2Biology is the only subject in which multiplication is the same thing as division…
3Why do cells divide? For reproduction For growth For repair & renewal asexual reproductionone-celled organismsFor growthfrom fertilized egg to multi-celled organismFor repair & renewalreplace cells that die from normal wear & tear or from injuryamoebaUnicellular organismsCell division = reproductionReproduces entire organism& increase populationMulticellular organismsCell division provides for growth & development in a multicellular organism that begins as a fertilized eggAlso use cell division to repair & renew cells that die from normal wear & tear or accidents
4Importance of Cell Division 1. Growth and Development2. Asexual Reproduction Tissue RenewalZygote Embryo Fetus Adult1 Cell cells millions cells 100 trillion cells
5DNA organization in Prokaryotes Nucleoid regionBacterial ChromosomeSingle (1) circular DNASmall(e.g. E. coli is 4.6X106 bp, ~1/100th human chromosome)Plasmids – extra chromosomal DNA
7The Cell Cycle Interphase (90% of cycle) Mitotic phase • G1 phase~ growth• S phase~ synthesis of DNA• G2 phase~ preparation for cell divisionMitotic phase• Mitosis~ nuclear division• Cytokinesis~ cytoplasm division
8Parts of Cell Cycle Interphase M phase G1 S phase G2 Mitosis (Division of nucleus)ProphasePrometaphaseMetaphaseAnaphaseTelophaseCytokinesis (Division of cytoplasm)
9Cell Division: Key Roles Genome: cell’s genetic informationSomatic (body cells) cellsGametes (reproductive cells): sperm and egg cellsChromosomes: condensed DNA moleculesDiploid (2n): 2 sets of chromosomesHaploid (1n): 1 set of chromosomesChromatin: DNA-protein complexChromatids: replicated strands of a chromosomeCentromere: narrowing “waist” of sister chromatidsMitosis: nuclear divisionCytokinesis: cytoplasm divisionMeiosis: gamete cell division
10Chromosome Organization When cells divide, daughter cells must each receive complete copy of DNAEach cell has about 2 meters of DNA in the nucleus; thin threads called chromatinBefore division, condenses to form chromosomesDNA also replicates before cell division to produce paired chromatids
14Prophase Chromatin condenses visible chromosomes chromatidsCentrioles move to opposite poles of cellanimal cellProtein fibers cross cell to form mitotic spindlemicrotubulesNucleolus disappearsNuclear membrane breaks down
15Prometaphase spindle fibers attach to centromeres creating kinetochoresmicrotubules attach at kinetochoresconnect centromeres to centrioleschromosomes begin moving
16Metaphase Centrosomes at opposite poles Centromeres are aligned Kinetochores of sister chromatids attached to microtubules (spindle)
18Anaphase Paired centromeres separate; sister chromatids liberated Chromosomes move to opposite polesEach pole now has a complete set of chromosomes
19Separation of chromatids In anaphase, proteins holding together sister chromatids are inactivatedseparate to become individual chromosomes1 chromosome2 chromatids2 chromosomessingle-strandeddouble-stranded
20Chromosome movementKinetochores use motor proteins that “walk” chromosome along attached microtubulemicrotubule shortens by dismantling at kinetochore (chromosome) endMicrotubules are NOT reeled in to centrioles like line on a fishing rod.The motor proteins walk along the microtubule like little hanging robots on a clothes line.In dividing animal cells, non-kinetochore microtubules are responsible for elongating the whole cell during anaphase, readying fro cytokinesis
21Telophase Cytokinesis begins cell division Daughter nuclei form Nuclear envelopes ariseChromatin becomes less coiledTwo new nuclei complete mitosisCytokinesis beginscell division
26Cytokinesis Animals Cytoplasmic division constriction belt of actin microfilaments around equator of cellcleavage furrow formssplits cell in twolike tightening a draw string
27Cytokinesis in Plants Plants cell plate forms vesicles line up at equatorderived from Golgivesicles fuse to form 2 cell membranesnew cell wall laid down between membranesnew cell wall fuses with existing cell wall
30Cell Cycle regulation Checkpoints cell cycle controlled by STOP & GO chemical signals at critical pointssignals indicate if key cellular processes have been completed correctly
31Checkpoint control system 3 major checkpoints:G1/Scan DNA synthesis begin?G2/Mhas DNA synthesis been completed correctly?commitment to mitosisspindle checkpointare all chromosomes attached to spindle?can sister chromatids separate correctly?
32G1/S checkpoint G1/S checkpoint is most critical primary decision point“restriction point”if cell receives “GO” signal, it dividesinternal signals: cell growth (size), cell nutritionexternal signals: “growth factors”if cell does not receive signal, it exits cycle & switches to G0 phasenon-dividing, working state
33“Go-ahead” signals Protein signals that promote cell growth & division internal signals“promoting factors”external signals“growth factors”Primary mechanism of controlphosphorylationkinase enzymeseither activates or inactivates cell signalsWe still don’t fully understanding the regulation of the cell cycle. We only have “snapshots” of what happens in specific cases.
34Cell cycle signals Cell cycle controls cyclins Cdks Cdk-cyclin complex inactivated CdkCell cycle controlscyclinsregulatory proteinslevels cycle in the cellCdkscyclin-dependent kinasesphosphorylates cellular proteinsactivates or inactivates proteinsCdk-cyclin complextriggers passage through different stages of cell cycleactivated Cdk
35External signals Growth factors coordination between cells protein signals released by body cells that stimulate other cells to dividedensity-dependent inhibitioncrowded cells stop dividingeach cell binds a bit of growth factornot enough activator left to trigger division in any one cellanchorage dependenceto divide cells must be attached to a substrate“touch sensor” receptors
36Growth Factors and Cancer Growth factors can create cancersproto-oncogenesnormally activates cell divisiongrowth factor genesbecome oncogenes (cancer-causing) when mutatedif switched “ON” can cause cancerexample: RAS (activates cyclins)tumor-suppressor genesnormally inhibits cell divisionif switched “OFF” can cause cancerexample: p53
37Cancer & Cell GrowthCancer is essentially a failure of cell division controlunrestrained, uncontrolled cell growthWhat control is lost?lose checkpoint stopsgene p53 plays a key role in G1/S restriction pointp53 protein halts cell division if it detects damaged DNAoptions:stimulates repair enzymes to fix DNAforces cell into G0 resting stagekeeps cell in G1 arrestcauses apoptosis of damaged cellALL cancers have to shut down p53 activityp53 is the Cell Cycle Enforcerp53 discovered at Stony Brook by Dr. Arnold Levine
38p53 — master regulator gene NORMAL p53p53 allows cellswith repairedDNA to divide.p53proteinDNA repair enzymep53proteinStep 1Step 2Step 3DNA damage is causedby heat, radiation, orchemicals.Cell division stops, and p53 triggers enzymes to repair damaged region.p53 triggers the destruction of cells damaged beyond repair.ABNORMAL p53abnormalp53 proteincancercellStep 1Step 2DNA damage iscaused by heat,radiation, orchemicals.The p53 protein fails to stopcell division and repair DNA.Cell divides without repair todamaged DNA.Step 3Damaged cells continue to divide.If other damage accumulates, thecell can turn cancerous.
39Development of CancerCancer develops only after a cell experiences ~6 key mutations (“hits”)unlimited growthturn on growth promoter genesignore checkpointsturn off tumor suppressor genes (p53)escape apoptosisturn off suicide genesimmortality = unlimited divisionsturn on chromosome maintenance genespromotes blood vessel growthturn on blood vessel growth genesovercome anchor & density dependenceturn off touch-sensor geneIt’s like an out-of-control car with many systems failing!
40What causes these “hits”? Mutations in cells can be triggered byUV radiationchemical exposureradiation exposureheatcigarette smokepollutionagegenetics
41Tumors Mass of abnormal cells Benign tumor Malignant tumor abnormal cells remain at original site as a lumpp53 has halted cell divisionsmost do not cause serious problems & can be removed by surgeryMalignant tumorcells leave original sitelose attachment to nearby cellscarried by blood & lymph system to other tissuesstart more tumors = metastasisimpair functions of organs throughout body
44New “miracle drugs”Drugs targeting proteins (enzymes) found only in cancer cellsGleevectreatment for adult leukemia (CML) & stomach cancer (GIST)1st successful drug targeting only cancer cellsProof of Principle: you can treat cancer by targeting cancer-specific proteins.GIST = gastrointestinal stromal tumors, which affect as many as 5,000 people in the United StatesCML = chronic myelogenous leukemia, adult leukemia, which affect as many as 8,000 people in the United StatesFastest FDA approval — 2.5 monthswithout Gleevecwith GleevecNovartes