Campbell Biology, 12th Edition, The Cell Cycle PDF

12 The Cell Cycle KEY CONCEPTS 12.1 Most cell division results in genetically identical daughter cells p. 235 12.2 The mitotic phase alternates with interphase in the cell cycle p. 237 12.3 The eukaryotic cell cycle is regulated by a molecular control system p. 244 Study Tip Make a visual s...

12 The Cell Cycle KEY CONCEPTS 12.1 Most cell division results in genetically identical daughter cells p. 235 12.2 The mitotic phase alternates with interphase in the cell cycle p. 237 12.3 The eukaryotic cell cycle is regulated by a molecular control system p. 244 Study Tip Make a visual study guide: Figure 12.1 presents the events of the cell cycle as a simplified linear diagram. As you learn more about the cell cycle, draw a detailed linear diagram of the stages of interphase, mitosis, and cytokinesis. Include explanatory labels. Add the circular chart from Figure 12.6 and show how the two diagrams are related. Two cells Four cells Figure 12.1 A multicellular organism starts out as a single cell that divides into two. Those two cells then divide into four, as shown in these fluorescence micrographs of a marine worm embryo. Cell division continues throughout an organism’s life, for growth or to replace worn-out or damaged cells. Each time a cell divides in this way, it is crucial that the daughter cells be genetically identical to the parent cell. The Cell Cycle Interphase G1 phase: Metabolic activity and growth How does one parent cell give rise to two genetically identical daughter cells? Parent cell Interphase: The cell grows; in preparation for cell division, the chromosomes are duplicated, with the genetic material (DNA) copied precisely. Go to Mastering Biology For Students (in eText and Study Area) • Get Ready for Chapter 12 • BioFlix® Animation: Mitosis • Animation: Microtubule Depolymerization Mitosis: The chromosome copies are For Instructors to Assign (in Item Library) • BioFlix® Tutorial: Mitosis (2 of 3): Mechanisms of Mitosis • Coaching Activity: Evaluating Science in the Media: Tanning and Skin Cancer Cytokinesis: The cell divides Ready-to-Go Teaching Module (in Instructor Resources) • Mitosis (Concept 12.2) The daughter cells may go on to divide, repeating the cycle. separated from each other and moved to opposite ends of the cell. into two daughter cells, genetically identical to each other and to the parent cell. Daughter cells 234 CONCEPT 12.1 Most cell division results in genetically identical daughter cells The ability of organisms to produce more of their own kind is the one characteristic that best distinguishes living things from nonliving matter. This unique capacity to procreate, like all biological functions, has a cellular basis. The continuity of life is based on the reproduction of cells, or cell division. Key Roles of Cell Division Cell division plays several important roles in life. When a prokaryotic cell divides, it is actually reproducing because 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, dividing cells in your bone marrow continuously make new blood cells (Figure 12.2c). 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 bubble that simply enlarges and splits in two. In both prokaryotes and eukaryotes, a crucial function of most cell divisions is the distribution of identical genetic . Figure 12.2 The functions of cell division. 100 om b (a) Asexual reproduction. An amoeba, a single-celled eukaryote, is dividing into two cells. Each new cell will be an individual organism (LM). 50 om c (b) Growth and development. This micrograph shows a sand dollar embryo shortly after the fertilized egg divided, forming two cells (LM). 20 om material—DNA—to two daughter cells. (The exception is meiosis, the special type of eukaryotic cell division that can produce sperm and eggs.) What is most remarkable about cell division is the accuracy with which the DNA is passed from one generation of cells to the next. A dividing cell replicates its DNA, distributes the two copies to opposite ends of the cell, and then splits into daughter cells. Cellular Organization of the Genetic Material A cell’s DNA, its genetic information, is called its genome. Although a prokaryotic genome is often a single DNA molecule, eukaryotic genomes usually consist of a number of DNA molecules. The overall length of DNA in a eukaryotic cell is enormous. A typical human cell, for example, has about 2 m of DNA—a length about 250,000 times greater than the cell’s diameter. Before the cell can divide to form genetically 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 manageable because the DNA molecules are packaged into structures called chromosomes (from the Greek chroma, color, and soma, body), so named because they take up certain dyes used in microscopy (Figure 12.3). Each eukaryotic chromosome consists of one very long, linear DNA molecule associated with many proteins (see Figure 6.9). The DNA molecule 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 chromosome and help control the activity of the genes. Together, the entire complex of DNA and proteins that is the building material of chromosomes is referred to as chromatin. As you will soon see, the chromatin of a chromosome varies in its degree of condensation during the process of cell division. . Figure 12.3 Eukaryotic chromosomes. Chromosomes (stained purple) are visible within the nucleus of this cell from an African blood lily. The thinner red threads in the surrounding cytoplasm are the cytoskeleton. The cell is preparing to divide (LM). b (c) Tissue renewal. These dividing bone marrow cells will give rise to new blood cells (LM). 20 om Mastering Biology Video: Cell Division in a Sea Urchin Embryo CHAPTER 12 The Cell Cycle 235 Every eukaryotic species has a characteristic number of chromosomes in each cell’s nucleus. For example, the nuclei of human somatic cells (all body cells except the reproductive cells) each contain 46 chromosomes, made up of two sets of 23, one set inherited from each parent. Reproductive cells, or gametes—such as sperm and eggs— have half as many chromosomes as somatic cells; in our example, human gametes have one set of 23 chromosomes. The number of chromosomes in somatic cells varies widely among species: 18 in cabbage plants, 48 in chimpanzees, 56 in elephants, 90 in hedgehogs, and 148 in one species of alga. We’ll now consider how these chromosomes behave during cell division. Distribution of Chromosomes During Eukaryotic Cell Division . Figure 12.4 A highly condensed, duplicated human chromosome. (SEM) Sister chromatids Centromeres, one on each sister chromatid 0.5 om DRAW IT Circle one sister chromatid of this chromosome. the cell. Once the sister chromatids separate, they are no longer called sister chromatids but are considered individual chromosomes; this is the step that essentially doubles the number of chromosomes during cell division. Thus, each new nucleus receives a collection of chromosomes identical to that of the parent cell (Figure 12.5). Mitosis, the division of the genetic material in the nucleus, is usually followed immediately by cytokinesis, the division of the cytoplasm. One cell has become two, each the genetic equivalent of the parent cell. When a cell is not dividing, and even as it replicates its DNA in preparation for cell division, each chromosome is in the form of a long, thin chromatin fiber. After DNA replication, however, the chromosomes condense as a part of cell division: Each chromatin fiber becomes . Figure 12.5 Chromosome duplication and distribution during cell division. densely coiled and folded, making the chromosomes much shorter and so Chromosomal thick that we can see them with a light Chromosomes DNA molecules microscope. 1 One of the multiple chromosomes Centromere Each duplicated chromosome consists in a eukaryotic cell is represented of two sister chromatids, which are here, not yet duplicated. At this stage, it is a long, thin chromatin joined copies of the original chromofiber containing one DNA molecule some (Figure 12.4). The two chromatids, and associated proteins. (For Chromosome each containing an identical DNA molsimplicity, the chromosome is arm shown in condensed form, and the ecule, are often attached all along their Chromosome duplication nuclear envelope is not shown.) lengths by protein complexes called (including DNA replication) and condensation cohesins; this attachment is known as sister chromatid cohesion. Each sister chromatid has a centromere, a region 2 Once duplicated, a chromosome made up of repetitive sequences in the consists of two sister chromatids connected along their entire chromosomal DNA where the chromatid lengths by sister chromatid is attached most closely to its sister chrocohesion. Each chromatid contains matid. This attachment is mediated by a copy of the DNA molecule. Sister proteins that recognize and bind to the chromatids centromeric DNA; other bound proteins condense the DNA, giving the dupliSeparation of sister chromatids into cated chromosome a narrow “waist.” two chromosomes The portion of a chromatid to either side of the centromere is referred to as an 3 Molecular and mechanical arm of the chromatid. (An unduplicated processes separate the sister chromatids into two chromosomes chromosome has a single centromere, and distribute them to two distinguished by the proteins that bind daughter cells. there, and two arms.) Later in the cell division process, the ? How many chromatid arms does the chromosome in 2 have? two sister chromatids of each duplicated Identify the point in the figure where one chromosome becomes two. chromosome separate and move into two Mastering Biology BioFlix® Animation: Chromosome Duplication new nuclei, one forming at each end of 236 UNIT TWO The Cell CONCEPT CHECK 12.1 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 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. CONCEPT 12.2 The mitotic phase alternates with interphase in the cell cycle In 1882, a German anatomist named Walther Flemming developed dyes that allowed him to observe, for the first time, the behavior of chromosomes during mitosis and cytokinesis. (In fact, Flemming coined the terms mitosis and chromatin.) During the period between one cell division and the next, it appeared to Flemming that the cell was simply growing larger. But we now know that many critical events occur during this stage in the life of a cell. Phases of the Cell Cycle Mitosis is just one part of the cell cycle, the life of a cell from the time it is first formed during division of a parent cell until its own division into two daughter cells (Figure 12.6). (Biologists use the words daughter or sister in relation to cells, but this is not meant to imply gender.) In fact, the mitotic (M) phase, which includes both mitosis and cytokinesis, is usually the shortest part of the cell cycle. The mitotic phase alternates with a much longer stage called interphase, which often accounts for about 90% of the cycle. Interphase can be divided into three phases: the G1 phase (“first gap”), the S phase (“synthesis”), and the G2 phase (“second gap”). . Figure 12.6 The cell cycle. In a dividing cell, the mitotic (M) phase alternates with interphase, a growth period. Unduplicated chromosomes INTERPHASE G1 phase: Metabolic activity and growth is es kin ito sis yto MIT C (M) OTI PHA C SE M From a fertilized egg, mitosis and cytokinesis produced the 37 trillion somatic cells that now make up your body, and the same processes continue to generate new cells to replace dead and damaged ones. In contrast, you produce gametes—eggs or sperm—by a variation of cell division called meiosis, which yields daughter cells with only one set of chromosomes, half as many chromosomes as the parent cell. Meiosis in humans occurs only in special cells in the ovaries or testes (the gonads). Generating gametes, meiosis reduces the chromosome number from 46 (two sets) to 23 (one set). Fertilization fuses two gametes together and returns the chromosome number to 46 (two sets). Mitosis then conserves that number in every somatic cell nucleus of the new human individual. In Chapter 13, we will examine the role of meiosis in reproduction and inheritance in more detail. In the remainder of this chapter, we focus on mitosis and the rest of the cell cycle in eukaryotes. Duplicated chromosomes S phase: Metabolic activity, growth, and DNA synthesis G2 phase: Metabolic activity, growth, and preparation for cell division MITOTIC (M) PHASE: Mitosis: Distribution of chromosomes into two daughter nuclei Cytokinesis: Division of cytoplasm, producing two daughter cells. Each daughter cell can start a new cell cycle. Mastering Biology Animation: The Cell Cycle The G phases were misnamed as “gaps” when they were first observed because the cells appeared inactive, but we now know that intense metabolic activity and growth occur throughout interphase. During all three phases of interphase, actually, a cell grows by producing proteins and cytoplasmic organelles such as mitochondria and endoplasmic reticulum. Duplication of the chromosomes, crucial for eventual division of the cell, occurs entirely during the S phase. (We’ll explore synthesis, or replication, of DNA in Concept 16.2.) Thus, a cell grows (G1), continues to grow as it copies its chromosomes (S), grows more as it completes preparations for cell division (G2), and divides (M). The daughter cells may then repeat the cycle. A particular human cell might undergo one division in 24 hours. Of this time, the M phase would occupy less than 1 hour, while the S phase might occupy 10–12 hours, or about half the cycle. The rest of the time would be apportioned between the G1 and G2 phases. The G2 phase usually takes 4–6 hours; in our example, G1 would occupy about 5–6 hours. G1 is the most variable in length in different types of cells. Some cells in a multicellular organism divide very infrequently or not at all. These cells spend their time 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 pancreas secretes digestive enzymes, for example. Mitosis is conventionally broken down into five stages: prophase, prometaphase, metaphase, anaphase, and telophase. Overlapping with the latter stages of mitosis, cytokinesis completes the mitotic phase. Figure 12.7 describes these stages in an animal cell. Study this figure thoroughly before proceeding to the next two sections, which examine mitosis and cytokinesis more closely. CHAPTER 12 The Cell Cycle 237 ▼ Figure 12.7 Exploring Mitosis in an Animal Cell G2 of Interphase Centrosomes (with centriole pairs) Nucleolus Chromosomes (duplicated, uncondensed) Nuclear envelope Plasma membrane G2 of Interphase • A nuclear envelope encloses the nucleus. Prophase Early mitotic spindle Aster Prometaphase Centromere Two sister chromatids of one chromosome Prophase Nonkinetochore microtubules Fragments of nuclear envelope Kinetochore Kinetochore microtubules Prometaphase • The chromatin fibers become more tightly coiled, condensing into discrete chromosomes observable with a light microscope. • The nuclear envelope fragments. • The nucleus contains one or more nucleoli (singular, nucleolus). • Two centrosomes have formed by duplication of a single centrosome. Centrosomes are regions in animal cells that organize the microtubules of the spindle. Each centrosome contains two centrioles. • The nucleoli disappear. • Each duplicated chromosome appears as two identical sister chromatids joined at their centromeres and, often, all along their arms by cohesins, resulting in sister chromatid cohesion. • The chromosomes have become even more condensed. • Chromosomes, duplicated during S phase, cannot be seen individually because they have not yet condensed. • The mitotic spindle (named for its shape) begins to form. It is composed of the centrosomes and the microtubules that extend from them. The radial arrays of shorter microtubules that extend from the centrosomes are called asters (“stars”). The fluorescence micrographs show dividing lung cells from a newt; this species has 22 chromosomes. Chromosomes appear blue, microtubules green, and intermediate filaments red. For simplicity, the drawings show only 6 chromosomes. 238 UNIT TWO The Cell • The centrosomes move away from each other, propelled partly by the lengthening microtubules between them. • The microtubules extending from each centrosome can now invade the nuclear area. • A kinetochore, a specialized protein structure, has now formed at the centromere of each chromatid (thus, two per chromosome). • Some of the microtubules attach to the kinetochores, becoming “kinetochore microtubules,” which jerk the chromosomes back and forth. • Nonkinetochore microtubules interact with those from the opposite pole of the spindle, lengthening the cell. ? How many molecules of DNA are in the prometaphase drawing? How many molecules per chromosome? How many double helices are there per chromosome? Per chromatid? 10 om Metaphase Anaphase Metaphase plate Nucleolus forming Cleavage furrow Daughter chromosomes Spindle Telophase and Cytokinesis Nuclear envelope forming Centrosome at one spindle pole Metaphase Anaphase • The centrosomes are now at opposite poles of the cell. • Anaphase is the shortest stage of mitosis, often lasting only a few minutes. • The chromosomes have all arrived at the metaphase plate, a plane that is equidistant between the spindle’s two poles. The chromosomes’ centromeres lie at the metaphase plate. • Anaphase begins when the cohesin proteins are cleaved. This allows the two sister chromatids of each pair to part suddenly. Each chromatid thus becomes an independent chromosome. • For each chromosome, the kinetochores of the sister chromatids are attached to kinetochore microtubules coming from opposite poles. • The two new daughter chromosomes begin moving toward opposite ends of the cell as their kinetochore microtubules shorten. Because these microtubules are attached at the centromere region, the centromeres are pulled ahead of the arms, moving at a rate of about 1 om/min. Telophase • Two daughter nuclei form in the cell. Nuclear envelopes arise from the fragments of the parent cell’s nuclear envelope and other portions of the endomembrane system. • Nucleoli reappear. • The chromosomes become less condensed. • Any remaining spindle microtubules are depolymerized. • Mitosis, the division of one nucleus into two genetically identical nuclei, is now complete. • The cell elongates as the nonkinetochore microtubules lengthen. Cytokinesis • By the end of anaphase, the two ends of the cell have identical—and complete— collections of chromosomes. • The division of the cytoplasm is usually well under way by late telophase, so the two daughter cells appear shortly after the end of mitosis. Mastering Biology BioFlix® Animation: Mitosis Video: Animal Mitosis (time-lapse) • In animal cells, cytokinesis involves the formation of a cleavage furrow, which pinches the cell in two. CHAPTER 12 The Cell Cycle 239 The Mitotic Spindle: A Closer Look Many of the events of mitosis depend on the mitotic spindle, which begins to form in the cytoplasm during prophase. This structure consists of fibers made of microtubules and associated proteins. While the mitotic spindle assembles, the other microtubules of the cytoskeleton partially disassemble, providing the material used to construct the spindle. The spindle microtubules elongate (polymerize) by incorporating more subunits of the protein tubulin (see Table 6.1) and shorten (depolymerize) by losing subunits. In animal cells, the assembly of spindle microtubules starts at the centrosome, a subcellular region containing material that functions throughout the cell cycle to organize the cell’s microtubules. (It is also a type of microtubule-organizing center.) 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 and prometaphase of mitosis as spindle microtubules grow out from them. By the end of prometaphase, the two centrosomes, 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 chromosome has a kinetochore, a structure made up of proteins that have assembled on specific sections of DNA at each centromere. The chromosome’s two kinetochores face in opposite directions. During prometaphase, some of the spindle microtubules attach to the kinetochores; these are called kinetochore microtubules. (The number of microtubules attached to a kinetochore varies among species, from one microtubule in yeast cells to 40 or so in some mammalian cells.) When one of a chromosome’s kinetochores 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 microtubules from the opposite pole attach to the kinetochore on the other chromatid. What happens next is like a tug-of-war that ends in a draw. The chromosome moves first in one direction and then in the other, back and forth, finally settling midway between the two ends of the cell. At metaphase, the centromeres of all the duplicated chromosomes are on a plane midway between the spindle’s two poles. This plane is called the metaphase plate, which is an imaginary plate rather than an actual cellular structure (Figure 12.8). Meanwhile, microtubules that do not attach to kinetochores have been elongating, and by metaphase they overlap and interact with other nonkinetochore microtubules from the opposite pole of the spindle. By metaphase, the microtubules of 240 UNIT TWO The Cell . Figure 12.8 The mitotic spindle at metaphase. The kinetochores of each chromosome’s two sister chromatids face in opposite directions. Here, each kinetochore is attached to a cluster of kinetochore microtubules (see TEM) extending from the nearest centrosome. Nonkinetochore microtubules overlap at the metaphase plate. The fluorescent micrograph is a rat kangaroo cell at metaphase. Sister chromatids Aster Centrosome Metaphase plate (imaginary) Kinetochores Overlapping nonkinetochore microtubules Kinetochore microtubules Microtubules 0.5 om Chromosomes 5 om Kinetochores DRAW IT On the lower micrograph, draw a line indicating the position of the metaphase plate. Draw arrows showing the directions of chromosome movement when anaphase begins. Mastering Biology Video: Spindle Formation During Mitosis Animation: Mitosis the asters have also grown and are in contact with the plasma membrane. The spindle is now complete. The structure of the spindle correlates well with its function during anaphase. Anaphase begins suddenly when the cohesins holding together the sister chromatids of each chromosome are cleaved by an enzyme called separase. Once separated, the chromatids become individual chromosomes that move toward opposite ends of the cell. How do the kinetochore microtubules function in this poleward movement of chromosomes? Apparently, two mechanisms are in play, both involving motor proteins. (To review how motor proteins move an object along a microtubule, see Figure 6.21.) Results of a cleverly designed experiment suggested that motor proteins on the kinetochores “walk” the chromosomes along the microtubules, which depolymerize at their kinetochore ends after the motor proteins have passed (Figure 12.9). (This is referred to as the “Pacman” mechanism because of its resemblance to the arcade game character that moves by eating all the dots in its path.) However, other researchers, working with different cell types or cells from other species, have shown that chromosomes 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 now is that both mechanisms are used and that their relative contributions vary among cell types. In a dividing animal cell, the nonkinetochore microtubules are responsible for elongating the whole cell during anaphase. Nonkinetochore microtubules from opposite poles overlap each other extensively during metaphase (see Figure 12.8). During anaphase, the region of overlap is reduced as motor proteins 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, elongating the cell. At the same time, the microtubules lengthen somewhat by the addition of tubulin subunits to their overlapping ends. As a result, the microtubules continue to overlap. At the end of anaphase, duplicate groups of chromosomes 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 eventually disassembles by depolymerization of microtubules. Cytokinesis: A Closer Look In animal cells, cytokinesis occurs by a process known as cleavage. The first sign of cleavage is the appearance of a cleavage furrow, a shallow groove in the cell surface near the old metaphase plate (Figure 12.10a). On the cytoplasmic side of the furrow is a contractile ring of actin microfilaments associated with molecules of the protein myosin. The actin microfilaments interact with the myosin molecules, causing the ring to contract. The contraction of the dividing cell’s ring of microfilaments is like the pulling of a drawstring. The cleavage furrow deepens until the parent cell is pinched in two, producing two completely separated cells, each with its own nucleus and its own share of cytosol, organelles, and other subcellular structures. Cytokinesis in plant cells, which have cell walls, is markedly different. There is no cleavage furrow. Instead, during telophase, vesicles derived from the Golgi apparatus move along microtubules to the middle of the cell, where they coalesce, producing a cell plate. Cell wall materials carried in the Inquiry . Figure 12.9 At which end do kinetochore microtubules shorten during anaphase? Experiment Gary Borisy and colleagues at the University of Wisconsin wanted to determine whether kinetochore microtubules depolymerize at the kinetochore end or the pole end as chromosomes move toward the poles during mitosis. First they labeled the microtubules of a pig kidney cell in early anaphase with a yellow fluorescent dye. (Nonkinetochore microtubules are not shown.) Kinetochore Spindle pole Then they marked a region of the kinetochore microtubules between one spindle pole and the chromosomes by using a laser to eliminate the fluorescence from that region, while leaving the microtubules intact (see below). As anaphase proceeded, they monitored the changes in microtubule length on either side of the non-fluorescent mark. Mark Results As the chromosomes moved poleward, the microtubule segments on the kinetochore side of the mark shortened, while those on the spindle pole side stayed the same length. Conclusion During anaphase in this cell type, chromosome movement is correlated with kinetochore microtubules shortening at their kinetochore ends and not at their spindle pole ends. This experiment supports the hypothesis that during anaphase, a chromosome is walked along a microtubule as the microtubule depolymerizes at its kinetochore end, releasing tubulin subunits. Chromosome movement Microtubule Motor protein Chromosome Kinetochore Tubulin subunits Data from G. J. Gorbsky, P. J. Sammak, and G. G. Borisy, Chromosomes move poleward in anaphase along stationary microtubules that coordinately disassemble from their kinetochore ends, Journal of Cell Biology 104:9–18 (1987). WHAT IF? If this experiment had been done on a cell type in which “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 microtubule portions on either side of the mark have changed? Mastering Biology Animation: Microtubule Depolymerization CHAPTER 12 The Cell Cycle 241 . Figure 12.10 Cytokinesis in animal and plant cells. (a) Cleavage of an animal cell (SEM) vesicles collect inside the cell plate as it grows (Figure 12.10b). The cell plate enlarges until its surrounding membrane fuses with the plasma membrane along the perimeter 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 100 om Cleavage furrow Contractile ring of microfilaments Daughter cells (b) Cell plate formation in a plant cell (TEM) Vesicles forming cell plate 1 om Wall of parent cell Cell plate New cell wall Daughter cells Mastering Biology Animation: Cytokinesis Video: Cytokinesis in an Animal Cell 242 UNIT TWO The Cell 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 asexual reproduction of single-celled eukaryotes, such as the 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 simpler than eukaryotic cells, the challenge of replicating their genomes in an orderly fashion and distributing the copies equally to two daughter cells is still formidable. For example, when it is fully stretched out, the chromosome of the bacterium Escherichia coli is about 500 times as long as the cell. 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 replicate 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 chromosome 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 the origins of replication with molecules that glow green in fluorescence microscopy (see Figure 6.3), researchers have 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, possibly anchored there by one or more proteins. How bacterial chromosomes move and how their specific location is established and maintained are active areas of research. Several proteins that play important roles have been identified. Polymerization of one protein resembling eukaryotic actin apparently functions . Figure 12.11 Mitosis in a plant cell. These light micrographs show mitosis in cells of an onion root. Nucleus Nucleolus Chromosomes condensing Chromosomes 1 Prophase. The chromo- somes are condensing and the nucleolus is beginning to disappear. Although not yet visible in the micrograph, the mitotic spindle is starting to form. Cell plate 2 Prometaphase. Discrete chromosomes are now visible; each consists of two aligned, identical sister chromatids. Later in prometaphase, the nuclear envelope will fragment. 3 Metaphase. The spindle is complete, and the chromosomes, attached to microtubules at their kinetochores, are all at the metaphase plate. . Figure 12.12 Bacterial cell division by binary fission. The bacterium E. coli, shown here, has a single, circular chromosome. Cell wall Origin of replication Plasma membrane Bacterial cell 1 Chromosome Two copies replication begins at of origin the origin. Soon after, one copy of the origin moves rapidly toward the other end of the cell by a mechanism involving an actin-like protein. 2 Replication continues. One copy of the origin is now at each end of the cell. Meanwhile, the cell elongates. Origin Bacterial chromosome Origin 3 Replication finishes. The plasma membrane is pinched inward by a tubulin-like protein, and a new cell wall is deposited. 4 Two daughter cells result. Mastering Biology Animation: Cell Division in Bacteria 4 Anaphase. Chromatids of each chromosome have separated. The daughter chromosomes are moving to the ends of the cell as their kinetochore microtubules shorten. 10 om 5 Telophase. Daughter nuclei are forming. Cytokinesis has started: The cell plate, which will divide the cytoplasm in two, grows toward the perimeter of the parent cell. in bacterial chromosome movement during cell division, and another protein that is related to tubulin helps pinch the plasma membrane inward, separating the two bacterial daughter cells. The Evolution of Mitosis EVOLUTION Given that prokaryotes preceded eukaryotes on Earth by more than a billion years, we might hypothesize that mitosis evolved from simpler prokaryotic mechanisms of cell reproduction. The fact that some of the proteins involved in bacterial binary fission are related to eukaryotic proteins that function in mitosis supports that hypothesis. As eukaryotes with nuclear envelopes and larger genomes evolved, the ancestral process of binary fission, seen today in bacteria, somehow gave rise to mitosis. Variations on cell division exist in different groups of organisms. These variant processes may be similar to mechanisms used by ancestral species and thus may resemble steps in the evolution of mitosis from a binary fission-like process presumably carried out by very early bacteria. Possible intermediate stages are suggested by two unusual types of nuclear division found today in certain unicellular eukaryotes—dinoflagellates, diatoms, and some yeasts (Figure 12.13). These two modes of nuclear division are thought to be cases where ancestral mechanisms have remained relatively unchanged over evolutionary 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 in cells of extinct species. This hypothesis uses only currently existing species as some possible examples of intermediate mechanisms. Other mechanisms may have existed in species that have gone extinct; we simply have no way of knowing. CHAPTER 12 The Cell Cycle 243 . Figure 12.13 Mechanisms of cell division in several groups of organisms. Some unicellular eukaryotes existing today have mechanisms of cell division that may resemble intermediate steps in the evolution of mitosis. Except for (a), cell walls are not shown. CONCEPT CHECK 12.2 1. How many chromosomes are shown in the illustration in Figure 12.8? Are they duplicated? How many chromatids are shown? 2. Compare cytokinesis in animal cells and plant cells. Bacterial chromosome (a) Bacteria. During binary fission in bacteria, the origins of the daughter chromosomes move to opposite ends of the cell. The mechanism involves polymerization of actin-like molecules and possibly proteins that may anchor the daughter chromosomes to specific sites on the plasma membrane. Chromosomes Microtubules Intact nuclear envelope (b) Dinoflagellates. In unicellular eukaryotes called dinoflagellates, the chromosomes attach to the nuclear envelope, which remains intact during cell division. Microtubules pass through the nucleus inside cytoplasmic tunnels, reinforcing the spatial orientation of the nucleus, which then divides in a process reminiscent of bacterial binary fission. Kinetochore microtubule Intact nuclear envelope (c) Diatoms and some yeasts. In these two other groups of unicellular eukaryotes, the nuclear envelope also remains intact during cell division. In these organisms, the microtubules form a spindle within the nucleus. Microtubules separate the chromosomes, and the nucleus splits into two daughter nuclei. Kinetochore microtubule Fragments of nuclear envelope (d) Most eukaryotes. In most other eukaryotes, including plants and animals, the spindle forms outside the nucleus, and the nuclear envelope breaks down during mitosis. Microtubules separate the chromosomes, and two nuclear envelopes then form. Mastering Biology Video: Nuclear Envelope Breakdown and Formation During Mitosis in C. elegans, a Eukaryote 244 UNIT TWO The Cell 3. During which stages of the cell cycle does a chromosome consist of two identical chromatids? 4. Compare the roles of tubulin and actin during eukaryotic cell division with the roles of tubulin-like and actin-like proteins during bacterial binary fission. 5. A kinetochore has been compared to a coupling device that connects a motor to the cargo that it moves. Explain. 6. MAKE CONNECTIONS What other functions do actin and tubulin carry out? Name the proteins they interact with to do so. (Review Figures 6.21a and 6.26a.) For suggested answers, see Appendix A. CONCEPT 12.3 The eukaryotic cell cycle is regulated by a molecular control system The timing and rate of cell division in different parts of a plant or animal are crucial to normal growth, development, and maintenance. The frequency of cell division varies with the type of cell. For example, human skin cells divide frequently 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 as fully formed nerve cells and muscle cells, do not divide at 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 cycles of normal cells but also to learn how cancer cells manage to escape the usual controls. The Cell Cycle Control System What controls the cell cycle? In the early 1970s, a variety of experiments led to the hypothesis that the cell cycle is driven by specific signaling molecules present in the cytoplasm. Some of the first strong evidence for this hypothesis came from experiments with mammalian cells grown in culture. In these experiments, 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. Similarly, if a cell undergoing mitosis (M phase) was fused with another cell in any stage of its cell cycle, even G1, the second nucleus immediately entered mitosis, with condensation of the chromatin and formation of a mitotic spindle. The experiment shown in Figure 12.14 and other experiments on animal cells and yeasts demonstrated that the . Figure 12.14 Inquiry Do molecular signals in the cytoplasm regulate the cell cycle? Experiment Researchers at the University of Colorado wondered whether a cell’s progression through the cell cycle is controlled by cytoplasmic molecules. They induced cultured mammalian cells at different phases of the cell cycle to fuse. Two experiments are shown. . Figure 12.15 Mechanical analogy for the cell cycle control system. In this diagram, the flat “stepping stones” around the perimeter represent sequential events. Like the control device of a washing machine, 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 at various checkpoints; three important checkpoints are shown (red). G1 checkpoint Results Duplicated chromosomes Experiment 1 Experiment 2 Control system G1 S G1 Fusion M G1 M S G2 Fusion M checkpoint G2 checkpoint S S When a cell in S phase was fused with a cell in G1, the G1 nucleus immediately entered S phase—DNA was synthesized. M M When a cell in M phase was fused with a cell in G1, the G1 nucleus immediately began mitosis—a spindle formed and the chromosomes condensed, even though the chromosomes had not been duplicated. 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 during the S or M phase control the progression to those phases. 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). WHAT IF? If the progression of phases did not depend on cytoplasmic molecules and each phase began when the previous one was complete, how would the results have differed? sequential events of the cell cycle are directed by a distinct cell cycle control system, a cyclically operating set of molecules in the cell that both triggers and coordinates key events in the cell cycle (Figure 12.15). The cell cycle control system has been compared to the control device of a washing machine. Like the washer’s timing device, the cell cycle control system proceeds on its own, according to a built-in clock. However, just as a washer’s cycle is subject to both internal control (such as the sensor that detects when the tub is filled with water) and external adjustment (such as starting or stopping the machine), the cell cycle is regulated at certain checkpoints by both internal and external signals. A checkpoint in the cell cycle is a control point where stop and go-ahead signals can regulate the cycle. Three important checkpoints are found in the G1, G2, and M phases (red gates in Figure 12.15), which will be discussed shortly. To understand how cell cycle checkpoints work, we’ll first identify some of the molecules that make up the cell cycle Mastering Biology Animation: Control of the Cell Cycle control system (the molecular basis for the cell cycle clock) and describe how a cell progresses through the cycle. We’ll then consider the internal and external checkpoint signals that can make the clock either pause or continue. The Cell Cycle Clock: Cyclins and Cyclin-Dependent Kinases Rhythmic fluctuations in the abundance and activity of cell cycle control molecules pace the sequential events of the cell cycle. These regulatory molecules are mainly proteins of two types: protein kinases and cyclins. As you learned in Concept 11.3, protein kinases are enzymes that activate or inactivate other proteins by phosphorylating them. Many of the kinases that drive the cell cycle are actually present at a constant concentration in the growing cell, but much of the time they are in an inactive form. To be active, such a kinase must be attached to a cyclin, a protein that gets its name from its cyclically fluctuating concentration in the cell. Because of this requirement, these kinases are called cyclin-dependent kinases, or Cdks. The activity of a Cdk rises and falls with changes in the concentration of its cyclin partner. Figure 12.16a shows the fluctuating activity of MPF, the cyclin-Cdk complex that was discovered first (in frog eggs). Note that the peaks of MPF activity correspond to the peaks of cyclin concentration. The cyclin level rises during the S and G2 phases and then falls abruptly during M phase. The initials MPF stand for “maturation-promoting factor,” but we can think of MPF as “M-phase-promoting factor” because it triggers the cell’s passage into the M phase, past the G2 checkpoint. When cyclins that accumulate during G2 associate with Cdk molecules, the resulting MPF complex CHAPTER 12 The Cell Cycle 245 is active—it phosphorylates a variety of proteins, initiating mitosis (Figure 12.16b). MPF acts both directly as a kinase and indirectly by activating other kinases. For example, MPF causes phosphorylation of various proteins of the nuclear . Figure 12.16 Molecular control of the cell cycle at the G2 checkpoint. The steps of the cell cycle are timed by rhythmic fluctuations in the activity of cyclin-dependent kinases (Cdks). Here we focus on a cyclin-Cdk complex in animal cells called MPF, which acts at the G2 checkpoint as a go-ahead signal, triggering the events of mitosis. M G1 S G2 M G1 S G2 M G1 MPF activity Cyclin concentration Time (a) Fluctuation of MPF activity and cyclin concentration during the cell cycle 1 Synthesis of cyclin begins in late S phase and continues through G2. Because cyclin is protected from degradation during this stage, it accumulates. G Cdk Degraded cyclin M G2 MPF 4 During anaphase, the cyclin component of MPF is degraded, terminating the M phase. The cell enters the G1 phase. 3 MPF promotes mitosis by phosphorylating various proteins. MPF‘s activity peaks during metaphase. Cdk n G2 checkpoint Cyclin is degraded Cyclin accumulatio S 1 5 During G1, the degradation of cyclin continues, and the Cdk component of MPF is recycled. Cyclin 2 Cyclin combines with Cdk, producing MPF. When enough MPF molecules accumulate, the cell passes the G2 checkpoint and begins mitosis. (b) Molecular mechanisms that help regulate the cell cycle 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. Mastering Biology Interview with Paul Nurse: Discovering how protein kinases control the cell cycle 246 UNIT TWO The Cell lamina (see Figure 6.9), which promotes fragmentation of the nuclear envelope during prometaphase of mitosis. There is also evidence that MPF contributes to molecular events required for chromosome condensation and spindle formation during prophase. During anaphase, MPF helps switch itself off by initiating a process that leads to the destruction of its own cyclin. The noncyclin part of MPF, the Cdk, persists in the cell, inactive until it becomes part of MPF again by associating with new cyclin molecules synthesized during the S and G2 phases of the next round of the cycle. The fluctuating activities of different cyclin-Cdk complexes are of major importance in controlling all the stages of the cell cycle; they also give the go-ahead signals at some checkpoints. As mentioned above, MPF controls the cell’s passage through the G2 checkpoint. Cell behavior at the G1 checkpoint is also regulated by the activity of cyclin-Cdk protein complexes. Animal cells appear to have at least three Cdk proteins and several different cyclins that operate at this checkpoint. Next, let’s consider checkpoints in more detail. Stop and Go Signs: Internal and External 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. Many signals registered at checkpoints come from cellular surveillance mechanisms inside the cell. These signals report whether crucial cellular processes that should have occurred by that point have in fact been completed correctly and thus whether or not the cell cycle should proceed. Checkpoints also register signals from outside the cell. The signals are transmitted within the cell by signal transduction pathways (see Figure 11.6). Three important checkpoints are those in the G1, G2, and M phases (see Figure 12.15). For many cells, the G1 checkpoint 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 go-ahead signal at that point, it may exit the cycle, switching into a nondividing state called the G0 phase (Figure 12.17a). Most cells of the human body are actually in the G0 phase. As mentioned earlier, mature nerve cells and muscle cells never divide. Other cells, such as liver cells, can be “called back” from the G0 phase to the cell cycle by external cues, such as growth factors released during injury. Biologists are currently working out the pathways that link signals originating inside and outside the cell with the responses by cyclin-dependent kinases and other proteins. An example of an internal signal occurs at the third important checkpoint, the M checkpoint (Figure 12.17b). Anaphase, the separation of sister chromatids, does not begin until all the chromosomes are properly attached to the spindle at the metaphase plate. Researchers have learned that as long as some kinetochores are unattached to spindle microtubules, the sister chromatids remain together, delaying anaphase. Only when . Figure 12.17 Two important checkpoints. At certain checkpoints in the the kinetochores of all the chromosomes are properly cell cycle (red gates), cells do different things depending on the signals they attached to the spindle does the appropriate regulareceive. Events of the (a) G1 and (b) M checkpoints are shown. In (b), the G2 tory protein complex become activated. (In this case, checkpoint has already been passed by the cell. the regulatory molecule is not a cyclin-Cdk complex but, instead, a different complex made up of several (a) G1 checkpoint proteins.) Once activated, the complex sets off a chain G1 checkpoint of molecular events that activates the enzyme separase, which cleaves the cohesins, allowing the sister chromaG0 tids to separate. This mechanism ensures that daughter cells do not end up with missing or extra chromosomes. There are checkpoints in addition to those in G1, G2, and M. For instance, a checkpoint in S phase stops cells with DNA damage from proceeding in the cell cycle. And, in 2014, researchers presented evidence for G1 G1 another checkpoint between anaphase and telophase In the absence of a go-ahead signal, If a cell receives a go-ahead signal, the that ensures anaphase is completed and the chromoa cell exits the cell cycle and enters cell continues on in the cell cycle. somes are well separated before cytokinesis can begin, G0, a nondividing state. thus avoiding chromosomal damage. What about the stop and go-ahead signals (b) M checkpoint themselves—what are the signaling molecules? Studies using animal cells in culture have led to the identifiG1 G1 cation of many external factors, both chemical and physical, that can influence cell division. For example, M G2 M cells fail to divide if an essential nutrient is lacking in G2 the culture medium. (This is analogous to trying to run a washing machine without the water supply hooked M checkpoint up; an internal sensor won’t allow the machine to continue past the point where water is needed.) And even if all other conditions are favorable, most types of Anaphase G2 mammalian cells divide in culture only if the growth checkpoint medium includes specific growth factors. As mentioned Prometaphase Metaphase in Concept 11.1, a growth factor is a protein released When all chromosomes are attached A cell in mitosis receives a stop signal by certain cells that stimulates other cells to divide. when any of its chromosomes are not to spindle fibers from both poles, a go-ahead signal allows the cell to attached to spindle fibers. Different cell types respond specifically to different proceed into anaphase. growth factors or combinations of growth factors. Consider, for example, platelet-derived growth factor WHAT IF? What might be the result if the cell ignored either checkpoint (PDGF), which is made by blood cell fragments called and progressed through the cell cycle? platelets. When an injury occurs, platelets release PDGF in the vicinity. The experiment illustrated in of a culture flask, at which point the cells stop dividing. If some Figure 12.18 demonstrates that PDGF is required for the divicells are removed, those bordering the open space begin dividing sion of cultured fibroblasts, a type of connective tissue cell. again and continue until the vacancy is filled. Follow-up studies Fibroblasts have PDGF receptors on their plasma membranes. revealed that the binding of a cell-surface protein to its counterThe binding of PDGF molecules to these receptors (which part on an adjoining cell sends a signal to both cells that inhibits are receptor tyrosine kinases; see Figure 11.8) triggers a signal cell division, preventing them from moving forward in the cell transduction pathway that allows the cells to pass the G1 cycle, even in the presence of growth factors. checkpoint and divide. PDGF stimulates fibroblast division Most animal cells also exhibit anchorage dependence not only in the artificial conditions of cell culture but also (see Figure 12.19a). To divide, they must be attached to somein an animal’s body. Thus, injury results in a proliferation of thing, such as the inside of a culture flask or the extracellular fibroblasts that helps heal the wound. matrix of a tissue. Experiments suggest that, like cell density, The effect of an external physical factor on cell division is anchorage is signaled to the cell cycle control system via clearly seen in density-dependent inhibition, a phenompathways involving plasma membrane proteins and elements enon in which crowded cells stop dividing (Figure 12.19a). of the cytoskeleton linked to them. Studies done many years ago showed that cultured cells normally Density-dependent inhibition and anchorage dependence divide until they form a single layer of cells on the inner surface appear to function not only in cell culture but also in the CHAPTER 12 The Cell Cycle 247 . Figure 12.18 The effect of platelet-derived growth factor (PDGF) on cell division. . Figure 12.19 Density-dependent inhibition and anchorage dependence of cell division. Individual cells are shown disproportionately large in the drawings. Scalpels 1 A sample of human connective tissue is cut up into small pieces. Cells anchor to dish surface and divide (anchorage dependence). Petri dish When cells have formed a complete single layer, they stop dividing (density-dependent inhibition). 2 Enzymes are used to digest the extracellular matrix in the tissue pieces, resulting in a suspension of free fibroblasts. 3 Cells are transferred to culture vessels containing a basic growth medium consisting of glucose, amino acids, salts, and antibiotics (to prevent bacterial growth). If some cells are scraped away, the remaining cells divide to fill the gap and then stop once they contact each other. 4 PDGF is added to half the vessels. The culture vessels are incubated at 37°C for 24 hours. 20 om Without PDGF With PDGF In the basic growth medium without PDGF (the control), the cells fail to divide. In the basic growth medium plus PDGF, the cells proliferate. The SEM shows cultured fibroblasts. (a) Normal mammalian cells. Cell density is limited to a single layer by contact with neighboring cells and the availability of nutrients, growth factors, and a substratum for attachment. MAKE CONNECTIONS 20 om 10 om PDGF signals cells by binding to a cell-surface receptor tyrosine kinase. If you added a chemical that blocked phosphorylation, how would the results differ? (See Figure 11.8.) body’s tissues, checking the growth of cells at some optimal density and location during embryonic development and throughout an organism’s life. Cancer cells, which we examine next, exhibit neither density-dependent inhibition nor anchorage dependence (Figure 12.19b). Loss of Cell Cycle Controls in Cancer Cells Cancer cells do not heed the normal signals that regulate the cell cycle. In culture, they do not stop dividing when growth factors are depleted. A logical hypothesis is that cancer cells do not need growth factors in their culture medium to grow and divide. They may make a required growth factor themselves, or they may have an abnormality in the signaling pathway that conveys the growth factor’s signal to the cell cycle control system even in the absence of that factor. Another possibility is an abnormal cell cycle control system. 248 UNIT TWO The Cell (b) Cancer cells. Cancer cells usually continue to divide well beyond a single layer, forming a clump of overlapping cells. They do not exhibit anchorage dependence or density-dependent inhibition. In these scenarios, the underlying basis of the abnormality is almost always a change in one or more genes (for example, a mutation) that alters the function of their protein products, resulting in faulty cell cycle control. We’ll explore the molecular basis for such changes in Concept 18.5. There are other important differences between normal cells and cancer cells that reflect malfunctions of the cell cycle. If and when they stop dividing, cancer cells do so at random points in the cycle, rather than at the normal checkpoints. Moreover, cancer cells can go on dividing indefinitely in culture if they are given a continual supply of nutrients; in essence, they are “immortal.” A striking example is a cell line that has been reproducing in culture since 1951. Cells of this line are called HeLa cells because their original source was a tumor removed from a woman named Henrietta Lacks. (Neither Ms. Lacks nor her family gave permission or even is an ongoing debate. Their metabolism may be altered, and they may cease to function in any constructive way. Abnormal changes on the cell surface cause cancer cells to lose attachments to neighboring cells and the extracellular matrix, allowing them to spread into nearby tissues. Cancer cells may also secrete signaling molecules that cause blood vessels to grow toward the tumor. A few tumor cells may separate from the original tumor, enter blood vessels and lymph vessels, and travel to other parts of the body. There, they may proliferate and form a new tumor. This spread of cancer cells to locations distant from their original site is called metastasis (see Figure 12.20). A tumor that appears to be local