apoptosis ii

8/8/2019 Apoptosis II

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INTRODUCTION

Cell death by injury

-Mechanical damage-Exposure to toxic chemicals

Cell death by suicide

-Internal signals

-External signals


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Why should a cell commit suicide?

Apoptosis is needed for proper development

The resorption of the tadpole tail

The formation of the fingers and toes of the fetus

The sloughing offof the inner lining of the uterus

The formation of the proper connections between neurons in

the brain

Apoptosis is needed to destroy cells

Cells infected with viruses

Cells of the immune system

Cells with DNA damage

Cancer cells


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Importance of Apoptosis

Important in normal physiology / development Development: Immune systems maturation,

Morphogenesis, Neural development

Adult: Immune privilege, DNA Damage and woundrepair.

Excess apoptosis Neurodegenerative diseases

Deficient apoptosis Cancer

Autoimmunity


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What makes a cell decide to commit suicide?

Withdrawal of positive (Growth) signals

growth factors for neurons Interleukin-2 (IL-2)

Receipt of negative (Death) signals

increased levels of oxidants within the cell damage to DNA by oxidants

death activators : Tumor necrosis factor alpha (TNF-E) Lymphotoxin (TNF-) Fas ligand (FasL)


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History of cell death / apoptosis research

1800s Numerous observation of cell death

1908 Mechnikov wins Nobel prize (phagocytosis)

1930-40 Studies of metamorphosis

1948-49 Cell death in chick limb & exploration of NGF1955 Beginning of studies of lysomes

1965 Necrosis & PCD described

1971 Term apoptosis coined

1977 Cell death genes in C. elegans1980-82 DNA ladder observed & ced-3 identified

1990 Apoptosis genes identified, including bcl-2,

fas/apo1 & p53, ced-3 sequenced

(Richerd et.al., 2001)


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Apoptosisvs. N

ecrosis

Cellular condensation

Membranes remainintact

Requires ATP

Cell is phagocytosed,no tissue reaction

Ladder-like DNAfragmentation

In vivo, individual cellsappear involved

Cellular swelling

Membranes arebroken

ATP is depleted

Cell lyses, eliciting aninflammatory reaction

DNA fragmentation israndom, or smeared

In vivo, whole areas ofthe tissue are affected

Necrosis Apoptosis


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Apoptosis: Pathways

DNA

damage

& p53

Death

Ligands

Effector

Caspase 3

Death

Receptors

Initiator

Caspase 8

PCD

Mitochondria/

Cytochrome C

Initiator

Caspase 9

Extrinsic Pathway

Intrinsic Pathway


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MAJORPLAYERSIN

APO

PTOSIS

Caspases

Death signals e.g. TNF &TNFR p53

BAX

Bcl-2 family


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Aspartate- AA

proteolysis

Nuclear

BAX (proapoptotic)

Cyt C

Apaf-1

p53DNA damage

Mitochondrial

InitiatorCaspase-8E / 9I

EffectorCaspase- 3

CAD(DNA-ase)

DNA nucleosomal200 bp fragments

bcl- 2Anti-apoptotic

p21Cell Cycle

Arrest

DNARepair


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CONCLUSION

an important process of cell death

can be initiated extrinsically through death ligands

(e.g. TRAIL, FasL) activating initiator caspase 8 throughinduced proximity.

can be initiated intrinsically through DNA damage (viacytochrome c) activating initiator caspase 9 through

oligomerization.

Initiator caspases 8 and 9 cleave and activateeffector caspase 3, which leads to cell death.


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The bcl-2 family

Group I

Group II

Group III

Bcl-2

bax

Bad

bidbik

BH4 BH3 BH1 BH2 TMN C

Receptor domain

phosphorylation

Raf-1

calcineurin Pore

formation

Membrane

anchorLigand

domain


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P53 & Apoptosis

p53 is an unstable tumor suppressor protein.

It is and acts via zinc finger DNA binding model.

It arrests cell growth between G1p S, thus DNA

repair can take place.

p53 production ofCIP(p21) CDKs inhibition

Cell cycle stop.


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3 mechanisms of caspase activation

a. Proteolytic cleavage e.g.

pro-caspase 3

b. Induced proximity, e.g.

pro-caspase 8

c. Oligomerization, e.g. cyt c,

Apaf-1 & caspase 9

apoptosis ii

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