1. AH Biology: Unit 1 Apoptosis

2. What do falling leaves, the development of a mouse’s paw and a tadpole losing its tail all have in common?

3. Answer: They all depend on programmed cell death.

4. Apoptosis: Programmed Cell Death A matter of life or death for cells! (Greek for ‘falling off’)

5. Control of apoptosis: contents Purpose of apoptosis Comparison to necrosis Mechanism of apoptosis Initiation of apoptosis: -intracellular death signals -extracellular death signals Malfunction of apoptosis: causes and consequences

6. Why do multicellular organisms need to regulate the death of their cells?

7. To allow body structures to grow and develop correctly.

9. Why do multicellular organisms need to regulate the death of their cells? To remove body structures that are no longer required.

11. Why do multicellular organisms need to regulate the death of their cells? To regulate the sizes of cell populations in adult bodies cell proliferation must be balanced with cell death. This allows organisms to precisely control the sizes of their tissues and organs.

12. Death can be good for the body… Normal tissue Tumour Cell division (proliferation) Cell death (by apoptosis)

14. Why do multicellular organisms need to regulate the death of their cells? To prevent cells from surviving in environments where they should not be present.

16. Why do multicellular organisms need to regulate the death of their cells? To kill cells that have been infected by pathogens. To prevent the survival of cells with damaged DNA (these have the potential to become cancerous). To eliminate white blood cells that would produce an immune response to the body’s own cells.

18. The two forms of cell death 1.Apoptosis: programmed cell deathApoptosis 2.Necrosis: uncontrolled cell death Animated comparisoncomparison

19. Apoptosis compared to necrosis: What happens to the cell when it dies? FeatureApoptosisNecrosis Regulated by organismYes: involves a series of enzyme-controlled reactions No: can occur as a result of injury DNA broken downYesOnly after cell has lysed Cell membrane disintegration NoYes Nuclear membrane broken down YesNo Number of cells affectedMay be single cellsUsually sheets of cells Energy requirementATP dependent (active process) Energy input not required (passive process) Fate of dead cellsIngested by neighbouring cells or phagocytes Ingested by phagocytes Leakage of cell contentsNoYes End pointCell fragments into smaller bodies Lysis of whole cell

20. The mechanism of apoptosis 1. Activation of procaspase proteins Active caspase B Active caspase A Inactive procaspase Prodomain

21. The mechanism of apoptosis 2. Caspase activation cascade Active caspase A Active caspase B Active caspase C

22. The mechanism of apoptosis 3. Caspases are proteinases: they cleave key cell proteins Inactive DNAse Active DNAse Nuclear lamins Fragmented nuclear lamins Gelsolin Actin-digesting enzyme Caspase activity

24. The mechanism of apoptosis 4. Caspase activity results in the controlled destruction of the cell Active DNAse Breakdown of nuclear DNA Fragmented nuclear lamins Disassembly of nucleus Actin-digesting enzyme Disassembly of cytoskeleton

25. Initiation of apoptosis: the death signal Adaptor proteins cause initiator procaspases to cluster together. Clustering induces a conformational change that activates the procaspases. Caspase activation Caspase cascade

26. Intracellular death signals Mitochondrion-mediated pathway 1. Damaged mitochondrion 3. Caspase cascade 2. Cytochrome C protein released

27. Intracellular death signals DNA damage can trigger apoptosis via the p53 protein.

28. Damaged DNA Caspase cascade Increased concentration of p53 protein in cell Increased transcription of genes that code for proteins that activate procaspases Increased protein kinase activity

29. Extracellular death signals: survival factors Animal cells undergo apoptosis if they are deprived of survival factors released by other cells. This ensures that cells only survive in locations where they are needed, when they are needed. The default program for most cells is suicide!

30. Extracellular death signals: inhibitory signal proteins ­ Some signal proteins oppose the effects of growth factors and survival factors. They can inhibit the growth of organs by stimulating apoptosis. ­ For example, mouse limb formation (see earlier images D, E, F and G).

31. Extracellular death signals Body cells infected with certain pathogens, eg some viruses, present fragments of antigenic proteins on surface receptor proteins on their cell membranes.

33. Extracellular death signals Activated killer T lymphocytes can recognise body cells displaying antigens. The lymphocytes bind surface receptor proteins on the target cell and trigger apoptosis.

34. Animation

35. Putting it together

36. Initiation of apoptosis by killer T lymphocytes Target cell Lymphocyte

37. Initiation of apoptosis by killer T lymphocytes Animation Target cell Caspase cascade

38. Which cellular events could cause the control of apoptosis to be impaired?

39. What could be the consequence of impaired apoptosis to: (a) the affected cell? (b) the organism containing the affected cell?

40. Cancer The development of some forms of leukemia is promoted by the loss of control of apoptosis. Mutations to the DNA of B lymphocytes can cause them to produce abnormally large quantities of a protein that inhibits apoptosis. p53 is a cancer-critical gene.

41. 3. Inhibition of procaspase activation 4. Cell develops resistance to apoptosis 5. Survival of B lymphocytes that would normally have died 1. Chromosome translocation 2. Over-expression of a regulatory protein

42. Further reading and viewing College of St Benedict/St John’s University website website Protein Data Bank website (p53)website Apoptosis animationanimation