Vous êtes sur la page 1sur 7

Chapter 18 Summary

SCI 231 Molecular Cell Biology

Cell death occurs by a programmed sequence of molecular events,
in which the cell systematically destroys itself from within and is
then eaten by other cells, leaving no trace: apoptosis.
Cells undergoing apoptosis undergo characteristic morphological
changes. They shrink and condense, the cytoskeleton collapses, the
nuclear envelope disassembles, and the nuclear chromatin
condenses and breaks up into fragments. The cell surface often
bulges outward and, if the cell is large, it breaks up into membraneenclosed fragments called apoptotic bodies. The surface of cells or
these bodies becomes chemically altered, so neighbors or
macrophages recognize it.
Cell death helps sculpt hands and feet during embryonic
development: the individual digits separate only as the cells
between them die. Apoptosis also ensures quality, killing cells that
are misplaced, abnormal, nonfunctional or potentially dangerous.
Apoptosis is triggered by specialized intracellular proteases, which
cleave specific sequences in numerous proteins inside the cell,
thereby bringing about changes that lead to cell death and
engulfment. These proteases have a cysteine at their active site and
cleave their target proteins at specific aspartic acid - they are
therefore called caspases. Caspases are synthesized in the cell as
inactive precursors and are only activated during apoptosis. There
are two major classes: initiator caspases (begin the process) and
executioner caspases (catalyze widespread protein cleavages).

An initiator caspase containsa protease domain in its carboxyterminal region, and a small protein interaction domain near its
amino terminus. It is initially made in an inactive, monomeric form
(procaspase). Apoptotic signals trigger the assembly of adaptor
proteins carrying multiple binding sites for the caspase aminoterminal domain. Upon binding to the adaptor proteins,
the initiator caspases dimerize and are thereby
activated, leading to cleavage of a specific site in their
protease domains. Each protease domain is then
rearranged into a large and small subunit. Executioner
caspases are initially formed as inactive dimers. Upon
cleavage at a site in the protease domain by an
initiator caspase, the executioner caspase dimer
undergoes an activating conformational change. It then
cleaves a variety of key proteins, leading to the
controlled death of the cell.
One of the target protein that is cleaved normally holds
a DNA-degrading endonuclease in an inactive form; its
cleavage frees the endonuclease to cut up the DNA in
the cell nucleus.

In healthy cells, the endonuclease CAD associated with its inhibitor,

iCAD. Activation of executioner caspases leads to the cleavage of
iCAD, unleashing the nuclease.
Extracellular signal proteins binding to cell-surface death
receptors trigger the extrinsic pathway of apoptosis. They are
transmembrane proteins containing an intracellular ligand-binding
domain, which is required for the receptors to activate the apoptotic
An example: Fas on the surface of a target cell is activated by Fas
ligand on the surface of a killer (cytotoxic) lymphocyte. When
activated by the binding of Fas ligand, the death domains on the
cytosolic tails of the Fas death receptors bind intracellular adaptor
proteins, which in turn bind initiator caspases, forming a deathinducing signaling complex (DISC). Once dimerized and
activated in the DISC, the initiator caspases cleave their partners,
stabilizing and releasing the active caspase dimer into the cytosol,

where it then activates downstream executioner caspases to induce

Cells can also activate their apoptosis program from inside the cell,
often in response to stresses or developmental signals. They are
governed by the intrinsic (or mitochondrial) pathway of
apoptosis, which depends on the release of mitochondrial proteins
into the cytosol, some of which activate a caspase proteolytic
cascade in the cytoplasm, leading to apoptosis.

A key protein in the intrinsic pathway is cytochrome c, a watersoluble component of the mitochondrial electron-transport chain.
When released into the cytosol, it takes on a new function: it binds
to an adaptor protein (Apaf1 apoptotic protease activating factor1), causing it to oligomerize into a wheel-like heptamer called an
apoptosome. The Apaf1 proteins in the apoptosome then recruit
initiator caspase-9 proteins, which are activated by proximity in the

apoptosome, which activate downstream executioner caspases.

The intrinsic pathway is tightly regulated to ensure that cells kill
themselves only when
appropriate. A major class of
regulators is the Bcl2 family of
proteins, which controls the
release of cytochrome c and other
intermembrane mitochondrial
proteins into the cytosol. Some
enhance it (pro-apoptotic), some
inhibit it (anti-apoptotic). They
can also bind together to inhibit
each others functions. The
proteins share four distinctive Bcl2 homology (BH) domains.
When an apoptotic stimulus triggers the intrinsic pathway, the proapoptotic effector Bcl2 family proteins (mainly Bax and Bak)
become activated and aggregate to form oligomers in the

mitochondrial outer membrane, inducing the release of cytochrome

c and other intermembrane proteins by an unknown mechanism.
The anti-apoptotic Bcl2 family proteins such as Bcl2 and BclXL
are also located on the cytosolic surface of the outer mitochondrial
membrane, where they help prevent inappropriate release of

intermembane proteins. For example, they bind Bak and prevent it

from oligomerizing.
The BH3-only proteins are produced or activated in response to an
apoptotic stimulus. They promote apoptosis by inhibiting antiapoptotic Bcl2 family proteins. Their BH3 domain binds to a long
hydrophobic groove on anti-apoptotic Bcl2 family proteins,
neutralizing their activity. This enables the aggregation of Bax and
Bak on the surface of the mitochondria.

factors are
signal molecules that inhibit apoptosis. Most animal cells require
continuous signaling from other cells to avoid apoptosis, so ensure
that cells survive only when and where they are needed. Nerve cells
are produced in excess in the developing nervous system and then
compete for limited amounts of survival factors that are secreted by
the target cells that they eventually connect to.
Survival factors usually bind to cell-surface receptors, which activate
intracellular signaling pathways that suppress the apoptotic survival
program, often by regulating members of the Bcl2 family. Some
survival factors stimulate the synthesis of anti-apoptotic Bcl2 family
proteins, for example. Many others activate the serine/threonine
protein kinase Akt, which, among many other targets,
phosphorylates and inactivates the pro-apoptotic BH3-only protein
Bad. When not phosphorylated, Bad promotes apoptosis by binding
to and inhibiting Bcl2; once phosphorylated, Bad dissociates, freeing
Bcl2 to suppress apoptosis. Akt also suppresses apoptosis by
phosphorylating and inactivating transcription regulatory proteins
that stimulate the transcriptionof genes encoding proteins that
promote apoptosis. Some survival factors act by phosphorylating
and inactivating anti-IAP proteins, thereby enabling IAP (inhibitors
of apoptosis) proteins to suppress apoptosis.
Decreased apoptosis contributes to many cancers. They may be
treated with drugs that simulate apoptosis small chemicals that
interfere with the function of anti-apoptotic Bcl2 family proteins.
These chemicals bind with high affinity, blocking their function.