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1. https://www.youtube.com/watch?v=Jmqd9Qj_PTA https://www.youtube.com/watch?v=eqJqhA8HSJ0 5:30 Tumor suppersson https://www.youtube.com/watch?v=5inw61JlQlw https://www.youtube.com/watch?v=2NVBsPfOtT8 https://www.youtube.com/watch?v=dpipegI4lgg

2. Cell Cycle: life of a cell from its formation until it divides Functions of Cell Division: Reproduction, Growth and Tissue Repair

3. Genome= all of a cell’s genetic info (DNA) • Prokaryote: single, circular chromosome • Eukaryote: more than one linear chromosomes • Eg. Human:46 chromosomes, mouse: 40, fruit fly: 8

4. (a) Prokaryotes. During binary fission, the origins of the daughter chromosomes move to opposite ends of the cell. The mechanism is not fully understood, but proteins may anchor the daughter chromosomes to specific sites on the plasma membrane. Bacterial chromosome Chromosomes (b) Dinoflagellates. In unicellular protists called dinoflagellates, the nuclear envelope remains intact during cell division, and the chromosomes attach to the nuclear envelope. Microtubules pass through the nucleus inside cytoplasmic tunnels, reinforcing the spatial orientation of the nucleus, which then divides in a fission process reminiscent of bacterial division. Microtubules Intact nuclear envelope (c) Diatoms. In another group of unicellular protists, the diatoms, the nuclear envelope also remains intact during cell division. But in these organisms, the microtubules form a spindle within the nucleus. Microtubules separate the chromosomes, and the nucleus splits into two daughter nuclei. Kinetochore microtubules Intact nuclear envelope Kinetochore microtubules (d) Most eukaryotes. In most other eukaryotes, including plants and animals, the spindle forms outside the nucleus, and the nuclear envelope breaks down during mitosis. Microtubules separate the chromosomes, and the nuclear envelope then re-forms. Centrosome Fragments of nuclear envelope A hypothetical sequence for the evolution of mitosis Figure 12.12 A-D

5. Cell Cycle ControlIn eukaryotes, heritable information is passed to the next generation via processes that include the cell cycle, mitosis or meiosis plus fertilization

6. G1 checkpoint Control system S G1 G2 M M checkpoint Figure 12.14 G2 checkpoint The Cell Cycle Control System • The cyclic events of the cell cycle • Are directed by a distinct cell cycle control system, which is similar to a clock

7. INTERPHASE S(DNA synthesis) G1 CytokinesisMitosis G2 MITOTIC(M) PHASE Figure 12.5 Cell Cycle ControlWhy? • Cells should only divide when they need to • Mitosis is under strict cellular controls

8. G1 checkpoint Control system S G1 G2 M M checkpoint Figure 12.14 G2 checkpoint Cell Cycle Checkpoints Its best to think of cell cycle as consisting of a series of “checkpoints” that the cell must pass through in order to be able to divide. If internal conditions are not appropriate, cell division will normally be prevented Breast cancer cell: It becomes a “selfish” cell

9. Cell Cycle Regulation • The clock has specific checkpoints • a critical control point where stop and “go-ahead” signals can regulate cycle • These signals report whether crucial cellular processes up to that specific point have been completed and completed correctly • There are 3 checkpoints 1. G1checkpoint 2. G2Checkpoint 3. M checkpoint • spindle assembly checkpoint

10. G0 G1 checkpoint G1 G1 If a cell does not receive a go-ahead signal at the G1checkpoint, cell exits the cell cycle and goes into G0, a nondividing state. If a cell receives a go-ahead signal at the G1 checkpoint, the cell continues on in cell cycle. Figure 12.15 A, B Which check point is most critical? G1Checkpoint called the “restriction point” • Determines if a cell should replicate its DNA • After cells will enter S phase or G0 phase • Senescence: cells that stop dividing

11. Chromosomes are lined up in the middle properly http://highered.mcgraw-hill.com/sites/0072495855/student_view0/chapter2/animation__control_of_the_cell_cycle.html

12. Some cells go into a resting phase G0 http://www.cellsalive.com/cell_cycle.htmCell Cycle animation

13. cell cycle animation Checkpoints animation

14. The Cell Cycle Clock: Cyclins and Cyclin-Dependent Kinases • Two types of regulatory proteins in cytoplasm are involved in cell cycle control • Cyclins • cyclin-dependent kinases (Cdks)

15. Internal Regulatory Molecules • Kinases: are enzyme that control cell cycle; only active when connected to cyclin protein (cyclin dependent kinases – Cdks). Kinases give the signal to cells to go onto the phase of the cell cycle when active. When inactive cells can not go onto the next phase of the cell cycle • Cyclins: proteins which attach to kinases to activate them; levels fluctuate in the cell cycle

16. INACTIVE FORM CYCLIN DEPENDENT KINASE (CDK) CYCLIN + ACTIVE FORM CDK/CYCLIN COMPLEX ATP  Specific Example is MPF Pi

17. Biochemical mechanism of Cell Regulation • Cyclin and Cyclin dependent kinases (cdk’s) • CDK’s - produce signal for cells to continue in cell cycle • Cyclins -proteins that activate cdk’s

18. Internal Regulatory Molecules MPF= maturation-promoting factor • specific cyclin-Cdk complexwhich allows cells to pass G2 and go to M phase

19. Cell Cycle Control…HOW? Internal and External Controls Internal Controls- protein molecules that are present in varying concentrations during cell cycle External Controls- proteins and other environment signals generated by other cells PDGF: Platelet Derived Growth factor Positional Inhibition Normal animal cells must be anchored and not too crowded (density dependent) Cancerous cells don’t care • Cdk: “Cyclin-dependent” kinase • Present in constant amount • Cyclin: the Cdk “on switch” • Made in increasing amount as the cell moves through interphase • No cyclin = no mitosis • MPF: Cyclin + Cdk • Mitosis Promotion Factor • Turns on other proteins needed for mitosis (e.g. microtubule formation)

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

21. “Go-ahead” signals • Protein signals that promote cell growth & division • internal signals • “promoting factors” • external signals • “growth factors” • Primary mechanism of control • Phosphorylation (addition of phosphate group) • Regulates the activity of proteins (enzymes) • kinase enzymes • either activates or inactivates cell signals • Deactivation is the removal of phosphate (dephosphorylation)

22. inactivated Cdk Protein signals • Promoting factors cyclins • regulatory proteins • levels cycle in the cell • Cdks • cyclin-dependent kinases • Enzyme activates cellular proteins • MPF (for G2 checkpoint) • Maturation/mitosis promoting factor • APC (for Mcheckpoint) • Anaphase promoting complex activated Cdk

23. Spindle checkpoint G2 / M checkpoint Chromosomes attached at metaphase plate • Replication completed • DNA integrity Inactive Active Active Inactive Cdk / G2cyclin (MPF) M cytokinesis APC C mitosis G2 G1 S Cdk / G1cyclin Inactive MPF = Mitosis Promoting Factor APC = Anaphase Promoting Complex Active G1 / S checkpoint • Growth factors • Nutritional state of cell • Size of cell

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

25. Internal Signals • 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) • CDKs & cyclin drive cell from one phase to next in cell cycle

26. 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 • each cell binds a bit of growth factor • not enough activator left to trigger division in any one cell • anchorage dependence • to divide cells must be attached to a substrate

27. Example of a Growth Factor • Platelet Derived Growth Factor (PDGF) • made by platelets in blood clots • binding of PDGF to cell receptors stimulates fibroblast cell division • Fibroblast (connective tissue cells) heal wounds Don’t forget to mentionerythropoietin!(EPO)

28. Growth factor signals growth factor nuclear pore nuclear membrane P P cell division cell surface receptor Cdk E2F protein kinase cascade P chromosome P Rb P E2F Rb nucleus cytoplasm

29. Cancer: Uncontrolled cell Division • Mutations Happen • Every second of every day, your DNA is beset by entropic forces • You have a whole series of genes that make sure mutated cells don’t divide • But what happens when these genes get mutated?

30. Growth Factors and Cancer • Growth factors can create cancers • proto-oncogenes (the accelerator) • Normal genes that become oncogenes (cancer-causing) when mutated • Stimulates cell growth • If switched “ON” can cause cancer • Ex: RAS (activates cyclins) • tumor-suppressor genes (brake pedal) • inhibits cell division • if switched “OFF” can cause cancer • Mutated version always off • example: p53

33. Cancer requires mutation in different genes to occur (multi-step pathways) A multiple-step model of colon cancer development

34. The Stages of Cancer 98% Survival 16% Survival 88% Survival 52% Survival Cancer cells spread through lymph and blood vessels to other parts of the body Cancer cell invades neighboring tissue Metastasis is what kills people Cancer cells may survive and establish a new tumor in another part of the body

35. Cancer & Cell Growth • Cancer is essentially a failure of cell division control • unrestrained, uncontrolled cell growth • What control is lost? • checkpoint stops • gene p53plays a key role in G1/S restriction point • p53 protein halts cell division if it detects damaged DNA • options: • stimulates repair enzymes to fix DNA • Forces and keeps cell into G0 resting stage • causes apoptosis of damaged cell • ALL cancers have to shut down p53 activity p53 is theCell CycleEnforcer p53 discovered at Stony Brook by Dr. Arnold Levine

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

37. 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 (p53) • escape apoptosis • turn off suicide genes • immortality = unlimited divisions • turn on chromosome maintenance genes • promotes blood vessel growth • turn on blood vessel growth genes • overcome anchor & density dependence • turn off touch-sensor gene It’s like anout-of-controlcar with manysystems failing!

38. What causes these “hits”? • Mutations in cells can be triggered by • UV radiation • chemical exposure • radiation exposure • heat • cigarette smoke • pollution • age • genetics

39. 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 tumor • 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

40. Traditional treatments for cancers • Treatments target rapidly dividing cells • high-energy radiation • kills rapidly dividing cells • chemotherapy • stop DNA replication • stop mitosis & cytokinesis • stop blood vessel growth

41. New “miracle drugs” • Drugs targeting proteins (enzymes) found only in cancer cells • Gleevec • treatment for adult leukemia (CML)& stomach cancer (GIST) • 1st successful drug targeting only cancer cells withoutGleevec withGleevec Novartes

42. Control of Cell Division • cell division capacities vary greatly among cell types • skin and blood cells divide often and continually • neuron cells divide a specific number of times then cease • chromosome tips (telomeres) that shorten with each mitosis provide a mitotic clock • cells divide to provide a more favorable surface area to volume relationship • growth factors and hormones stimulate cell division • hormones stimulate mitosis of smooth muscle cells in uterus • epidermal growth factor stimulates growth of new skin • contact (density dependent) inhibition • tumors are the consequence of a loss of cell cycle control

43. Cell Cycle Checkpoints and Cancer • When the regulation of cell growth is lost, cancer may develop. Cancer is the uncontrolled growth of cells.

44. Stem and Progenitor Cells • Stem cell • can divide to form two new stem cells • self-renewal • can divide to form a stem cell and a progenitor cell • totipotent – can give rise to every cell type • pluripotent – can give rise to a restricted number of cell types • Progenitor cell • committed cell • can divide to become any of a restricted number of cells • pluripotent

45. Stem and Progenitor Cells

46. Clinical Application Diseases at the Organelle Level • MELAS – mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes • mitochondria are missing a gene necessary to carry out important energy producing reactions • usually inherited by mother • causes strokes, severe headaches, muscle weakness and numb hands • ALD – adrenoleukodystrophy • peroxisomes are missing enzymes • causes dizziness, weakness, darkening skin, and abnormal heart rhythms • Tay-Sachs Disease • lysosomes are abnormally large and lack one enzyme • causes nervous system failure and early death