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 leaflet3. Loss of electrical potential across the inner membrane of the

mitochondria4. 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 ismediated by caspases

Procaspase activation during apoptosis

Some human caspases

Caspases involved in inflammation caspases 1 (ICE), 4, 5

Caspases involved in apoptosisInitiator caspases caspases 2, 8, 9, 10Executioner caspases caspases 3, 6, 7

Examples of target proteinsNuclear laminsProtein that holds the endonuclease in an inactive stateComponents of the cytoskeleton and cell-cell adhesion proteins

The two best understood signaling pathways that activate acaspase cascade in mammalian cells are the extrinsic pathway and the intrinsic pathway

Each pathway uses its own initiator procaspasesand 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 therelease 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 rolesof IAPs and anti-IAPs in thecontrol of apoptosis inmammalian 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