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Cell division, cell growth, cell Cycle • Interphase and meiosis I MEIOSIS I: Separates homologous chromosomes INTERPHASE PROPHASE I METAPHASE I ANAPHASE I 2. cross over Sister chromatids Nuclear envelope Chromatin Chiasmata Spindle Tetrad Chromosomes duplicate Figure 13.8 Sister chromatids remain attached Centromere (with kinetochore) Centrosomes (with centriole pairs) Homologous Microtubule chromosomes attached to separate kinetochore Tertads line up Homologous chromosomes (red and blue) pair and exchange segments; 2n = 6 in this example 1. Synapsis (聯會) (synaptonemal complex) Metaphase plate Pairs of homologous chromosomes split up • Telophase I, cytokinesis, and meiosis II MEIOSIS II: Separates sister chromatids TELOPHASE I AND CYTOKINESIS PROPHASE II Cleavage furrow Figure 13.8 Two haploid cells form; chromosomes are still double METAPHASE II ANAPHASE II Sister chromatids separate TELOPHASE II AND CYTOKINESIS Haploid daughter cells forming During another round of cell division, the sister chromatids finally separate; four haploid daughter cells result, containing single chromosomes • A comparison of mitosis and meiosis MITOSIS MEIOSIS Parent cell (before chromosome replication) Chiasma (site of crossing over) MEIOSIS I Prophase I Prophase Chromosome replication Duplicated chromosome (two sister chromatids) Chromosome replication Tetrad formed by synapsis of homologous chromosomes 2n = 6 Metaphase Chromosomes positioned at the metaphase plate Anaphase Telophase Sister chromatids separate during anaphase 2n Tetrads positioned at the metaphase plate Homologues separate during anaphase I; sister chromatids remain together Metaphase I Anaphase I Telophase I Haploid n=3 Daughter cells of meiosis I 2n MEIOSIS II Daughter cells of mitosis n n n n Daughter cells of meiosis II Sister chromatids separate during anaphase II Cell cycle: --- the life of a cell from the time it is first formed from a dividing parent cell until its own division into two cells. Smallest unit of life all living things must reproduce Cells replicate for growth, replacement, and repair Cell division functions in reproduction, growth, and renewal. 200 µm 20 µm Cell Cycle The Cell’s Time Clock • • Cell division requires Mitosis & Cytokinesis Phases of a dividing cell’s life – interphase • cell grows • replicates chromosomes • produces new organelles & biomolecules – mitotic phase • cell separates & divides chromosomes – mitosis • cell divides cytoplasm & organelles – cytokinesis Cytokinesis M Mitosis G2 Gap 2 S Synthesis G1 Gap 1 G0 Resting Cell cycle M Mitosis G2 Gap 2 G1 Gap 1 • 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 S Synthesis cell grows & matures to never divide again liver cells G0 brain nerve cells G0 Resting • Cell performs normal function • Three subphases: – G1: cell duplicates most organelles – S: quantity of DNA in the cell is doubled as chromosomes are replicated. Each chromosome has a pair of sister chromatids connected by a centromere that contains a kinetochore – G2: chemical components stockpiled • Nucleolus present Interphase Mitosis • Mitotic events can be • Nuclear division categorized into discrete without a reduction in stages based on what is chromosome number happening to structure of the cell • Each new cell (daughter cell) will • Stage include: – Prophase have the same • Prometaphase quantity of DNA as the – Metaphase parental cell – Anaphase • Why is this important? – Telophase Prophase (Including Prometaphase) • Pro • Three things visibly occur – Chromosomes condense (shorten) – Centrosomes migrate to the poles while producing spindle fibers – Nuclear membrane fragments Metaphase • Meta • Chromosomes are moved by growing spindle fibers to the equator of the cell (metaphase plate) • Centrosomes are at the poles, nuclear membrane is gone Metaphase Plate Anaphase • Ana • Centromere splits into two • Spindle fibers shorten from kinetochore end separating sister chromatids • Activated kinetochores “pull” chromatids along the spindle fibers and toward the poles Telophase • Telo • Nuclear membrane reforms around each region of chromosomes • Nucleolus reforms • Cytokinesis (division of the cytoplasm) may occur Cytokinesis May Vary Between Major Taxonomic Groups Cytokinesis divides the cytoplasm * Cleavage furrow Actin + Myosin Cleavage furrow Contractile ring of microfilaments 100 µm * No cleavage furrow Vesicles forming cell plate Wall of patent cell 1 µm Cell plate New cell wall Daughter cells Daughter cells (a) Cleavage of an animal cell (SEM) (b) Cell plate formation in a plant cell (SEM) Regulation of Cell Division 2006-2007 Coordination of cell division • A multicellular organism needs to coordinate cell division across different tissues & organs – critical for normal growth, development & maintenance • coordinate timing of cell division • coordinate rates of cell division • not all cells can have the same cell cycle 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? Frequency of cell division • Frequency of cell division varies by cell type – embryo • cell cycle < 20 minute – skin cells • divide frequently throughout life • 12-24 hours cycle M metaphase anaphase telophase prophase – liver cells C • retain ability to divide, but keep it in reserve • divide once every year or two – mature nerve cells & muscle cells • do not divide at all after maturity • permanently in G0 G2 S interphase (G1, S, G2 phases) mitosis (M) cytokinesis (C) G1 Overview of Cell Cycle Control There’s no turning back, now! • Two irreversible points in cell cycle – replication of genetic material – separation of sister chromatids • Checkpoints – process is assessed & possibly halted sister chromatids centromere single-stranded chromosomes double-stranded chromosomes Cell Cycle Regulation • Cell cycle events are triggered by the cell-cycle control system; a set of molecules found in the cytoplasm affected by internal and external controls • Checkpoints in G1, G2, and M phases of the cycle • G1 checkpoint is most critical. May throw cells out of cyclic phase into G0, never to divide again Other Internal and External Factors • Internal – M checkpoint does not proceed until signal is received that all kinetochores are attached to spindle microtubules • External – Growth factors: cycle will not proceed if requirements are not met – Social signals • Density-dependent inhibition: under crowded conditions chemical requirements are insufficient to allow cell growth • Anchorage dependence: some cells must be attached to a substrate in order to replicate – DNA damage inhibits growth External signals: ex. Growth factors ~ Cells fail to divide if an essential nutrient is left out of the culture medium. ~ GFs trigger a signal transduction pathway that allows the cells to pass the G1 checkpoint and divide. PDGF PDGF receptor cell Signal transduction Cell division External signals • Growth factors – coordination between cells – protein signals released by body cells that stimulate other cells to divide • density-dependent inhibition – crowded cells stop dividing – each cell binds a bit of growth factor » not enough activator left to trigger division in any one cell • anchorage dependence – to divide cells must be attached to a substrate » “touch sensor” receptors External signals: physical factor Density-dependent inhibition of cell division ~ Crowded cells stop dividing single layer Cells anchor to dish surface and divide (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 (densitydependent inhibition). 25 µm • Most animal cells exhibit anchorage dependence – In which they must be attached to a substratum to divide Anchorage dependence * Cancer cells: ~ Exhibit neither density- dependent inhibition nor Normal cell ~ single layer Cancer cells do not exhibit anchorage dependence or density-dependent inhibition. anchorage dependence 25 µm 25 µm Growth factor signals growth factor nuclear pore nuclear membrane P P cell division cell surface receptor protein kinase cascade Cdk P P E2F chromosome P cytoplasm nucleus Internal signal of a Growth Factor • Platelet Derived Growth Factor (PDGF) – made by platelets in blood clots – binding of PDGF to cell receptors stimulates cell division in fibroblast (connective tissue) • heal wounds Don’t forget to mention erythropoietin! (EPO) The 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. ~ similar to a clock G1 checkpoint Control system G1 M G2 M checkpoint G2 checkpoint S The cell cycle is regulated at certain checkpoints by both internal and external controls. 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/S • can DNA synthesis begin? – G2/M • has DNA synthesis been completed correctly? • commitment to mitosis – spindle checkpoint • are all chromosomes attached to spindle? • can sister chromatids separate correctly? Spindle checkpoint G2 / M checkpoint Chromosomes attached at metaphase plate • Replication completed • DNA integrity Inactive Active Inactive Cdk / G2 cyclin (MPF) M Active APC C cytokinesis mitosis G2 G1 S MPF = Mitosis Promoting Factor APC = Anaphase Promoting Complex Cdk / G1 cyclin Active G1 / S checkpoint Inactive • Growth factors • Nutritional state of cell • Size of cell G1/S checkpoint • G1/S checkpoint is most critical – primary decision point • “restriction point” – if cell receives “GO” signal, it divides • internal signals: cell growth (size), cell nutrition • external signals: “growth factors” – if cell does not receive signal, it exits cycle & switches to G0 phase • non-dividing, working 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 “called G1 Gap 1 G0 Resting back” to cell cycle by external cues nerve & muscle cells highly specialized; arrested in G0 & can never divide Cell Cycle Checkpoints • If cell size inadequate – G1 or G2 arrest • If nutrient supply inadequate – G1 arrest • If an essential external stimulus is lacking – G1 arrest (at R) • If the DNA is not replicated – S arrest • If DNA damage is detected – G1 or G2 arrest • If the spindle formation is improper, chromosome misalignment – M-phase arrest R “Go-ahead” signals • Protein signals that promote cell growth & division – internal signals • “promoting factors” – external signals • “growth factors” • Primary mechanism of control – phosphorylation • kinase enzymes • either activates or inactivates cell signals Cell cycle signals inactivated Cdk • Cell cycle controls – cyclins • regulatory proteins • levels cycle in the cell – Cdk’s • cyclin-dependent kinases • phosphorylates cellular proteins – activates or inactivates proteins – Cdk-cyclin complex • triggers passage through different stages of cell cycle activated Cdk Types of Cyclins and Cdks • There are many types of cyclins, but the 4 main ones are: – – – – Cyclin D (G1 cyclin) Cyclin E (S-phase cyclin) Cyclin A (S-phase and mitotic cyclin) Cyclin B (mitotic cyclin) • These are the 3 main cdks – Cdk4 (G1 Cdk) – Cdk2 (S-phase Cdk) – Cdk1 (mitotic Cdk) • The complex of Cdk1 and cyclin B is called mitosis promoting factor (MPF) a.k.a maturation promoting factor Cyclin Concentration Rise and fall of cyclins Mitosis Cdks and cyclins Cyclin-dependent kinases (Cdks) are enzymes that are present in the cell cytoplasm at all times. However, they are inactive unless they are bound by a specific partner-protein called a cyclin to form a Cdk-cyclin complex The amount of cyclins in the cell changes – because they get degraded A Cdk-cyclin complex will push the cell cycle forward. Figure 19-35 Phosphorylation and Dephosphorylation in the Activation of a Cdk-Cyclin Complex MPF: M-phase Promoting Factor • MPF is composed of two key subunits: Cdc2 and Cyclin B. – Cdc2 is the protein that encoded by genes which are required for passage through START as well as for entry into mitosis. – Cyclin B is a regulatory subunit required for catalytic activity of the Cdc2 protein kinase. What does MPF do? The complex of Cdk1 and cyclin B is called mitosis promoting factor (MPF) MPF activity is dependent upon Cyclin B • The cyclins were identified as proteins that accumulate throughout interphase and are rapidly degraded toward the end of mitosis. • It is suggested that they might function to induce mitosis, with their periodic accumulation and destruction controlling entry and exit from M phase. MPF activity is dependent upon Cyclin B • Accumulation and degradation of cyclins Figure 19-34 Fluctuating Levels of Mitotic Cyclin and MPF During the Cell Cycle MPF regulation • Cdc2 forms complexes with cyclin B during S and G2. • Cdc2 is then phosphorylated on threonine-161, which is required for Cdc2 activity, as well as on tyrosine-15 (and threonine-14 in vertebrate cells), which inhibits Cdc2 activity. Dephosphorylation of Thr14 and Tyr15 activates MPF at the G2 to M transition. • MPF activity is then terminated toward the end of mitosis by proteolytic degradation of cyclin B. MPF regulation • Demonstration of regulation of MPF Figure 19-40 A General Model for Cell Cycle Regulation 1970s-’80s | 2001 Cyclins & Cdks • Interaction of Cdk’s & different cyclins triggers the stages of the cell cycle Leland H. Hartwell checkpoints Tim Hunt Cdks Sir Paul Nurse cyclins • external signals is density-dependent inhibition, in which crowded cells stop dividing but lost of contact inhibition and outgrowth in cancer cells Tumors • Mass of abnormal cells – 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 Tumors • Benign - A spontaneous growth of tissue which forms an abnormal mass is called a tumor. A tumor that is noninvasive and noncancerous is referred to as a benign tumor. • Malignant - A tumor that invades neighboring cells and is cancerous is referred to as a malignant tumor. • Matastasis – Cancer that has spread to other tissues. 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 – promotes blood vessel growth • turn on blood vessel growth genes – overcome anchor & density dependence • turn off touch censor gene It’s like an out of control car! Cancer & Cell Growth • Cancer is essentially a failure of cell division control M Mitosis G2 Gap 2 G1 Gap 1 S Synthesis – unrestrained, uncontrolled cell growth • What control is lost? – checkpoint stops – gene p53 plays a key role in G1 checkpoint p53 is the Cell Cycle Enforcer • 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 G0 Resting 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. Growth Factors and Cancer • Growth factors influence cell cycle – proto-oncogenes • normal genes that become oncogenes (cancercausing) 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 What causes these “hits”? • Mutations in cells can be triggered by UV radiation chemical exposure radiation exposure heat cigarette smoke pollution age genetics How we naturally fight cancer cells • Tumor suppressor genes like p53 – Can arrest the cell cycle – Can launch the apoptotic pathway, causing the rogue cells to lyse A mutation in the p53 gene can lead to cancer • Immune cells (WBCs) such as NK cells can attack and lyse tumor cells – Some immune cells can signal the rogue cells to launch the apoptotic pathways Traditional treatments for cancers • Treatments target rapidly dividing cells – high-energy radiation • kills rapidly dividing cells – chemotherapy • stop DNA replication • stop mitosis & cytokinesis • stop blood vessel growth 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?? Signal Transduction Pathways • What are they? – Signal transduction refers to any process by which a cell converts one kind of signal or stimulus into another. – A large number of proteins, enzymes and other molecules participate in a "signal cascade“ • What is the end result? – Either the activation or inhibition of a certain enzyme in the cytoplasm – Either the expression or suppression of a particular gene Just a few examples of Signal Transduction Pathways • Cell Division signals • Apoptotic signals • Insulin pathways Apoptotic Pathways Insulin Signaling Pathway The binding of insulin to its receptor on a cell starts a cascade of cellular events which finally leads to the uptake of glucose and the lowering of blood glucose levels. “Go-ahead” signals • Protein signals that promote cell growth & division – internal signals • “promoting factors” – external signals • “growth factors” • Primary mechanism of control – phosphorylation • kinase enzymes • either activates or inactivates cell signals