Cell Division, Cell Cycle Control, and Cancer Events in Interphase Events in mitosis How is the Cell Cycle controlled? Energy requirements Some Interesting Questions

Events in Interphase 1. Growth (G1) phase 2. S phase G1 checkpoint: also called the restriction point. DNA damage monitored by p53. 2. S phase DNA synthesis Duplication of Chromosomes 3. Growth (G2) phase

p53 A tumour-suppressor protein. Sometimes called the “Guardian Angel” of the cell. Activated by DNA damage. Once activated, p53 can induce the activation of other proteins by acting as a transcription factor. Since p53 may induce apoptosis, maybe it also should be called the Angel of Death?!

p53 Mutations may inactivate p53. Alternatively, some viruses (such as HPV) produce a protein which inactivates p53. In both cases, a loss of function occurs that may be a step in the progression of a cell to the transformed state.

DNA Replication Occurs during the S phase of the Cell Cycle Replication is semi-conservative DNA polymerase and accessory enzymes are required for DNA synthesis

Chromosome condensation The protein condensin links DNA loops together during the process of Chromosome condensation.

Events in Mitosis I Mitotic Spindle Forms Centrosomes move to opposite sides of the cell Chromosomes become condensed Nuclear envelope fragments Microtubules connect to the kinetochore

Events in Mitosis II Chromosomes “convene” or group at the metaphase plate Note: Homologous chromosomes do NOT pair up during mitosis. Sister chromatids separate and the chromosomes migrate to opposite sides of the cell. Failure of sister chromatids to separate is called . . .

Nondisjunction If sister chromatids of a chromosome fail to separate, both will be pulled to one pole of the cell. One daughter cell will receive too many chromosomes while its counterpart, the other daughter cell, will receive too few chromosomes.

Cytoskeletal Requirements Microtubules Microfilaments during cytokinesis in animal cells

Microtubules Spindle microtubules assemble at the centrosome. Once the nuclear envelope disassembles, some microtubules attach to the kinetochore of chromosomes A “tug-of-war” ensues where the chromosomes move back and forth. This involves the tubulin polymerization and depolymerization which lengthens or shortens microtubules.

Energy requirements I ATP needed for DNA and protein synthesis Movement of chromosomes through action of motor proteins at kinetochores Condensin

Energy requirements II Phosphorylation and dephosphorylation of proteins active in the cell cycle during Cell Surface receptor activation Signal transduction pathways Nuclear membrane disassembly and assembly Cyclin and cyclin-dependent kinase (cdk) ATP or GTP will be needed to serve as the phosphate donor for the above phosphorylation events.

Some Interesting Questions What keeps DNA from getting all tangled up as it condenses? How do Chromosomes move? How does the nuclear membrane just “disappear” and then reform? What can go wrong? What triggers a cell to start dividing?

Cell Growth Signals PDGF (platelet-derived growth factor), a protein released by platelets at the site of injury, will trigger fibroblasts to divide by a series of steps that involve 1. Reception: PDGF (the ligand) binds to the PDGF receptor, which becomes activated by phosphorylation. 2. Signal transduction. 3. Response. For the fibroblast, the response will be to divide.

Cell cycle control Checkpoints: stop signals Go signals Role of Tumor suppressor genes (such as p53 and the retinoblastoma protein-Rb) Go signals Proto-oncogenes: normal cellular genes (such as ras) that activate cell division pathways

Loss of Cell cycle control I Cancer Gain of function: proto-oncogenes mutated to a permanently active form, becoming an oncogene. (This situation is like a stuck accelerator on a car) Loss of function: tumor-suppressor genes inactivated by mutations or the action of viruses (such as HPV). (This situation is like a broken brake on a car)

Loss of Cell cycle control II Defects in DNA repair enzymes may contribute to the induction of cancer: failure in DNA repair may lead to mutations that activate proto-oncogenes or inactivate tumor suppressor genes

No penguins here! “I say cell division should be fast!” Slow and steady” “I say cell division should be fast!”