17

|

 |

 



Introduction

Cell death and cell proliferation are

balanced throughout the life of
multicellular organisms.

Animal development involves not only cell

proliferation and differentiation but also
cell death.
Most cell death occurs by a normal
physiological process of programmed cell
death.
Introduction

In adult organisms, cell death must be

balanced by cell renewal.
Most tissues contain stem cells that can
replace cells that have been lost.
ïrogrammed Cell Death

ïrogrammed cell death is carefully

regulated.
In adults, it balances cell proliferation
and maintains constant cell numbers.
It also eliminates damaged and
potentially dangerous cells.
ïrogrammed Cell Death

During development, programmed cell

death plays a key role by eliminating
unwanted cells from a variety of
tissues.
ïrogrammed Cell Death

¢
: Accidental cell death from acute

injury.
: ïrogrammed cell death; an
active process.
‡ Characterized by:
^ DNA fragmentation
^ Chromatin condensation
^ Fragmentation of the nucleus and
cell
Figure 17.1 Apoptosis
ïrogrammed Cell Death

Apoptotic cells and cell fragments are

recognized and phagocytosed by
macrophages and neighboring cells,
and are rapidly removed from tissues.
Necrotic cells swell and lyse; the
contents are released into the
extracellular space and cause
inflammation.
ïrogrammed Cell Death

Apoptotic cells express ³eat me´ signals,

such as phosphatidylserine.
In normal cells, phosphatidylserine is
restricted to the inner leaflet of the
plasma membrane.
Figure 17.2 ïhagocytosis of apoptotic cells
ïrogrammed Cell Death

Caspases are the ultimate executioners

of programmed cell death.
They bring about the events of apoptosis
by cleaving 100 different cell target
proteins.

The activation of an initiator caspase

starts a chain reaction of caspase
activation leading to death of the cell.
Figure 17.4 Caspase targets
ïrogrammed Cell Death

Ced-4 and its mammalian homolog (Apaf-1)

bind to caspases and promote their
activation.
In mammalian cells, caspase-9 is activated
by binding to Apaf-1 in a protein complex
called the m .
Cytochrome R is also required, which is
released from mitochondria.
Figure 17.5 Caspase activation
ïrogrammed Cell Death

R
in   
 is closely related to
a mammalian gene called R , which
was first identified as an oncogene.


 inhibits apoptosis. Cancer cells
are unable to undergo apoptosis.
ïrogrammed Cell Death

Mammalian cells encode about 20

proteins related to Bcl-2, in three
functional groups.
Some inhibit apoptosis, while others
induce caspase activation.
The fate of the cell is determined by the
balance of activity of proapoptotic and
antiapoptotic Bcl-2 family members.
ïrogrammed Cell Death

In mammalian cells, members of the Bcl-2

family act at the mitochondria, which
play a central role in controlling
programmed cell death.
Cytochrome R is released from
mitochondria, which triggers caspase
activation in the apoptosome.
Figure 17.8 The mitochondrial pathway of apoptosis
ïrogrammed Cell Death

Caspases are also regulated by a family

of proteins called the 2 (inhibitor of
apoptosis).
They either inhibit caspase activity or
target caspases for ubiquitination and
degradation in the proteasome.
ïrogrammed Cell Death

Regulation of programmed cell death is

mediated by signaling pathways, some
acting to induce cell death and others
acting to promote cell survival.
Many forms of cell stress, such as DNA
damage, can trigger programmed cell
death.
ïrogrammed Cell Death

A major pathway leading to cell cycle

arrest in response to DNA damage is
mediated by the transcription factor
.
Activation of p53 due to DNA damage
can also lead to apoptosis.
Figure 17.10 Role of p53 in DNA damage-induced apoptosis
ïrogrammed Cell Death

A major intracellular signaling pathway

that promotes cell survival is initiated
by the enzyme 2 m , which
activates Akt.
Akt then phosphorylates a number of
proteins that regulate apoptosis.
Figure 17.11 The ïI 3-kinase pathway and cell survival
ïrogrammed Cell Death

ïolypeptides in the   


m
 (¢) family signal cell death by
activating cell surface receptors.
These receptors directly activate a
distinct initiator caspase, caspase-8.
Figure 17.12 Cell death receptors (ïart 1)
ïrogrammed Cell Death

ïrogrammed cell death can also occur

by non-apoptotic mechanisms such as
mm
.
In normal cells, autophagy provides a
mechanism for gradual turnover of the
cell¶s components by uptake of
proteins or organelles into vesicles that
fuse with lysosomes.