CHAPTER 12  THE CELL CYCLE I. The key roles of cell division A. Reproduction 1. Prokaryotic 2. Eukaryotic a. Plants & some animals B. Development 1. Zygote  multicellular C. Renewal & repair II. Terminology A. Cell division B. Cell cycle 12.1  Cell division results in genetically identical daughter cells I. Cellular organization of the genetic material A. DNA  Chromatin (normal state)  Chromosome  Sister chromatids

II. Distribution of chromosomes during eukaryotic cell division A. Sister chromatids  chromosomes 1. Sister chromatids identical 2. Attached at centromere a. Cohesins b. Sister chromatid cohesion 3. Sister chromatids separate a. Become individual chromosomes 12.2  The mitotic phase alternates with interphase in the cell cycle I. Phases of cell cycle A. Interphase 1. Growth & copy phase 2. Mitosis preparatory phase 3. Accounts for 90% of cell cycle

4. 3 subphases a. G 1 phase  ~ 5-6 hrs. 1. Growth b. S phase (synthesis)  ~ hrs. 1. Growth & chromosome duplication c. G 2 phase  ~ 4-6 hrs. 1. Growth & complete preparation for division

B. Mitosis 1. Prophase a. Chromatin condenses into chromosome b. Mitotic spindle forms 2. Prometaphase a. Nuclear envelope disappears b. Kinetichore c. Microtubules attach

3. Metaphase a. Centrosomes at opposite poles b. Chromosomes line up on metaphase plate 4. Anaphase a. Sister chromatids separate b. Chromosomes pulled to opposite ends c. Cell elongates 5. Telophase a. Nuclear envelope reforms b. Chromosomes begin to uncoil c. Cleavage furrow begins to form

C. Cytokinesis 1. Cleavage furrow complete 2. Cells divide

II. Binary fission A. Prokaryotic cell division B. Origin of replication 1. Area of replication initiation 2. Duplicated 3. Chromosome duplicates a. Origin of replication moves to opposite sides of cell 4. Cell divides 12.3  The eukaryotic cell cycle is regulated by a molecular control system I. Evidence A. Fusing 2 cells at different phases

II. The cell cycle control system A. A cyclically operating set of molecules in the cell that both triggers & coordinates key events in the cell cycle B. Checkpoints 1. A control point within the cycle where stop & go-ahead signals regulate the cycle a. Allows the cell to assess internal state & integrate external signals 2. The stop signal is the default a. At each checkpoint the cycle will stop unless a go-ahead signal is received 3. The checkpoints a. G 1, G 2, & M

b. G 1  “ restriction point ” 1. Appears to be most important 2. If go-ahead signal received will usually complete cycle 3. If no go-ahead signal will leave cycle & enter G 0 phase a. Non-dividing phase C. The cell cycle clock: Cyclins & cyclin-dependant kinases 1. The clock a. The sequence & time of the cell cycle b. Controlled by molecules

2. Molecular basis of cell cycle clock a. Protein kinases 1. An enzyme that activates or inactivates other proteins by phosphoralization 2. Remains at a constant [ ] within the cell 3. Usually in an inactive form a. To become active it must attach to a cyclin 1. Cyclin-dependant kinases (Cdk) b. Cyclin 1. A protein that cyclically fluctuates in [ ] in cell a. Synthesized during S phase 2. Causes the activity of Cdks to fluctuate due to [ ] changes a. The higher the [ ] the faster/shorter a particular phase is

c. Examples 1. MPF a. Cyclin-Cdk complex that promotes mitosis b. Promotes the cell ’ s passage past the G 2 checkpoint c. During anaphase, cyclin is degraded recycling Cdk

D. Stop & Go signs: Internal & external signals at the checkpoint 1. Internal a. Each checkpoint has its own set of Cdk enzymes b. G 1 checkpoint 1. p53 a. DNA proofreader 1. Detects damage to DNA a. If damage detected will halt cell in the G 1 phase 1. Stimulates repair enzymes a. If damage repaired cell continues to the S phase b. If damage cannot be repaired cell death initiated 1. Apoptosis b. If no damage cell continues to S phase

c. G 2 checkpoint 1. MPF d. M checkpoint 1. Cdk enzymes detect/control spindle microtubules to kinetichores 2. If not all spindle microtubules are attached anaphase is delayed 2. External a. PDGF (platelet-derived growth factor) 1. Tissue damage causes platelets (blood) to release PDGF 2. PDGF triggers fibroblasts (connective tissue) to pass G 1 checkpoint & divide a. Tissue healing b. Density-dependant inhibition 1. Cell-surface proteins of neighboring cells bind causing a release of a growth-inhibiting signal to both cells c. Anchorage dependence

III. Loss of cell cycle controls in cancer cells A. Cancer defined 1. Uncontrolled cell growth B. What controls are lost 1. Density-dependant inhibition & anchorage dependence 2. p53 defective a. Damaged DNA passed along to next generation C. Cancer terminology 1. Transformation a. The starting point 1. A single normal cell “ transforms ” into a cancer cell a. Why? 1. DNA mutation? 2. Benign tumor a. Abnormal cells remain in original site b. Most cause no serious problems & removed surgically 3. Malignant tumor (cancer) a. Abnormal cells that invade nearby tissues

4. Metastasis a. Spread of cancer cells to locations distant from original site 1. Cancer cells may secrete molecules causing blood vessels to move towards tumor