1. Regulation of the Cell Cycle / Cancer Chapter 12

2. What you need to know! The cell cycle is regulated by a molecular control system Cancer results from genetic changes that affect cell cycle control.

3. Signals Influencing Cell Cycle Can be internal (current situation of cell) –Start and stop signals External (hormones, space) –start and stop signals

4. Internal Signals Stop Signals: Cell too small, not enough nutrients available Incomplete DNA synthesis Incomplete kinetochore attachment Start Signals: High levels of hormone Cyclin Active form of MPF (mitosis promoting factor) kinase – MPF concentration is stable but exists in inactive and active form Completed DNA replication Successful attachment of all sister chromatids to kinetochore spindle fibers

5. External Signals Stop signals: No room or surrounding space to grow (in vivo and vitro) No anchorage in Petri dish (in vitro) Start signals: Growth hormones –PDGF – platelet derived growth factor –GH – various growth hormones Example: HGH = human growth hormone

6. I. Cell-Cycle Checkpoints Checkpoints at crucial places where cell division comes to a halt: G1 Restriction point: will cell enter G0 or S? S checkpoint: is all DNA duplicated? G2 checkpoint: is everything ready for mitosis? M (metaphase) checkpoint: are all sister chromatids ready for separation? Each checkpoint needs to be overridden by the specific go ahead signals for this phase

7. G1 Restriction Point Cell is fully mature Space is present Nutrients present = Growth hormones will induce S-phase OR Cell is not fully mature No space Limited nutrients No growth hormones = cell will enter G 0

8. S Checkpoint DNA is completely duplicated Rising levels of Cyclin

9. G2 Checkpoint Peak levels of cyclin Increased activation of MPF kinase leads to nuclear envelope disintegration and prophase

10. Metaphase Checkpoint Kinetochore spindle fibers successfully attached to all kinetochore motors, which sends signals that disintegrate protein clamps between sister chromatids Cyclin is degraded MPF kinase is deactivated

11. Cell-Cycle Control in Cancer Cells Cancer cells have numerous mutations (cumulative mutations increase with age) in the genes that code for restriction point protein machinery They escape the normal cell cycle control mechanisms a.No density dependent inhibition (in vivo and vitro) b.No anchorage dependence (in vitro) c.No dependence on growth factors d.Cancer cells are immortal (no cell cycle limit)

12. Biology of Cancer If cells become abnormal they are located by the immune system and destroyed If they evade recognition they will start forming tumors Benign tumors Cells stay at original location Slow proliferation

13. Malignant Tumors Invade other locations: metastasis  cells breaking off the tumor get carried by the blood stream and get stuck in other capillary beds (lungs, liver, kidneys) or cycle through the lymphatic system and get stuck in the lymph nodes Uncontrolled proliferation: constant cell cycling/mitosis –chemotherapy drugs attack all cells in cell cycle by blocking the formation of spindle fibers Cancer cells send signals to the body to provide angiogenesis = growth of blood vessels into growing tumors –anti angiogenesis drugs are used as treatment

14. Malignant Tumors Can differ in: # of chromosomes, metabolic rate, abnormal cell surfaces, and large nuclei Names include: carcinoma, sarcoma, lymphoma, etc. There are 4 levels of malignancy for cancer cells indicating how aggressive/mutated the cell is with level 1 being the least and level 4 being the most aggressive type of cancer Viruses can cause cancer There is a genetic predisposition for cancer (it’s hereditary)