyclin combines the responses by cyclin-dependent kinases and other pro- anaphase, the mitosis by phos- with Cdk, producing teins. An example of an internal signal occurs at the third cyclin com- phorylating MPF. When enough important checkpoint, the M checkpoint (Figure 12.17b). ponent of MPF is various proteins. MPF molecules degraded, MPF‘s activity accumulate, the cell Anaphase, the separation of sister chromatids, does not terminating the peaks during passes the G2 begin until all the chromosomes are properly attached M phase. The metaphase. checkpoint and to the spindle at the metaphase plate. Researchers have cell enters the begins mitosis. G1 phase. learned that as long as some kinetochores are unattached (b) Molecular mechanisms that help regulate the cell cycle to spindle microtubules, the sister chromatids remain together, delaying anaphase. Only when the kinetochores VISUAL SKILLS Explain how the events in the diagram in (b) are related to the “Time” axis of the graph in (a), beginning at the left. of all the chromosomes are properly attached to the Interview with Paul Nurse: Discovering how protein kinases spindle does the appropriate regulatory protein complex control the cell cycle become activated. (In this case, the regulatory molecule 246 Unit two The Cell  Figure 12.17 Two important G1 checkpoint checkpoints. At certain checkpoints in the cell cycle (red gates), cells do different things depending on the G0 signals they receive. Events of the (a) G1 and (b) M checkpoints are shown. In (b), the G2 checkpoint has already been passed by the cell. WHAT IF? What might be the result if the cell ignored either checkpoint and G1 G1 progressed through the cell cycle? In the absence of a go-ahead signal, If a cell receives a go-ahead signal, the a cell exits the cell cycle and enters cell continues on in the cell cycle. G0, a nondividing state. G1 S (a) G1 checkpoint M G2 G1 G1 M G2 M G2 is not a cyclin-Cdk complex but, instead, a different complex made up of several pro- teins.) Once activated, the complex sets off M checkpoint a chain of molecular events that activates the enzyme separase, which cleaves the cohesins, G2 allowing the sister chromatids to separate. This Anaphase checkpoint mechanism ensures that daughter cells do not end up with missing or extra chromosomes. Prometaphase Metaphase There are checkpoints in addition to those in A cell in mitosis receives a stop signal When all chromosomes are attached when any of its chromosomes are not to spindle fibers from both poles, G1, G2, and M. For instance, a checkpoint in attached to spindle fibers. a go-ahead signal allows the cell to S phase stops cells with DNA damage from proceed into anaphase. (b) M checkpoint proceeding in the cell cycle. And, in 2014, research- ers presented evidence for another checkpoint between anaphase and telophase that ensures anaphase is completed receptors on their plasma membranes. The binding of PDGF and the chromosomes are well separated before cytokinesis molecules to these receptors (which are receptor tyrosine can begin, thus avoiding chromosomal damage. kinases; see Figure 11.8) triggers a signal transduction path- What about the stop and go-ahead signals themselves— way that allows the cells to pass the G1 checkpoint and divide. what are the signaling molecules? Studies using animal cells PDGF stimulates fibroblast division not only in the artificial in culture have led to the identification of many external fac- conditions of cell culture but also in an animal’s body. When tors, both chemical and physical, that can influence cell divi- an injury occurs, platelets release PDGF in the vicinity. The sion. For example, cells fail to divide if an essential nutrient is resulting proliferation of fibroblasts helps heal the wound. lacking in the culture medium. (This is analogous to trying to The effect of an external physical factor on cell division is run a washing machine without the water supply hooked up; clearly seen in density-dependent inhibition, a phenom- an internal sensor won’t allow the machine to continue past enon in which crowded cells stop dividing (Figure 12.19a). As the point where water is needed.) And even if all other condi- first observed many years ago, cultured cells normally divide tions are favorable, most types of mammalian cells divide in until they form a single layer of cells on the inner surface of culture only if the growth medium includes specific growth a culture flask, at which point the cells stop dividing. If some factors. As mentioned in Concept 11.1, a growth factor is cells are removed, those bordering the open space begin divid- a protein released by certain cells that stimulates other cells ing again and continue until the vacancy is filled. Follow-up to divide. Different cell types respond specifically to different studies revealed that the binding of a cell-surface protein to its growth factors or combinations of growth factors. counterpart on an adjoining cell sends a signal to both cells Consider, for example, platelet-derived growth factor (PDGF), that inhibits cell division, preventing them from moving for- which is made by blood cell fragments called platelets. The ward in the cell cycle, even in the presence of growth factors. experiment illustrated in Figure 12.18 demonstrates that Most animal cells also exhibit anchorage dependence PDGF is required for the division of cultured fibroblasts, (see Figure 12.19a). To divide, they must be attached to a type of connective tissue cell. Fibroblasts have PDGF a substratum, such as the inside of a culture flask or the chapter 12 The Cell Cycle 247  Scalpels Figure 12.18 Figure 12.19 Density-dependent inhibition The effect of and anchorage dependence of cell division. Individual 1 A sample of human connective tissue is platelet-derived cells are shown disproportionately large in the drawings. cut up into small growth factor pieces. (PDGF) on cell division. Cells anchor to dish surface and Petri divide (anchorage dependence). dish 2 Enzymes are used to digest the extracellular When cells have formed a matrix in the tissue complete single layer, they stop pieces, resulting in a dividing (density-dependent suspension of free inhibition). fibroblasts. 3 Cells are transferred to culture vessels containing If some cells are scraped away, a basic growth medium the remaining cells divide to fill consisting of glucose, 4 PDGF is added to half the gap and then stop once they amino acids, salts, and the vessels. The culture contact each other (density- antibiotics (to prevent vessels are incubated dependent inhibition). bacterial growth). at 37°C for 24 hours. Without PDGF With PDGF 20 μm In the basic growth medium In the basic growth medium plus without PDGF (the control), PDGF, the cells proliferate. The (a) Normal mammalian cells. Cell density is limited to a single layer the cells fail to divide. SEM shows cultured fibroblasts. by contact with neighboring cells and the availability of nutrients, growth factors, and a substratum for attachment. MAKE CONNECTIONS PDGF signals cells by binding to a cell-surface receptor tyrosine kinase. If you added a chemical that blocked phosphorylation, 10 μm how would the results differ? (See Figure 11.8.) 20 μm (b) Cancer cells. Cancer cells usually continue to divide well beyond extracellular matrix of a tissue. Experiments suggest that like a single layer, forming a clump of overlapping cells. They do not cell density, anchorage is signaled to the cell cycle control exhibit anchorage dependence or density-dependent inhibition. system via pathways involving plasma membrane proteins and elements of the cytoskeleton linked to them. Density-dependent inhibition and anchorage dependence growth factor themselves, or they may have an abnor- appear to function not only in cell culture but also in the mality in the signaling pathway that conveys the growth body’s tissues, checking the growth of cells at some optimal factor’s signal to the cell cycle control system even in the density and location during embryonic development and absence of that factor. Another possibility is an abnormal throughout an organism’s life. Cancer cells, which we dis- cell cycle control system. In these scenarios, the underly- cuss next, exhibit neither density-dependent inhibition nor ing basis of the abnormality is almost always a change in anchorage dependence (Figure 12.19b). one or more genes (for example, a mutation) that alters the function of their protein products, resulting in faulty Loss of Cell Cycle Controls in Cancer Cells cell cycle control. Cancer cells do not heed the normal signals that regulate There are other important differences between normal the cell cycle. In culture, they do not stop dividing when cells and cancer cells that reflect derangements of the cell growth factors are depleted. A logical hypothesis is that cycle. If and when they stop dividing, cancer cells do so at cancer cells do not need growth factors in their culture random points in the cycle, rather than at the normal check- medium to grow and divide. They may make a required points. Moreover, cancer cells can go on dividing indefinitely 248 Unit two The Cell in culture if they are given a continual supply of nutrients; in The changes that have occurred in cells of malignant tumors essence, they are “immortal.” A striking example is a cell line show up in many ways besides excessive proliferation. These that has been reproducing in culture since 1951. Cells of this cells may have unusual numbers of chromosomes, though line are called HeLa cells because their original source was a whether this is a cause or an effect of tumor-related changes is a tumor removed from a woman named Henrietta Lacks. Cells topic of debate. Their metabolism may be altered, and they may in culture that acquire the ability to divide indefinitely are cease to function in any constructive way. Abnormal changes said to have undergone transformation, the process that on the cell surface cause cancer cells to lose attachments to causes them to behave like cancer cells. By contrast, nearly all neighboring cells and the extracellular matrix, allowing them normal, nontransformed mammalian cells growing in culture to spread into nearby tissues. Cancer cells may also secrete sig- divide only about 20 to 50 times before they stop dividing, naling molecules that cause blood vessels to grow toward the age, and die. Finally, cancer cells evade the normal controls tumor. A few tumor cells may separate from the original tumor, that trigger a cell to undergo apoptosis when something enter blood vessels and lymph vessels, and travel to other parts is wrong—for example, when an irreparable mistake has of the body. There, they may proliferate and form a new tumor. occurred during DNA replication preceding mitosis. This spread of cancer cells to locations distant from their origi- nal site is called metastasis (see Figure 12.20). ABC News Video: Henrietta Lacks’ Cells A tumor that appears to be localized may be treated with Abnormal cell behavior in the body can be catastrophic. high-energy radiation, which damages DNA in cancer cells The problem begins when a single cell in a tissue undergoes much more than DNA in normal cells, apparently because the first of many steps that converts a normal cell to a cancer the majority of cancer cells have lost the ability to repair such cell. Such a cell often has altered proteins on its surface, and damage. To treat known or suspected metastatic tumors, che- the body’s immune system normally recognizes the cell as motherapy is used, in which drugs that are toxic to actively “nonself”—an insurgent—and destroys it. However, if the cell dividing cells are administered through the circulatory sys- evades destruction, it may proliferate and form a tumor, a tem. As you might expect, chemotherapeutic drugs interfere mass of abnormal cells within otherwise normal tissue. The with specific steps in the cell cycle. For example, the drug abnormal cells may remain at the original site if they have Taxol freezes the mitotic spindle by preventing microtubule too few genetic and cellular changes to survive at another depolymerization, which stops actively dividing cells from site. In that case, the tumor is called a benign tumor. Most proceeding past metaphase and leads to their destruction. benign tumors do not cause serious problems (depending on The side effects of chemotherapy are due to the effects of the their location) and can be removed by surgery. In contrast, drugs on normal cells that divide frequently, due to the func- a malignant tumor inc