Chapter 18 Apoptosis

1. Chapter 18 Apoptosis Apoptosis is only one form of programmed cell death. In animal cells, cell necrosis is another form of programmed cell death.

2. Programmed cell death eliminates unwanted cells Two distinct forms of cell death – apoptosis and necrosis

3. In metazoans, apoptosis is vital for • - normal development • - maintenance of tissue homeostasis • an effective immune system • Its disturbance is implicated in numerous pathological conditions ranging from • degenerative disorders to autoimmunity to cancer Sculpting the digits in the developing mouse paw by apoptosis

4. Apoptosis during the metamorphosis of a tadpole into a frog

5. Apoptotic cells are biochemically recognizable • Characteristic biochemical changes in cells undergoing apoptosis • 1. Chromosomal DNA cleaved into fragments • Change in the plasma membrane – phosphatidylserine • in the outer leaflet • Loss of electrical potential across the inner membrane of the • mitochondria • Relocation of cytochrome c from the intermembrane space of • the mitochondria to the cytosol

6. Cleavage of chromosomal DNA into a characteristic ladder of fragments

7. Apoptosis depends on an intracellular proteolytic cascade that is mediated by caspases Procaspase activation during apoptosis

8. Some human caspases Caspases involved in inflammation caspases 1 (ICE), 4, 5 Caspases involved in apoptosis Initiator caspases caspases 2, 8, 9, 10 Executioner caspases caspases 3, 6, 7 Examples of target proteins Nuclear lamins Protein that holds the endonuclease in an inactive state Components of the cytoskeleton and cell-cell adhesion proteins

10. The two best understood signaling pathways that activate a caspase cascade in mammalian cells are the extrinsic pathway and the intrinsic pathway Each pathway uses its own initiator procaspases and activation complex

11. Cell-surface death receptors activate the extrinsic pathway of apoptosis The extrinsic pathway of apoptosis activated through Fas death receptors

12. The intrinsic pathway of apoptosis depends on mitochondria

13. Release of cytochrome c from mitochondria during apoptosis

14. Bcl2 proteins regulate the intrinsic pathway of apoptosis The three classes of Bcl2 proteins

15. The three major mammalian factions of the Bcl-2 family. The BH3-only proteins (yellow) are essential initiators of apoptosis that primarily antagonize their pro-survival relatives (blue), whereas either Bax or Bak (red) is required downstream of Bcl-2.

16. The role of BH123 pro-apoptotic Bcl2 proteins (mainly Bax and Bak) in the release of mitochondrial intermembrane proteins in the intrinsic pathway of apoptosis

17. How pro-apoptotic BH3-only and anti-apoptotic Bcl2 proteins regulate the intrinsic pathway of apoptosis

18. IAPs inhibit caspases A proposed model for the roles of IAPs and anti-IAPs in the control of apoptosis in mammalian cells

19. Extracellular survival factors inhibit apoptosis in various ways

20. Three ways that extracellular survival factors can inhibit apoptosis

21. Either excessive or insufficient apoptosis can contribute to disease