Mitosis and the Cell Cycle

Mitosis and the Cell Cycle

Chapter 12 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 Getting from there to here Cell division o Continuity of life = Reproduction of cells reproduction unicellular organisms growth repair & renew Cell cycle o Life of a cell from origin to division into 2 new daughter cells Getting the right stuff What is passed to daughter cells? o Exact copy of genetic material = DNA This division step = mitosis o Assortment of organelles & cytoplasm This division step = cytokinesis Copying DNA Dividing cell duplicates DNA o Separates each copy to opposite ends of cell o 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 in the mammalian genome ~30 errors per cell cycle called mutations A bit about DNA DNA is organized in chromosomes o Double helix DNA molecule o Associated proteins = histone proteins o 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 o Narrow at their centromeres o Contain identical copies of the chromosome s DNA Cell Division cycle Phases of a dividing cell s life o Interphase Cell grows Replicates chromosomes Produces new organelles & biomolecules o Mitotic phase Cell separates & divides chromosomes Mitosis Cell divides cytoplasm & organelles Cytokinesis

Interphase 90% of cell life cycle o Cell doing its everyday job Produce RNA, synthesize proteins o Prepares for duplication if triggered Characteristics o Nucleus well-defined o DNA loosely packed in long chromatin fibers Divided into 3 phases: G1 = 1st Gap o cell doing its everyday job o cell grows S = DNA Synthesis o copies chromosomes G2 = 2nd Gap o prepares for division o cell grows o produces organelles, proteins, membranes

Interphase G2 Nucleus well-defined o Chromosome duplication complete o DNA loosely packed in long chromatin fibers Prepares for mitosis o Produces proteins & organelles Mitosis Copying cell s DNA & dividing it between 2 daughter nuclei Mitosis is divided into 4 phases o Prophase o Metaphase o Anaphase o Telophase Prophase Chromatin (DNA) condenses o visible as chromosomes chromatids o fibers extend from the centromeres Centrioles move to opposite poles of cell Fibers (microtubules) cross cell to form mitotic spindle o actin, myosin Nucleolus disappears Nuclear membrane breaks down Prometaphase Proteins attach to centromeres o Creating kinetochores Microtubules attach at kinetochores o Connect centromeres to centrioles Chromosomes begin moving Kinetochore Each chromatid has own kinetochore proteins o Microtubules attach to kinetochore proteins Metaphase Spindle fibers align chromosomes along the middle of cell o meta = middle o metaphase plate o helps to ensure chromosomes separate properly o so each new nucleus receives only 1 copy of each chromosome

Anaphase Sister chromatids separate at kinetochores o Separate to become individual chromosomes o Move to opposite poles o Pulled at centromeres o Pulled by motor proteins walking along microtubules Increased production of ATP by mitochondria Poles move farther apart o Polar microtubules lengthen Telophase Chromosomes arrive at opposite poles o Daughter nuclei form o Nucleoli from o Chromosomes disperse No longer visible under light microscope Spindle fibers disperse Cytokinesis begins o Cell division Cytokinesis in Animals Cytokinesis in Plants

Cytokinesis in Plants Vesicles move to equator line up & fuse to form 2 membranes = cell plate o Derived from Golgi New cell wall is laid down between membranes o New cell wall fuses with existing cell wall Evolution of Mitosis Mechanisms intermediate between binary fission & mitosis seen in modern organisms o Protists

Regulation of Cell Division Coordination of cell division Multicellular organism o Need to coordinate across different parts of organism Timing of cell division Rates of cell division o Crucial for normal growth, development & maintenance Do all cells have same cell cycle? Frequency of cell division Frequency of cell division varies with cell type o Skin cells divide frequently throughout life o Liver cells retain ability to divide, but keep it in reserve o Mature nerve cells & muscle cells do not divide at all after maturity Cell Cycle Control Two irreversible points in cell cycle: o Replication of genetic material. o Separation of sister chromatids. Cell can be put on hold at specific checkpoints. Checkpoint control system Checkpoints o Cell cycle controlled by STOP & GO chemical signals at critical points. o Signals indicate if key cellular processes have been completed correctly. Checkpoint control system 3 major checkpoints: o G 1 Can DNA synthesis begin? o G 2 Has DNA synthesis been completed correctly? Commitment to mitosis o M phases Spindle checkpoint Can sister chromatids separate correctly? 1

G 1 checkpoint G 1 checkpoint is most critical o primary decision point restriction point o If cell receives go signal, it divides o If does not receive go signal, cell exits cycle & switches to G 0 phase non-dividing state G 0 phase Non-dividing, differentiated state Most human cells in G 0 phase o Liver cells In G 0, but can be called back to cell cycle by external cues o Nerve & muscle cells o Highly specialized; arrested in G 0 & can never divide. Go-ahead signals Signals that promote cell growth & division o proteins o internal signals promoting factors o external signals growth factors Primary mechanism of control o phosphorylation kinase enzymes Protein signals Promoting factors o Cyclins regulatory proteins levels cycle in the cell o Cdks cyclin-dependent kinases enzyme activates cellular proteins o MPF maturation (mitosis) promoting factor o APC anaphase promoting complex Cyclin & Cyclin dependent kinases CDKs & cyclin drive cell from one phase to next in cell cycle o 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) 2

External signals Growth factors: 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 o Not enough left to trigger cell division Anchorage dependence To divide cells must be attached to a substrate Growth Factors and Cancer Growth factors influence cell cycle o Proto-oncogenes Normal genes that become oncogenes (cancer-causing) when mutated Stimulates cell growth If switched on can cause cancer Example: RAS (activates cyclins) o Tumor-suppressor genes Inhibits cell division If switched off can cause cancer Example: p53 Cancer & Cell Growth Cancer is essentially a failure of cell division control o Unrestrained, uncontrolled cell growth What control is lost? o Checkpoint stops o Gene p53 plays a key role in G 1 checkpoint p53 protein halts cell division if it detects damaged DNA Stimulates repair enzymes to fix DNA Forces cell into G 0 resting stage. Keeps cell in G 1 arrest. Causes apoptosis of damaged cell. ALL cancers have to shut down p53 activity. 3

Development of Cancer Cancer develops only after a cell experiences ~6 key mutations ( hits ) 1. Unlimited growth a. Turn on growth promoter genes 2. Ignore checkpoints a. Turn off tumor suppressor genes 3. Escape apoptosis a. Turn off suicide genes 4. Immortality = unlimited divisions a. Turn on chromosome maintenance genes 5. Promotes blood vessel growth a. Turn on blood vessel growth genes 6. Overcome anchor & density dependence a. Turn off touch sensor genes What causes these hits? Mutations in cells can be triggered by o UV radiation o chemical exposure o radiation exposure o heat o cigarette smoke o pollution o age o genetics Tumors Mass of abnormal cells o 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 o 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 o High-energy radiation & chemotherapy with toxic drugs Kill rapidly dividing cells o Drugs targeting proteins (enzymes) found only in tumor cells Gleevec Treatment for adult leukemia (CML) & stomach cancer (GIST) 1st successful targeted drug 4