APOPTOSIS

Programmed Cell Death

A genetically controlled cell suicide
pathway
 The History of the Cell Death Study

• First observed in 1842 by a German scientist Carl Vogt in Jent und

Gassman, Solothurn 1842; 130
He wrote “The role of the core of the notochord in the formation of the vertebrae is quite simply that its cells are
resolved , beginning when the proliferation of the surrounding cartilage exerts pressure on the notochore”. “The light
vesicular nuclei of the embryonic cells have disappeared; at least I could not detect any trace of them”.

• 1951, Glucksmann, A (in Cambridge Philosophical Society of bilogical

review 26, 59) reviewed and rediscovered developmental cell deaths in
embryological tissues
• 1964, Lockshin, RA and Williams, CM first used the term of “programmed
cell death” to describe the breakdown of the intersegmental muscles of
silkworms
• 1972, three British scientists Kerr, Wyllie and Currie proposed the term of
“apoptosis” for morphology of naturally occurring or physiological cell
deaths. They recognized the importance of apoptosis and suggested that
it is a basic biological phenomenon with wide-ranging implications in
tissue kinetics.
The Morphology of Apoptosis

Cytoplasm shrinks
Chromosomes condense and fragment
Nuclear membrane breaks down
Apoptotic body formation
Engulfment of the cell corpse
 Classification of cell death

Cell death

Necrotic Physiological

apoptosis autophagic other

Caspase-dependent Caspase-independent

receptor-caspase 8 mitochondria-caspase 9
 APOPTOSIS

What is it?

Why is it important?

How is it controlled?

What is its role in age-related disease?

 APOPTOSIS
Programmed cell death

Orderly cellular self destruction

Process: as crucial for survival of multi-cellular

organisms as cell division
 Forms of cell death

Necrosis Apoptosis Mitotic catastrophe

Passive Active Passive

Pathological Physiological or Pathological

pathological

Swelling, lysis Condensation, Swelling, lysis

cross-linking

Dissipates Phagocytosed Dissipates

Inflammation No inflammation Inflammation

Externally induced Internally or Internally induced

externally induced
Difference Between Apoptosis
and Necrosis
• Necrosis (pathological cell death): dying
cells swell and lyse; toxic contents leak
out and result in inflammatory response.

• Apoptosis (physiological or programmed

cell death): dying cells shrink, are
engulfed by other cells, leave no trace,
and don’t result in harmful outcomes
 APOPTOSIS

Evolutionarily conserved

•Occurs in all animals studies (plants too!)

•Stages and genes conserved from nematodes

and flies to humans
STAGES OF APOPTOSIS
Healthy cell

DEATH SIGNAL

Commitment to die (reversible)

EXECUTION (irreversible)

Dead cell (condensed, crosslinked)

ENGULFMENT

DEGRADATION
 STAGES OF APOPTOSIS

Genetically controlled: Caenorhabditis elegans

Soil nematode (worm)

ces2 ces1 ced9 ced3,4

Healthy cell Committed cell Dead cell

BCL2 Caspases

C. Elegans genes == mammalian genes

Cells are balanced between life and death
DAMAGE Physiological death signals

DEATH SIGNAL

PROAPOPTOTIC ANTIAPOPTOTIC
PROTEINS PROTEINS
 APOPTOSIS: important in embryogenesis

Morphogenesis (eliminates excess cells):

Selection (eliminates non-functional cells):

 APOPTOSIS: important in embryogenesis

Immunity (eliminates dangerous cells):

Self antigen
recognizing cell

Organ size (eliminates excess cells):

 APOPTOSIS: important in adults
Tissue remodeling (eliminates cells no longer needed):

Apoptosis
Virgin mammary gland Late pregnancy, lactation Involution
(non-pregnant, non-lactating)

- Testosterone
Apoptosis

Prostate gland
 APOPTOSIS: important in adults
Tissue remodeling (eliminates cells no longer needed):

Apoptosis

Resting lymphocytes + antigen (e.g. infection) - antigen (e.g. recovery)

Steroid immunosuppressants: kill

lymphocytes by apoptosis

Lymphocytes poised to die by apoptosis

 APOPTOSIS: important in adults
Maintains organ size and function:

Apoptosis
+ cell division

Cells lost by apoptosis are replaced by cell division

(remember limited replicative potential of cells)

 APOPTOSIS: control
Receptor pathway (extrinsic, physiological):
FAS ligand TNF

Death receptors:
(FAS, TNF-R, etc) Death
domains

Adaptor proteins

Pro-caspase 8 (inactive) Caspase 8 (active)

Pro-execution caspase (inactive)

Execution caspase (active)

MITOCHONDRIA Death
 APOPTOSIS: control
Intrinsic pathway (damage):
Mitochondria

BAX Cytochrome c release BCL-2

BAK BCL-XL
BOK BCL-W
BCL-Xs Pro-caspase 9 cleavage MCL1
BAD BFL1
BID DIVA
B IK NR-13
BIM Pro-execution caspase (3) cleavage Several
NIP3 viral
BNIP3 proteins

Caspase (3) cleavage of cellular proteins,

Nuclease activation,
Etc.

Death
 APOPTOSIS: control

Physiological Intrinsic
receptor pathway damage pathway

MITOCHONDRIAL SIGNALS

Caspase cleavage cascade

Orderly cleavage of proteins and DNA

CROSSLINKING OF CELL CORPSES; ENGULFMENT

(no inflammation)
APOPTOSIS: Role in Disease

TOO MUCH: Tissue atrophy

Neurodegeneration
Thin skin
etc

TOO LITTLE: Hyperplasia

Cancer
Athersclerosis
etc
 APOPTOSIS: Role in Disease
Neurodegeneration

Neurons are post-mitotic (cannot replace themselves)

Neuronal death caused by loss of proper connections,

loss of proper growth factors (e.g. NGF),
damage (especially oxidative damage)

Neuronal dysfunction or damage results in loss of synapses

(synaptosis; reversible)
apopsosis (irreversible)

PARKINSON'S DISEASE
ALZHEIMER'S DISEASE
HUNTINGTON'S DISEASE etc.
 APOPTOSIS: Role in Disease
Cancer

Apoptosis eliminates damaged cells

(damage => mutations => cancer

Tumor suppressor p53 controls senescence

and apoptosis responses to damage

Most cancer cells defective in apoptotic response

High levels of anti-apoptotic proteins

or
Low levels of pro-apoptotic proteins
===> CANCER
 APOPTOSIS: Role in Disease
AGING

Aging --> both too much and too little apoptosis

(evidence for both)

Too much (accumulated oxidative damage?)

---> tissue degeneration

Too little (defective sensors, signals?

---> dysfunctional cells accumulate
hyperplasia (precancerous lesions)
 Functions of apoptosis
Sculpt body structures, e.g. hand digit

Serve some function but no longer needed

e.g. tadpole tail of frog.

Needed in one sex but not another

e.g. Mullerian duct important for female
is eliminated in males by apoptosis.

Produced in excess, e.g. extra neurons are

removed by apoptosis during neurogenesis.

Serve in immune system as a defense

mechanism to get rid of harmful or
damaged cells.