1. AP Biology Chapter 12. Regulation of Cell Division

2. Coordination of cell division  Multicellular organism  need to coordinate across different parts of organism  timing of cell division  rates of cell division  crucial for normal growth, development & maintenance  do all cells have same cell cycle? Why is this such a hot topic right now?

3. Frequency of cell division  Frequency of cell division varies with cell type  skin cells  divide frequently throughout life  liver cells & muscle, bone  retain ability to divide, but keep it in reserve  mature nerve cells do not divide at all after maturity

4. Cell Cycle Control  Two irreversible points in cell cycle  replication of genetic material  separation of sister chromatids  Cell can be put on hold at specific checkpoints centromere sister chromatids single-stranded chromosomes double-stranded chromosomes There’s no turning back, now!

5. 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

6. Checkpoint control system  3 major checkpoints: G1G1  can DNA synthesis begin? G2G2  has DNA synthesis been completed correctly?  commitment to mitosis  M phases  spindle checkpoint  can sister chromatids separate correctly?

7. G 1 checkpoint  G 1 checkpoint is most critical  primary decision point  “restriction point”  if cell receives “go” signal, it divides  if does not receive “go” signal, cell exits cycle & switches to G 0 phase  non-dividing state

8. G 0 phase  G 0 phase  non-dividing, differentiated state  most human cells in G 0 phase  liver cells, bones, muscles  in G 0, but can be “called back” to cell cycle by external cues  nerve highly specialized; arrested in G 0 & don’t divide

9.  How do cells know when to divide?  cell communication = signals  chemical signals in cytoplasm give a cue  signals usually mean proteins  activators  inhibitors Activation of cell division experimental evidence: Can you explain this?

10. “Go-ahead” signals  Signals that promote cell growth & division  proteins  internal signals  “promoting factors”  external signals  “growth factors”  Primary mechanism of control  phosphorylation  kinase enzymes

11. Protein s ignals  Promoting factors  Cyclins  regulatory proteins  concentrations “cycle” in the cell  Cdks  cyclin-dependent kinases  enzyme activates cellular proteins  MPF  maturation (the ok into mitosis) promoting factor  combo of a cdk (enzyme) and cyclin (substrate)  APC  anaphase promoting complex

12. Cyclins & Cdks  Interaction of Cdks & different Cyclins triggers the stages of the cell cycle. Leland H. Hartwell checkpoints Tim Hunt Cdks Sir Paul Nurse cyclins 1970s-’80s | 2001

13. Chromosomes attached at metaphase plate Replication completed DNA integrity Growth factors Nutritional state of cell Size of cell Cdk / G 1 cyclin Cdk / G 2 cyclin (MPF) G2G2 S G1G1 C M Spindle checkpoint G 2 / M checkpoint APC Active Inactive Active Inactive Active mitosis cytokinesis GoGo G 1 / S checkpoint Restriction Point

14. Cyclin & Cyclin dependent kinases  CDKs & cyclin drive cell from one phase to next in cell cycle  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)

15. External signals  Growth factors  external signals  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 not enough left to trigger cell division  anchorage dependence  to divide cells must be attached to a substrate

16. E2F Nucleus Cytoplasm Cell division Growth factor Protein kinase cascade Nuclear membrane Nuclear pore Cdk Cell surface receptor P P P P P E2F Rb Chromosome Growth factor - external signal Cell signaling transduction. When RAS is switched on by incoming signals, it switches on other proteins that ultimately turn on genes associated with cell growth, differentiation, and survival. 90% of cancers have faulty RAS proteins.

17. Example of a Growth Factor  Platelet Derived Growth Factor (PDGF)  made by platelets (blood cells)  binding of PDGF to cell receptors stimulates fibroblast (connective tissue) cell division  wound repair growth of fibroblast cells (connective tissue cells) helps heal wounds

18. Growth Factors and Cancer  Growth factors influence cell cycle  proto-oncogenes  normal genes that become oncogenes (cancer-causing) when mutated  stimulates cell growth  if switched on can cause cancer  example: RAS (activates cyclins)  speeds up the cell cycle  tumor-suppressor genes  inhibits cell division  if switched off can cause cancer  example: p53

19. Cancer & Cell Growth  Cancer is essentially a failure of cell division control  unrestrained, uncontrolled cell growth  What control is lost?  checkpoint stops  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 0 arrest  causes apoptosis (process of programmed cell death) of damaged cell  ALL cancers have to shut down p53 activity p53 discovered at Stony Brook by Dr. Arnold Levine p53 is the Cell Cycle Enforcer

20. DNA damage is caused by heat, radiation, or chemicals. p53 allows cells with repaired DNA to divide. Step 1 DNA damage is caused by heat, radiation, or chemicals. Step 1 Step 2 Damaged cells continue to divide. If other damage accumulates, the cell can turn cancerous. Step 3 p53 triggers the destruction of cells damaged beyond repair. ABNORMAL p53 NORMAL p53 Abnormal p53 protein Cancer cell Step 3 The p53 protein fails to stop cell division and repair DNA. Cell divides without repair to damaged DNA. Cell division stops, and p53 triggers enzymes to repair damaged region. Step 2 DNA repair enzyme p53 protein p53 protein p53 — master regulator gene

21. 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 (add telomeres TTAGGG)  promotes blood vessel growth to get nutrients to cells  turn on blood vessel growth genes (PDGF - platelet-derived growth factor)  overcome anchor & density dependence  turn off touch sensor gene It’s like an out of control car

22.  Stages of Cancer – based on Tumor (size/extent of the primary tumor) Lymph node involvement Amount of metastasis (development of malignant growths away from the origin) Cancer has 5 stages: 0 – 1 – 2 – 3 – 4 (zero being the best 4 being the worst) Stages of a malignant tumor: Clear margin http://www.cancercenter.com/breast-cancer/types/tab/male-breast-cancer/

23.  Mutations in cells can be triggered by UV radiation cigarette smoke viruses pollution radiation exposure age genetics chemical exposure Be proactive: Avoid things that are known to cause cancer Pay attention to your body (follow up on changes) Get regular physical examinations Mammograms, biopsies, etc. as called for/needed

24. 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

25. Cancer is a disease of the cell cycle. Some of the body’s cells divide uncontrollably and tumors form. Tumors in Liver Tumor in Colon

26. Traditional treatments for cancers  Treatments target rapidly dividing cells  high-energy radiation  chemotherapy with toxic drugs  kill rapidly dividing cells

27. Oncology – the study of cancer There are several sub-specialties within oncology, where their expertise is in managing particular types of cancers: Radiology (diagnosis – through x-rays, mammograms, CAT scans) Histopathology (diagnosis – through tissue samples, prognosis) Radiation oncology (treatment) Surgical oncology (treatment) Pharmacotherapy (treatment) Gynecologic oncology (female reproductive cancers) Pediatric oncology (treatment of cancer in children)

28. SUMMARY Normal Cell Division 1. DNA is replicated properly. 2. Chemical signals start and stop the cell cycle. 3. Cells communicate with each other so they don’t become overcrowded. Cancer Cells 1. Mutations occur in the DNA when it’s replicated. 2. Chemical signals that start & stop the cell cycle are ignored. 3. Cells do not communicate with each other and tumors form.

29. New “miracle drugs”  Drugs targeting proteins (enzymes) found only in tumor cells  Gleevec  Treatment for adult leukemia (CML)  Treatment for stomach cancer (GIST)  1st successful targeted drug