1. Apoptosis, necrosis, and death Chapter 18

2. Continuity of life Only from existing cells come new cells. We are all decedents of the first cells on the planet. A cell reproduces by duplicating its contents and then dividing into two This cycle of events is known as the cell cycle

3. Consideration How do cells duplicate their contents? How do they partition the duplicated contents and split into two? How do they coordinate all the machinery that is required for these two processes?

4. Cell division timing Different cells have cell cycles of different lengths; –Nerve Cells = never –Human Liver Cells = 1 year –Intestinal epithelial cells = 12 hours –Yeast cells = 1.5 to 3 hours –Bacteria = 90 minutes

5. 18_02_four_phases.jpg Eukaryotic Cell Cycle

6. Four phases –M phase (mitotic phase) –G1 phase (Gap 1) –S phase (synthesis phase) –G2 phase (Gap 2) Four phases –M phase (mitotic phase) –G1 phase (Gap 1) –S phase (synthesis phase) –G2 phase (Gap 2)

7. Central Control The cell-cycle control system regulates the entire process A great analogy is to think of it as a washing machine control knob Cannot implement the next program until the first one in completed. Feedback systems operate to provide information on how processes are progressing.

8. 18_03_control_system.jpg

9. Checkpoints The cell cycle halts at various points until signals are sent to proceed

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11. Cycle regulation The key players are the kinases and phoshatases

12. IMPORTANT PRINCIPLE Proteins may have phosphate groups added to certain amino acids These phosphates are added by enzymes called KINASES Proteins may have phosphate groups removed from certain amino acids These phosphates are removed by enzymes called PHOSPHATASES The same proteins may be repeatedly activated and deactivated by simply adding or removing phosphate groups

13. 18_05_ Cdks.jpg The cell-cycle is regulated by the phosphorylation of special proteins called Cdks (shown in red). However, these proteins must associate with other peptides before they become functional. These other peptides are known as cyclins (shown in green). The cell just regulates the concentration of different cyclins (hence their name - as they vary in concentration during the cell cycle)

14. 18_06_M_Cdk.jpg The cyclin which drives cells into M phase is called M-cyclin. It interacts with a kinase called M-Cdk. Levels of M-cyclin build steadily. Then it is rapidly removed from the cell by rapid degradation by the proteasome Removal of M-cyclin results in the inactivation of M-Cdk and the cell divides. APC (anaphase promoting complex) decides when to remove M-cyclin from the cell.

15. 18_07_cyclin_degradat.jpg The key molecular event that marks many proteins for destruction by the proteasome is ubiquitation - a type of modification. Here the M-cyclin is ubiquitinated and is thus quickly destroyed.

16. 18_16_G1_checkpoint.jpg The Go (G zero) state results in the dismantling of most of the replication machine. Nerve and muscle cells are in this state. Many other cells come to this important checkpoint each time after they have divided.

17. 18_17_arrest_checkpt.jpg In conclusion, the cell is faced with a number of points in the cell cycle where it has to satisfy certain molecular requirements before it is permitted to continue along the cell cycle.

18. Cell Death The body is very good at maintaining a constant number of cells. So there has to exist mechanisms for ensuring other cells in the body are removed, when appropriate. Two forms –Apoptosis - suicide - programmed cell death –Necrosis - killing - decay and destruction

19. 18_18_sculpts_digits.jpg Cell Death -occurs more often than one imagines! a) Most embryo development involves programmed cell death.

20. 18_19_tadpole_frog.jpg b) The tail of the tadpole is absorbed via apoptosis. Also, in adult multicellular organisms cell death is a regular occurrence. In humans EACH HOUR we lose many many BILLIONS of cells via apoptosis. Most of these are healthy cells which have no defects. WHY? Development and regulation controls. i.e. B and T cells are removed that do not pass certain tests.

21. 18_20_Apoptosis_.jpg Apoptosis results in a quick and clean cell death, without damaging its neighbours, or eliciting an immune response. Every cell is equipped with the ‘cell death pathway’. Apoptosis is an intracellular proteolytic pathway. The DNA is broken into small 200 bp units. The cytoplasm shrinks. The mitochondria release cytochrome c. The outer surface of the plasma membrane gets coated with a different sugar - one that macrophages can sense and phagocytose.

22. Caspases Proteins which degrade other proteins are employed by apoptosis - caspases Made as inactive precursors - procaspases These are activated by other proteins when the right signal is received One caspase cleaves the lamin proteins resulting in the irreversible breakdown of the nuclear membrane.

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24. 18_22_Bcl_2_family.jpg

25. Control of cell numbers and cell size Three processes operate to control the eventual form a body part takes –Cell growth –Cell division –Cell death Single celled organisms grow as fast as they are able to limited by factors such a food availability Multicellular organisms receive signals from other cells in the body

26. These signals can be classified into three catergories –Mitogens - these allow the cell to enter the cell cycle –Growth factors - increase in cell mass –Survival factors - suppress apoptosis

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28. 18_27_nerve_target.jpg

29. 18_28_regulating_Bcl2.jpg