1. Apoptosis By Douglas R. Green
Chapter 12
Apoptosis By
Douglas R. Green

2. 12.1 Introduction
Programmed cell death is a developmental process that usually proceeds by apoptosis.
Apoptosis is also the mode of cell death occurring in a variety of other settings.
It has roles in:
normal homeostasis
inhibition of cancer
disease processes

3. 12.1 Introduction
Most animal cells possess the molecules comprising the pathways that can cause death by apoptosis.
These pathways are activated by appropriate stimuli.

4. 12.2 Caspases orchestrate apoptosis by cleaving specific substrates
Proteases called “caspases” fall into three types:
Initiator
Executioner
Inflammatory
The first two types function in apoptosis.

5. Many substrates for caspases have been identified.
12.2 Caspases orchestrate apoptosis by cleaving specific substrates
The morphological and biochemical features of cells undergoing apoptosis are caused by the action of the executioner caspases on their substrates.
Many substrates for caspases have been identified.
In some cases the effects of their cleavage on the cell are known.

6. 12.3 Executioner caspases are activated by cleavage, whereas initiator caspases are activated by dimerization
Cleavage of executioner caspases at specific sites is necessary and sufficient for their activation.

7. This cleavage is usually mediated by the initiator caspases.
12.3 Executioner caspases are activated by cleavage, whereas initiator caspases are activated by dimerization
This cleavage is usually mediated by the initiator caspases.
Initiator caspases are activated by adaptor molecules that contain protein-protein interaction domains called death folds.

8. 12.4 Some inhibitors of apoptosis proteins (IAPs) block caspases
The inhibitors of apoptosis proteins comprise a family of proteins with different functions.
Some of these proteins:
bind to and inhibit caspases
induce their degradation by the proteasome

9. 12.4 Some inhibitors of apoptosis proteins (IAPs) block caspases
Since executioner caspases are activated by cleavage, and since these caspases can cleave and activate each other…
…any proteolytic activity of the caspases will be rapidly amplified in cells, resulting in their death by apoptosis.
It is important that there be mechanisms present to limit potential “accidental” activation of caspases in cells that have not been signaled to die.

10. 12.5 Some caspases have functions in inflammation
In addition to the initiator and executioner caspases, another set of proteases in this family acts to process cytokines rather than regulate apoptosis.

11. 12.6 The death receptor pathway of apoptosis transmits external signals
Two well-characterized pathways of apoptosis are:
the death receptor (extrinsic) pathway
the mitochondrial (intrinsic) pathway
Caspase activation and apoptosis are induced by the binding of specialized ligands in the TNF family to their receptors (death receptors).

12. 12.7 Apoptosis signaling by TNFR1 is complex
Binding of TNF to one of its receptors, TNFR1, induces both apoptotic and antiapoptotic signals.

13. 12.8 The mitochondrial pathway of apoptosis
Most apoptosis in mammalian cells proceeds via a pathway in which:
the mitochondrial outer membranes are disrupted
thus, releasing the contents of the mitochondrial intermembrane space into the cytosol
Mitochondrial outer membrane permeabilization (MOMP) is a key feature of this pathway.

14. 12.9 Bcl-2 family proteins mediate and regulate MOMP and apoptosis
The Bcl-2 family proteins are central to the mitochondrial pathway of apoptosis.
There are 3 classes of Bcl-2 proteins that induce, directly cause, or inhibit MOMP.

15. 12.10 The multidomain Bcl-2 proteins Bax and Bak are required for MOMP
are essential for the permeabilization of the mitochondrial outer membrane
are required for the mitochondrial pathway of apoptosis
Bax and Bak probably directly cause the membrane disruption associated with MOMP.

16. 12.11 The activation of Bax and Bak are controlled by other Bcl-2 family proteins
The antiapoptotic members of the Bcl-2 family block the permeabilization of the mitochondrial outer membrane by Bax and Bak.
The BH3-only proteins of the Bcl-2 family either:
directly activate Bax and Bak or
interfere with the antiapoptotic Bcl-2 protein functions

17. 12.12 Cytochrome c, released upon MOMP, induces caspase activation
Holocytochrome c triggers the activation of cytosolic APAF-1.
Cytosolic APAF-1 binds and activates caspase-9.

18. 12.13 Some proteins released upon MOMP block IAPs
The mitochondrial intermembrane space proteins Smac and Omi antagonize the caspase-inhibitory activity of IAPs.

19. 12.14 The death receptor pathway of apoptosis can engage MOMP through the cleavage of the BH3- only protein Bid
Caspase-8, activated upon ligation of death receptors, cleaves the BH3-only protein Bid.
This activates Bid.

20. Bid acts as a link between the two apoptotic pathways.
12.14 The death receptor pathway of apoptosis can engage MOMP through the cleavage of the BH3- only protein Bid
Bid then triggers Bax and Bak to cause MOMP, thereby engaging the mitochondrial pathway of apoptosis.
Bid acts as a link between the two apoptotic pathways.

21. 12.15 MOMP can cause caspase-independent cell death
Once MOMP occurs, cells generally die even if caspase activation is blocked or disrupted.
The precise mechanisms of this cell death are not fully known.

22. 12.16 The mitochondrial permeability transition can cause MOMP
In some forms of cell death, the mitochondria are disrupted by a change in the mitochondrial inner membrane.
This leads to swelling and rupture of the organelle.

23. 12.17 Many discoveries about apoptosis were made in nematodes
Apoptosis in nematodes follows a simple pathway with similarities to the mitochondrial pathway of apoptosis in the vertebrates.

24. 12.18 Apoptosis in insects has features distinct from mammals and nematodes
Apoptosis in insect cells follows a pathway with some similarities to the mitochondrial pathway of apoptosis in vertebrates.

25. 12.19 The clearance of apoptotic cells requires cellular interaction
The removal of apoptotic cells from the body occurs by an active process.

26. 12.20 Apoptosis plays a role in diseases such as viral infection and cancer
Viral infection and cancer are conditions in which apoptotic pathways may be blocked.

27. 12.21 Apoptotic cells are gone but not forgotten
The uptake and clearance of apoptotic cells has lasting effects on the immune system.