2Overview: The Key Roles of Cell Division The continuity of lifeIs based upon the reproduction of cells, or cell divisionFigure 12.1
3Unicellular organisms often reproduce by mitotic cell division (asexual) …but so do others100 µmAn amoeba, a single-celled eukaryote, is dividing into two cells. Each new cell will be an individual organism.SporesVegetative propagationAnimation of bacterial DNA replication = Binary fission.budding
4Multicellular organisms depend on cell division for Development from a fertilized cellGrowthRepair20 µm200 µm(b) Growth and development This micrograph shows a sand dollar embryo shortly after the fertilized egg divided, forming two cells (LM).(c) Tissue renewal. These dividing bone marrow cells (arrow) will give rise to new blood cells (LM).Figure 12.2 B, C
5CELL DIVISION Is an integral part of the cell cycle MITOTIC cell division results in genetically identical daughter cellsCells duplicate their genetic materialBefore they divide, ensuring that each daughter cell receives an exact copy of the genetic material, DNA
6Cellular Organization of the Genetic Material A cell’s endowment of DNA, its genetic informationIs called its genomeThe DNA molecules in a cellAre packaged into chromosomes50 µm
7Eukaryotic chromosomes Consist of chromatin, a complex of DNA and protein that condenses during cell divisionIn animalsSomatic cells have two sets of chromosomesDiploid (2n)Gametes have one set of chromosomesHaploid (n)
8Distribution of Chromosomes During Cell Division In preparation for cell divisionDNA is replicated and the chromosomes condense0.5 µmChromosome duplication (including DNA synthesis)CentromereSeparation of sister chromatidsSister chromatidsCentromeresA eukaryotic cell has multiple chromosomes, one of which is represented here. Before duplication, each chromosome has a single DNA molecule.Once duplicated, a chromosome consists of two sister chromatids connected at the centromere. Each chromatid contains a copy of the DNA molecule.Mechanical processes separate the sister chromatids into two chromosomes and distribute them to two daughter cells.Figure 12.4Each duplicated chromosome has two sister chromatids, which separate during cell division
9Eukaryotic cell division consists of Mitosis, the division of the nucleusCytokinesis, the division of the cytoplasmIn meiosisSex cells are produced after a reduction in chromosome number
10Phases of the Cell Cycle The cell cycle consists ofThe mitotic phaseInterphaseNotice the time spent in interphaseINTERPHASEG1S (DNA synthesis)G2Cytokinesis MitosisMITOTIC (M) PHASEFigure 12.5
11What happens during Interphase? Interphase can be divided into subphasesG1 phaseS phaseG2 phaseThe G0 phase (referred to the G zero phase) or resting phase is a period in the cell cycle in which cells exist in a quiescent state. G0 phase is viewed as either an extended G1 phase, where the cell is neither dividing nor preparing to divide, or a distinct quiescent stage that occurs outside of the cell cycle. Some types of cells, such as nerve and heart muscle cells, become quiescent when they reach maturity.
12MITOSISThe mitotic phaseIs made up of mitosis and cytokinesis
13Kinetochore microtubule PMATMitosis consists of four distinct phasesProphaseG2 OF INTERPHASEPROPHASEPROMETAPHASECentrosomes (with centriole pairs)Chromatin (duplicated)Early mitotic spindleAsterCentromereFragments of nuclear envelopeKinetochoreNucleolusNuclear envelopePlasma membraneChromosome, consisting of two sister chromatidsKinetochore microtubuleFigure 12.6Nonkinetochore microtubules
14TELOPHASE AND CYTOKINESIS MetaphaseAnaphaseTelophaseCentrosome at one spindle poleDaughter chromosomesMETAPHASEANAPHASETELOPHASE AND CYTOKINESISSpindleMetaphase plateNucleolus formingCleavage furrowNuclear envelope formingFigure 12.6
15The Mitotic Spindle: A Closer Look Is an apparatus of microtubules that controls chromosome movement during mitosisThe spindle arises from the centrosomesAnd includes spindle microtubules and asters
16Some spindle microtubules Attach to the kinetochores of chromosomes and move the chromosomes to the metaphase plateCentrosomeAsterSister chromatidsMetaphase PlateKinetochoresOverlapping nonkinetochore microtubulesKinetochores microtubulesChromosomesMicrotubules0.5 µm1 µmFigure 12.7
17In anaphase, sister chromatids separate And move along the kinetochore microtubules toward opposite ends of the cellEXPERIMENT1 The microtubules of a cell in early anaphase were labeled with a fluorescent dye that glows in the microscope (yellow).Spindle poleKinetochoreFigure 12.8
18Nonkinetechore microtubules from opposite poles Overlap and push against each other, elongating the cellIn telophaseGenetically identical daughter nuclei form at opposite ends of the cell
19Cytokinesis: A Closer Look In animal cellsCytokinesis occurs by a process known as cleavage, forming a cleavage furrowCleavage furrowContractile ring of microfilamentsDaughter cells100 µm(a) Cleavage of an animal cell (SEM)Figure 12.9 A
20(b) Cell plate formation in a plant cell (SEM) In plant cells, during cytokinesisA cell plate formsDaughter cells1 µmVesicles forming cell plateWall of patent cellCell plateNew cell wall(b) Cell plate formation in a plant cell (SEM)Figure 12.9 B
21Mitosis in a plant cell Nucleus Chromatine condensing Chromosome 1Prophase. The chromatin is condensing. The nucleolus is beginning to disappear. Although not yet visible in the micrograph, the mitotic spindle is staring to from.Prometaphase. We now see discrete chromosomes; each consists of two identical sister chromatids. Later in prometaphase, the nuclear envelop will fragment.Metaphase. The spindle is complete, and the chromosomes, attached to microtubules at their kinetochores, are all at the metaphase plate.Anaphase. The chromatids of each chromosome have separated, and the daughter chromosomes are moving to the ends of cell as their kinetochore microtubles shorten.Telophase. Daughter nuclei are forming. Meanwhile, cytokinesis has started: The cell plate, which will divided the cytoplasm in two, is growing toward the perimeter of the parent cell.2345NucleusNucleolusChromosomeChromatine condensingFigure 12.10
22Mitosis and cytokinesis narrated animation How the Cell Cycle Works narrated animation
23The Cell Cycle Control System The sequential events of the cell cycleAre directed by a distinct cell cycle control system, which is similar to a clockFigure 12.14Control systemG2 checkpointM checkpointG1 checkpointG1SG2M
24The clock has specific checkpoints Where the cell cycle stops until a go-ahead signal is receivedG1 checkpointG1G0(a) If a cell receives a go-ahead signal at the G1 checkpoint, the cell continues on in the cell cycle.(b) If a cell does not receive a go-ahead signal at the G1checkpoint, the cell exits the cell cycle and goes into G0, anondividing state.Figure A, B
25Regulation of the Cell Cycle The frequency of cell divisionVaries with the type of cellThe cell cycle is regulated by a molecular control systemMolecules present in the cytoplasmRegulate progress through the cell cycleTwo types of regulatory proteins are involved in cell cycle controlCyclinsCyclin-dependent kinases (Cdks)Narrated animation “Control of the Cell Cycle”
26Cell division is tightly controlled by complexes made of several specific proteins. These complexes contain enzymes called cyclin-dependent kinases (CDKs), which turn on or off the various processes that take place in cell division.CDK partners with a family of proteins called cyclins.One such complex is mitosis-promoting factor (MPF), sometimes called maturation-promoting factor, which contains cyclin A or B and cyclin-dependent kinase (CDK). (See Figure 2a.)CDK is activated when it is bound to cyclin, interacting with various other proteins that, in this case, allow the cell to proceed from G2 into mitosis.The levels of cyclin change during the cell cycle (Figure 2b). In most cases, cytokinesis follows mitosis.Narrated animation: Cell Proliferation Signaling Pathway
27As shown in Figure 3, different CDKs are produced during the phases As shown in Figure 3, different CDKs are produced during the phases. The cyclins determine which processes in cell division are turned on or off and in what order by CDK. As each cyclin is turned on or off, CDK causes the cell to move through the stages in the cell cycle.
28Both internal and external signals Control the cell cycle checkpoints There are three checkpoints a cell must pass through: the G1 checkpoint, G2 checkpoint, and the M-spindle checkpoint (Figure 4).At each of the checkpoints, the cell checks that it has completed all of the tasks needed and is ready to proceed to the next step in its cycle.Cells pass the G1 checkpoint when they are stimulated by appropriate external growth factors; for example, platelet-derived growth factor (PDGF) stimulates cells near a wound to divide so that they can repair the injury.The G2 checkpoint checks for damage after DNA is replicated, and if there is damage, it prevents the cell from going into mitosis.The M-spindle (metaphase) checkpoint assures that the mitotic spindles or microtubules are properly attached to the kinetochores (anchor sites on the chromosomes). If the spindles are not anchored properly, the cell does not continue on through mitosis.The cell cycle is regulated very precisely.Mutations in cell cycle genes that interfere with proper cell cycle control are found very often in cancer cells.
29Growth Factor proteins Growth factorsStimulate other cells to divideEXPERIMENTA sample of connective tissue was cut up into small pieces.Enzymes were used to digest the extracellular matrix, resulting in a suspension of free fibroblast cells.Cells were transferred to sterile culture vessels containing a basic growth medium consisting of glucose, amino acids, salts, and antibiotics (as a precaution against bacterial growth). PDGF was added to half the vessels. The culture vessels were incubated at 37°C.321Petri plateWithout PDGFWith PDGFScalpelsFigure 12.17
30Environmental effects on cell cycling In density-dependent inhibitionCrowded cells stop dividingMost animal cells exhibit anchorage dependenceIn which they must be attached to a substratum to divideCells anchor to dish surface anddivide (anchorage dependence).When cells have formed a complete single layer, they stop dividing (density-dependent inhibition).If some cells are scraped away, the remaining cells divide to fill the gap and then stop (density-dependent inhibition).Normal mammalian cells. The availability of nutrients, growth factors, and a substratum for attachment limits cell density to a single layer.(a)25 µmFigure A
31Cancer cellsExhibit neither density-dependent inhibition nor anchorage dependence25 µmCancer cells do not exhibit anchorage dependence or density-dependent inhibition.Cancer cells. Cancer cells usually continue to divide well beyond a single layer, forming a clump of overlapping cells.(b)Most oncogenes are mutations of certain normal genes called proto-oncogenes.Proto-oncogenes are the "good" genes that normally control what kind of cell it is and how often it divides.When a proto-oncogene mutates (changes) into an oncogene, it becomes a "bad" gene that can become permanently turned on or activated when it is not supposed to be. When this happens, the cell grows out of control, which can lead to cancer.
32Loss of cell cycle control How cell division (and thus tissue growth) is controlled is very complex. The following terms are some of the features that are important in regulation, and places where errors can lead to cancer.Cancer is a disease where regulation of the cell cycle goes awry and normal cell growth and behavior is lost.Cdk (cyclin dependent kinase, adds phosphate to a protein), along with cyclins, are major control switches for the cell cycle, causing the cell to move from G1 to S or G2 to M.MPF (Maturation Promoting Factor) includes the CdK and cyclins that triggers progression through the cell cycle.p53 is a protein that functions to block the cell cycle if the DNA is damaged. If the damage is severe this protein can cause apoptosis (cell death).p53 levels are increased in damaged cells. This allows time to repair DNA by blocking the cell cycle.A p53 mutation is the most frequent mutation leading to cancer. An extreme case of this is Li Fraumeni syndrome, where a genetic a defect in p53 leads to a high frequency of cancer in affected individuals.p27 is a protein that binds to cyclin and cdk blocking entry into S phase. Recent research (Nature Medicine 3, 152 (1997)) suggests that breast cancer prognosis is determined by p27 levels. Reduced levels of p27 predict a poor outcome for breast cancer patients.
33Loss of Cell Cycle Controls in Cancer Cells Do not respond normally to the body’s control mechanismsForm tumorsP53 is a tumor suppressor protein that in humans is encoded by the TP53 geneRas proteins also play a role in cell growth and division. Overactive Ras signaling can ultimately lead to cancer(rat sarcoma)BRCA1 and BRCA 2 are tumor-suppressor genes expressed in the cells of breast and other tissue, where it helps repair damaged DNA, or destroy cells if DNA cannot be repaired. If BRCA itself is damaged, damaged DNA is not repaired properly and this increases risks for cancers
34Malignant tumors invade surrounding tissues and can metastasize Exporting cancer cells to other parts of the body where they may form secondary tumorsTumorGlandulartissueCancer cellBlood vesselLymph vesselMetastatic TumorA tumor grows from a single cancer cell.1Cancer cells invade neighboring tissue.2Cancer cells spread through lymph and blood vessels toother parts of the body.3A small percentage of cancer cells may survive and establish a new tumor in another part of the body.4Figure 12.19
35MeiosisConcept 13.3: Meiosis reduces the number of chromosome sets from diploid to haploidMeiosis takes place in two sets of divisions, meiosis I and meiosis IIAnimated comparison between mitosis and meiosis
36OverviewMeiosis IReplicates the diploid number of chromosomes and recombines them randomlyMeiosis IIReduces the number of chromosomes from diploid to haploidNarrated animation of the stages of meiosis
37Interphase and meiosis I Centrosomes(with centriole pairs)SisterchromatidsChiasmataSpindleTetradNuclearenvelopeChromatinCentromere(with kinetochore)Microtubuleattached tokinetochoreTertads line upMetaphaseplateHomologouschromosomesseparateSister chromatidsremain attachedPairs of homologouschromosomes split upChromosomes duplicateHomologous chromosomes(red and blue) pair and exchangesegments; 2n = 6 in this exampleINTERPHASEMEIOSIS I: Separates homologous chromosomesPROPHASE IMETAPHASE IANAPHASE IFigure 13.8
38Telophase I, cytokinesis, and meiosis II TELOPHASE I ANDCYTOKINESISPROPHASE IIMETAPHASE IIANAPHASE IITELOPHASE II ANDMEIOSIS II: Separates sister chromatidsCleavagefurrowSister chromatidsseparateHaploid daughter cellsformingDuring another round of cell division, the sister chromatids finally separate;four haploid daughter cells result, containing single chromosomesTwo haploid cellsform; chromosomesare still doubleFigure 13.8
39A Comparison of Mitosis and Meiosis Meiosis and mitosis can be distinguished from mitosis by three events in Meiosis lSynapsis and crossing overHomologous chromosomes physically connect and exchange genetic informationTetrads on the metaphase plateAt metaphase I of meiosis, paired homologous chromosomes (tetrads) are positioned on the metaphase platesSeparation of homologuesAt anaphase I of meiosis, homologous pairs move toward opposite poles of the cellIn anaphase II of meiosis, the sister chromatids separateFlash animation of these events
40Daughter cells of meiosis II A comparison of mitosis and meiosisFigure 13.9MITOSISMEIOSISProphaseDuplicated chromosome(two sister chromatids)ChromosomereplicationParent cell(before chromosome replication)Chiasma (site ofcrossing over)MEIOSIS IProphase ITetrad formed bysynapsis of homologouschromosomesMetaphaseChromosomespositioned at themetaphase plateTetradsMetaphase IAnaphase ITelophase IHaploidn = 3MEIOSIS IIDaughtercells ofmeiosis IHomologuesseparateduringanaphase I;sisterchromatidsremain togetherDaughter cells of meiosis IInSister chromatids separate during anaphase IIAnaphaseTelophaseSister chromatidsseparate duringanaphase2nDaughter cellsof mitosis2n = 6
41Meiosis leads to greater genetic variation in offspring Concept 13.4: Genetic variation produced in sexual life cycles contributes to evolutionReshuffling of genetic material in meiosis (crossing over) animationProduces genetic variation