2. 2011-12 Control of the Cell Cycle

3. 2011-12 Cell Cycle Control Cell cycle controlled by internal and external signals –External signals Growth factors Received at the plasma membrane Cause completion of cell cycle –Internal signals Family of proteins called cyclins Increase and decrease as cell cycle continues Without them cycle stops at G 1, M or G 2 Allows time for any damage to be repaired

4. 2011-12 The Cell Cycle

5. 2011-12 Apoptosis Often defined as programmed cell death Mitosis and apoptosis are opposing forces –Mitosis increases cell number –Apoptosis decreases cell number Cells harbor apoptosis enzymes (caspases) –Ordinarily held in check by inhibitors –Can be unleashed by internal or external signals Signal protein P53 –Stops cycle at G 1 when DNA damaged –Initiates DNA attempt at repair If successful, cycle continues to mitosis If not, apoptosis is initiated

6. 2011-12 Apoptosis

7. 2011-12 Evidence for cytoplasmic chemical signals Mammalian cells in different phases 2nd cell begins mitosis too early

8. 2011-12 Role of protein kinases Kinases transfer phosphates to other proteins from ATP and bring about further effects in cell cycle events Activity of protein kinases depends of fluctuating levels of proteins called cyclins during cell cycle; and their attachment to cyclins; kinase referred to as a Cdk (cyclin-dependent kinase) (Cdk)

9. 2011-12 G 2 checkpoint regulation accumulation MPF = M-phase promoting factor (1st cyclin-Cdk complex discovered); “threshold effect” –Causes chromosome condensation; –nuclear envelope to fragment –Brings about switching itself “off” by promoting a proteolytic process which destroys MPF (noncyclin part of molecule persists in cell until cyclin is regenerated again) Proteolytic enzymes also degrade proteins which hold sister chromatids together; allows anaphase to begin G 1 occurs in similar fashion with rise and fall of other cyclins

10. 2011-12 M-phase checkpoint depends on molecular signaling from kinetochores –Chromosomes must be attached to spindle microtubules before anaphase may proceed Unattached kinetochores trigger a signaling pathway which keeps APC (anaphase-promoting-complex) inactive After all kinetochores become attached, APC becomes active –Contains proteolytic enzymes which degrade cyclin

11. 2011-12 External signaling factors Chemical factors –Essential nutrients: cells won’t divide without them –Growth factors usually necessary for tissue-cultured mammalian cells to divide PDGF = platelet-derived growth factor stimulates cell division in fibroblasts –PDGF is used in the laboratory as well as being found in mammals during wound-healing Other types of cells probably have different receptors for different growth factors or combinations of growth factors

12. 2011-12 Physical factors –Crowding of cells (density-dependent inhibition) causes cells to stop growing. Too densely packed cells might have insufficient nutrients and growth regulators to support cell division

13. 2011-12 Anchorage-dependence –For cell division, many cells must adhere to a substratum (bottom of culture dish, extracellular matrix, etc.) Communicate anchorage to cell-cycle control mechanism via membrane proteins and cytoskeletal elements attached to those proteins Cancer cells don’t display either density-dependent inhibition or anchorage-dependent inhibition

14. 2011-12 The Cell Cycle and Cancer Abnormal growth of cells is called a neoplasm –Benign neoplasms are not cancerous Encapsulated Do not invade neighboring tissue or spread –Malignant neoplasms are cancerous Not encapsulated Readily invade neighboring tissues May also detach and lodge in distant places – metastasis Results from mutation of genes regulating the cell cycle Carcinogenesis – development of cancer –Tends to be gradual –May be years before cell is obviously cancerous

15. 2011-12 Cancer cells out of cell cycle loop Don’t stop growing or dividing when growth factors are depleted –May make own growth factors Are invasive –Don’t demonstrate anchorage-dependence inhibition Are immortal –Most cells’ “internal clocks” allow 20-50 cell divisions before they stop; cancer cells keep on going Cancer cells that do stop dividing, do so at random places in cell cycle -- not at checkpoints

16. 2011-12 What about our immune system? Cells which escape normal cell cycle controls are products of mutated or transformed cells Immune system normally recognizes and destroys transformed cells which have converted from normal cells –When cancer cells escape destruction they may proliferate into a tumor within normal tissue If cells remain in this isolated located the mass is a benign tumor and can be surgically removed A malignant tumor becomes invasive and impairs normal function of one or more body organs; at this time patient is said to have cancer

17. 2011-12

18. Malignant tumors Anomalous (not normal) cell cycle; excessive proliferation May contain unusual numbers of chromosomes May have aberrant metabolism Has lost attachments to neighboring cells and ECM -- usually caused by abnormal cell surface changes. May become invasive into other tissues/organs -- metastasis –Metastasis treated with radiation and chemotherapy

19. 2011-12 Characteristics of Cancer Cells Lack differentiation Have abnormal nuclei Form tumors –Mitosis controlled by contact with neighboring cells – contact inhibition –Cancer cells have lost contact inhibition Undergo metastasis –Original tumor easily fragments –New tumors appear in other organs Undergo angiogenesis –Formation of new blood vessels

20. 2011-12 Cancer Cells Versus Normal Cells

21. 2011-12 Cancer Cells

22. 2011-12 Origins of Cancer: Oncogenes Mutations in DNA repair mechanisms Oncogenes –Proto-oncogenes promote the cell cycle in various ways –Tumor suppressor genes inhibit the cell cycle in various ways –Both normally regulated in coordination with organism’s growth plan –If either mutates, may lose control and become oncogene

23. 2011-12 Origins of Cancer: Telomerase Chromosomes normally have special material at each end called telomeres (end parts) These get shorter each cell division When they get very short –The cell will no longer divide –Almost like running out of division tickets Telomerase is an enzyme that adds telomeres Mutations in telomerase gene: –Keeps adding new telomeres –Allow cancer cells to continually divide –Like counterfeit tickets

24. 2011-12 Causes of Cancer

25. 2011-12 End