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Chapter 18

Apoptosis
Apoptosis is only one form of programmed cell death.

In animal cells, cell necrosis is another form of programmed cell
death.
Two distinct forms of cell death apoptosis and necrosis
Programmed cell death eliminates unwanted cells
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
Apoptosis during the metamorphosis of a tadpole into a frog
Apoptotic cells are biochemically recognizable
Characteristic biochemical changes in cells undergoing apoptosis

1. Chromosomal DNA cleaved into fragments
2. Change in the plasma membrane phosphatidylserine
in the outer leaflet
3. Loss of electrical potential across the inner membrane of the
mitochondria
4. Relocation of cytochrome c from the intermembrane space of
the mitochondria to the cytosol
Cleavage of chromosomal DNA into a characteristic ladder of fragments
Apoptosis depends on an intracellular proteolytic cascade that is
mediated by caspases
Procaspase activation during apoptosis
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

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

Cell-surface death receptors activate the extrinsic pathway
of apoptosis
The extrinsic pathway of apoptosis activated through Fas death receptors
The intrinsic pathway of apoptosis depends on mitochondria
Release of cytochrome c from mitochondria during apoptosis
Bcl2 proteins regulate the intrinsic pathway of apoptosis
The three classes of Bcl2 proteins
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.
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
How pro-apoptotic BH3-only and anti-apoptotic Bcl2 proteins regulate
the intrinsic pathway of apoptosis
IAPs inhibit caspases
A proposed model for the roles
of IAPs and anti-IAPs in the
control of apoptosis in
mammalian cells
Extracellular survival factors inhibit apoptosis in various ways
Three ways that extracellular survival factors can inhibit apoptosis
Either excessive or insufficient apoptosis can contribute to disease