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Biology is the only subject in which multiplication is the same thing as division… Chapter 11. How Cells Divide The Cell Cycle: Cell Growth, Cell Division Where it all began… You started as a cell smaller than a period at the end of a sentence… . And now look at you… How did you get from there to here? Getting from there to here… Cell division continuity of life = reproduction of cells reproduction unicellular organisms growth repair & renew Cell cycle life of a cell from origin to division into 2 new daughter cells Getting the right stuff What is passed to daughter cells? exact copy of genetic material = DNA this part of the cell cycle = mitosis assortment of organelles & cytoplasm this part of the cell cycle = cytokinesis chromosomes (stained orange) in kangaroo rat epithelial cell Copying DNA Dividing cell duplicates DNA separates each copy to opposite ends of cell splits into 2 daughter cells human cell duplicates ~3 meters DNA separates 2 copies so each daughter cell has complete identical copy error rate = ~1 per 100 million bases 3 billion base pairs mammalian genome ~30 errors per cell cycle mutations A bit about DNA DNA is organized in chromosomes double helix DNA molecule associated proteins = histone proteins DNA-protein complex = chromatin organized into long thin fiber Copying DNA with care… After DNA duplication chromatin condenses coiling & folding to make a smaller package from DNA to chromatin to highly condensed mitotic chromosome Chromosome Duplicated chromosome consists of 2 sister chromatids narrow at their centromeres contain identical copies of the chromosome’s DNA M Mitosis Cell cycle Cell has a “life cycle” cell is formed from a mitotic division cell grows & matures to divide again G1, S, G2, M epithelial cells, blood cells, stem cells G2 Gap 2 G1 Gap 1 S Synthesis cell grows & matures to never divide again liver cells G0 brain nerve cells Muscle cells G0 Resting M Mitosis Cell Division cycle Phases of a dividing G2 Gap 2 G1 Gap 1 cell’s life interphase S Synthesis cell grows replicates chromosomes produces new organelles & biomolecules mitotic phase cell separates & divides chromosomes mitosis cytokinesis cell divides cytoplasm & organelles G0 Resting Interphase 90% of cell life cycle cell doing its “everyday job” produce RNA to synthesize proteins prepares for duplication if triggered Characteristics nucleus well-defined DNA loosely packed in long chromatin fibers Interphase Divided into 3 phases: G1 = 1st Gap cell doing its “everyday job” cell grows S = DNA Synthesis copies chromosomes G2 = 2nd Gap prepares for division cell grows produces organelles, proteins, membranes Interphase G2 Nucleus well-defined chromosome duplication complete DNA loosely packed in long chromatin fibers Prepares for mitosis produces proteins & organelles Mitosis copying cell’s DNA & dividing it between 2 daughter nuclei Mitosis is divided into 4 phases prophase metaphase anaphase telophase Prophase Chromatin (DNA) condenses visible as chromosomes chromatids fibers extend from the centromeres Centrioles move to opposite poles of cell Fibers (microtubules) cross cell to form mitotic spindle actin, myosin Nucleolus disappears Nuclear membrane breaks down Prometaphase Proteins attach to centromeres creating kinetochores Microtubules attach at kinetochores connect centromeres to centrioles Chromosomes begin moving Kinetochore Each chromatid has own kinetochore proteins microtubules attach to kinetochore proteins Metaphase Spindle fibers align chromosomes along the middle of cell meta = middle metaphase plate helps to ensure chromosomes separate properly so each new nucleus receives only 1 copy of each chromosome Anaphase Sister chromatids separate at kinetochores move to opposite poles pulled at centromeres pulled by motor proteins “walking”along microtubules increased production of ATP by mitochondria Poles move farther apart polar microtubules lengthen Separation of chromatids In anaphase, proteins holding together sister chromatids are inactivated separate to become individual chromosomes 1 chromosome 2 chromatids 2 chromosomes Chromosome movement Kinetochores use motor proteins that “walk” chromosome along attached microtubule microtubule shortens by dismantling at kinetochore (chromosome) end Telophase Chromosomes arrive at opposite poles daughter nuclei form nucleoli form chromosomes disperse no longer visible under light microscope Spindle fibers disperse Cytokinesis begins cell division Cytokinesis Animals cleavage furrow forms ring of actin microfilaments form around equator of cell myosin proteins tightens to form a cleavage furrow, which splits the cell in two like tightening a draw string Control of Cell Cycle Overview Cytokinesis in Animals Mitosis in whitefish blastula Mitosis in animal cells Cytokinesis in Plants Plants vesicles move to equator line up & fuse to form 2 membranes = cell plate derived from Golgi new cell wall is laid down between membranes new cell wall fuses with existing cell wall Cytokinesis in plant cell Mitosis in plant cell onion root tip Evolution of mitosis Mitosis in eukaryotes likely evolved from binary fission in bacteria single circular chromosome no membranebound organelles Dinoflagellates algae “red tide” Bioluminescence Development of microtubules during mitosis Diatoms microscopic algae marine Freshwater Development of kinetochores Evolution of mitosis Mechanisms intermediate between binary fission & mitosis seen in modern organisms protists Any Questions?? Regulation of Cell Division Coordination of cell division Multicellular organism need to coordinate across different parts of organism timing of cell division rates of cell division crucial for normal growth, development & maintenance do all cells have same cell cycle? Why is this such a hot topic right now? Frequency of cell division Frequency of cell division varies with cell type skin cells divide frequently throughout life liver cells retain ability to divide, but keep it in reserve mature nerve cells & muscle cells do not divide at all after maturity Cell Cycle Control Two irreversible points in cell cycle replication of genetic material separation of sister chromatids Cell can be put on hold at specific checkpoints sister chromatids There’s no turning back, now! centromere single-stranded chromosomes double-stranded chromosomes Checkpoint control system Checkpoints cell cycle controlled by STOP & GO chemical signals at critical points signals indicate if key cellular processes have been completed correctly Checkpoint control system 3 major checkpoints: G1 can DNA synthesis begin? G2 has DNA synthesis been completed correctly? commitment to mitosis M phases spindle checkpoint can sister chromatids separate correctly? G1 checkpoint G1 checkpoint is most critical primary decision point “restriction point” if cell receives “go” signal, it divides if does not receive “go” signal, cell exits cycle & switches to G0 phase non-dividing state G0 phase G0 phase non-dividing, differentiated state most human cells in G0 phase liver cells M Mitosis G2 Gap 2 S Synthesis in G0, but can be G1 Gap 1 G0 Resting “called back” to cell cycle by external cues nerve & muscle cells highly specialized; arrested in G0 & can never divide Activation of cell division How do cells know when to divide? cell communication = signals chemical signals in cytoplasm give cue signals usually mean proteins activators inhibitors experimental evidence: Can you explain this? “Go-ahead” signals Signals that promote cell growth & division proteins internal signals “promoting factors” external signals “growth factors” Primary mechanism of control kinase enzymes Protein signals Promoting factors Cyclins regulatory proteins levels of this cycle in the cell Cdks cyclin-dependent kinases enzyme activates cellular proteins MPF maturation (mitosis) promoting factor APC anaphase promoting complex 1970s-’80s | 2001 Cyclins & Cdks Interaction of Cdks & different Cyclins triggers the stages of the cell cycle. Leland H. Hartwell checkpoints Tim Hunt Cdks Sir Paul Nurse cyclins Spindle checkpoint G2 / M checkpoint Chromosomes attached at metaphase plate • Replication completed • DNA integrity Active Inactive Inactive Cdk / G2 cyclin (MPF) M Active APC C cytokinesis mitosis G2 G1 S Cdk / G1 cyclin Active Inactive G1 / S checkpoint • Growth factors • Nutritional state of cell • Size of cell Cyclin & Cyclin dependent kinases CDKs & cyclin drive cell from one phase to next in cell cycle proper regulation of cell cycle is so key to life that the genes for these regulatory proteins have been highly conserved through evolution the genes are basically the same in yeast, insects, plants & animals (including humans) External signals Growth factors external signals protein signals released by body cells that stimulate other cells to divide density-dependent inhibition crowded cells stop dividing mass of cells use up growth factors not enough left to trigger cell division anchorage dependence to divide cells must be attached to a substrate Growth factor signals Growth factor Nuclear pore Nuclear membrane P Cell surface receptor Protein kinase cascade P Cytoplasm P Cell division Cdk P E2F Chromosome P Nucleus Example of a Growth Factor Platelet Derived Growth Factor (PDGF) made by platelets (blood cells) binding of PDGF to cell receptors stimulates fibroblast (connective tissue) cell division wound repair growth of fibroblast cells (connective tissue cells) helps heal wounds Growth Factors and Cancer Growth factors influence cell cycle proto-oncogenes normal genes that become oncogenes (cancer-causing) when mutated stimulates cell growth if switched on can cause cancer example: RAS (activates cyclins) tumor-suppressor genes inhibits cell division if switched off can cause cancer example: p53 M Mitosis Cancer & Cell Growth G2 Gap 2 Cancer is essentially a failure of cell division control S Synthesis G1 Gap 1 G0 Resting unrestrained, uncontrolled cell growth What control is lost? p53 is the Cell Cycle Enforcer checkpoint stops gene p53 plays a key role in G1 checkpoint p53 protein halts cell division if it detects damaged DNA stimulates repair enzymes to fix DNA forces cell into G0 resting stage keeps cell in G1 arrest causes apoptosis of damaged cell ALL cancers have to shut down p53 activity p53 discovered at Stony Brook by Dr. Arnold Levine p53 — master regulator gene NORMAL p53 p53 allows cells with repaired DNA to divide. p53 protein DNA repair enzyme p53 protein Step 1 Step 2 Step 3 DNA damage is caused by heat, radiation, or chemicals. Cell division stops, and p53 triggers enzymes to repair damaged region. p53 triggers the destruction of cells damaged beyond repair. ABNORMAL p53 Abnormal p53 protein Step 1 Step 2 DNA damage is caused by heat, radiation, or chemicals. The p53 protein fails to stop cell division and repair DNA. Cell divides without repair to damaged DNA. Cancer cell Step 3 Damaged cells continue to divide. If other damage accumulates, the cell can turn cancerous. Development of Cancer Cancer develops only after a cell experiences ~6 key mutations (“hits”) unlimited growth turn on growth promoter genes ignore checkpoints turn off tumor suppressor genes escape apoptosis turn off suicide genes immortality = unlimited divisions turn on chromosome maintenance genes It’s like an out of control car! promotes blood vessel growth turn on blood vessel growth genes overcome anchor & density dependence turn off touch sensor gene What causes these “hits”? Mutations in cells can be triggered by UV radiation chemical exposure radiation exposure heat cigarette smoke pollution age genetics Tumors Mass of abnormal cells http://www.hhmi.org/bioint eractive/cancer/angiogene sis.html Benign tumor abnormal cells remain at original site as a lump p53 has halted cell divisions most do not cause serious problems & can be removed by surgery Malignant tumors cells leave original site lose attachment to nearby cells carried by blood & lymph system to other tissues start more tumors = metastasis impair functions of organs throughout body Traditional treatments for cancers Treatments target rapidly dividing cells high-energy radiation & chemotherapy with toxic drugs kill rapidly dividing cells New “miracle drugs” Drugs targeting proteins (enzymes) found only in tumor cells Gleevec treatment for adult leukemia (CML) & stomach cancer (GIST) 1st successful targeted drug Any Questions?? Sexual reproduction lifecycle 2 copies diploid 2n 1 copy haploid 1n fertilization meiosis We’re mixing things up here! A good thing? 1 copy haploid 1n Meiosis Reduction Division special cell division in sexually reproducing organisms reduce 2n 1n diploid haploid “half” makes gametes sperm, eggs Warning: meiosis evolved from mitosis, so stages & “machinery” are similar but the processes are radically different. Do not confuse the two! Overview of meiosis I.P.M.A.T.P.M.A.T 2n=4 interphase 1 prophase 1 metaphase 1 anaphase 1 n=2 prophase 2 metaphase 2 anaphase 2 telophase 2 telophase 1 Double division of meiosis DNA replication Repeat I can’t after hear you! me! 1st division of meiosis separates homologous pairs Meiosis 1 Meiosis 2 2nd division of meiosis separates sister chromatids Preparing for meiosis 1st step of meiosis Duplication of DNA Why bother? meiosis evolved after mitosis 2n = 6 single stranded convenient to use “machinery” of mitosis DNA replicated in S phase of interphase of MEIOSIS (just like in mitosis) M1 prophase 2n = 6 double stranded Meiosis 1 1st division of meiosis 2n = 4 single stranded separates homologous pairs prophase 1 2n = 4 double stranded metaphase 1 2n = 4 double stranded synapsis tetrad telophase 1 IRepeat can’t after hear you! me! 1n = 2 double stranded Meiosis 2 2nd division of meiosis 1n = 2 double stranded separates sister chromatids prophase 2 What does this division look like? 1n = 2 single stranded 1n = 2 double stranded metaphase 2 4 telophase 2 Steps of meiosis Meiosis 1 interphase prophase 1 metaphase 1 anaphase 1 telophase 1 Meiosis 2 prophase 2 metaphase 2 anaphase 2 telophase 2 1st division of meiosis separates homologous pairs (2n 1n) “reduction division” 2nd division of meiosis separates sister chromatids (1n 1n) * just like mitosis * Trading pieces of DNA Crossing over during Prophase 1, sister chromatids intertwine synapsis homologous pairs swap pieces of chromosome DNA breaks & re-attaches synapsis tetrad prophase 1 Crossing over 3 steps What are the advantages of sexual reproduction? cross over breakage of DNA re-fusing of DNA New combinations of traits Meiosis 1 Meiosis 2 “Let’s roll tape” Meiosis square dance – find link! http://www.youtube.com/watch? v=iCL6d0OwKt8 Mitosis vs. Meiosis Mitosis vs. Meiosis Mitosis 1 division daughter cells genetically identical to parent cell produces 2 cells 2n 2n produces cells for growth & repair no crossing over Meiosis 2 divisions daughter cells genetically different from parent produces 4 cells 2n 1n produces gametes crossing over Putting it all together… meiosis fertilization mitosis + development gametes 46 meiosis 23 23 egg 23 46 23 zygote fertilization sperm 46 46 46 46 46 46 46 46 46 mitosis & mitosis development The value of sexual reproduction Sexual reproduction introduces genetic variation genetic recombination during meiosis independent assortment of chromosomes random alignment of homologous chromosomes in Meiosis 1 crossing over mixing of alleles across homologous chromosomes random fertilization which sperm fertilizes which egg? Driving evolution metaphase1 variation for natural selection Variation from genetic recombination Independent assortment of chromosomes meiosis introduces genetic variation gametes of offspring have different combination of genes compared to the gametes from their parents random assortment in humans produces 223 (8,388,608) different combinations in gametes from Mom from Dad offspring new gametes made by offspring Variation from crossing over Crossing over creates completely new combinations of traits on each chromosome creates an infinite variety in gametes Variation from random fertilization Sperm + Egg = ? any 2 parents will produce a zygote with over 70 trillion (223 x 223) possible diploid combinations Sexual reproduction creates variability Sexual reproduction allows us to maintain both genetic similarity & differences. Michael & Kirk Douglas Chris & Liam Hemsworth Martin & Charlie Sheen, Emilio Estevez Sperm production Epididymis Testis Coiled seminiferous tubules germ cell (diploid) primary spermatocyte (diploid) MEIOSIS I secondary spermatocytes (haploid) Vas deferens spermatids (haploid) spermatozoa Spermatogenesis continuous & prolific process Cross-section of seminiferous tubule each ejaculation = 100-600 million sperm MEIOSIS II Egg production Oogenesis eggs in ovaries halted before Anaphase 1, prior to birth Meiosis 1 completed during maturation (in humans ~ once/month following puberty) Meiosis 2 completed after unequal division fertilization 1 egg + 2 polar bodies Meiosis 1 completed during egg maturation ovulation What is the advantage of this development system? Meiosis 2 completion triggered by fertilization Oogenesis primary follicles germinal cell (diploid) fallopian tube fertilization primary oocyte (diploid) MEIOSIS I secondary oocyte (haploid) first polar body MEIOSIS II developing follicle mature follicle with secondary oocyte ruptured follicle (ovulation) after fertilization second polar body ovum (haploid) corpus luteum Differences across kingdoms Not all organisms use haploid & diploid stages in same way which one is dominant (2n or n) differs but still alternate between haploid & diploid must for sexual reproduction Any Questions?? What are the DISadvantages of sexual reproduction?