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The Molecular Mechanisms of Apoptosis

99年度

課程 :希望能藉由講述細胞凋亡的現象進一步探討在此現象中的

一些分子所扮演的角色及功能,和這些分子所主導的機轉對於細胞凋亡的

進行的影響。期望同學在修習此課程後能對細胞凋亡的發生、進行、其

對生物功能影響能有更廣泛及深入的了解。

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General introduction of the programmed cell death (PCD)

Definition of apoptosis

The evolutionarily conserved apoptotic pathway

The historical view of apoptosis

The origin and evolution of PCD/apoptosis: the

evidence and theory

Outline

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Programmed cell death (PCD)

  A genetically controlled cell suicide

  Often occurs at a specific point in development

  Include apoptosis and non-apoptosis   non-apoptosis: autophagy-induced cell death,

necroptosis, PARP1-mediated cell death,

entosis, pyroptosis

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Non-apoptotic PCD

  Pyroptosis: caspase 1-dependent cell death

 Necroptosis : RIP1 kinase-dependent necrosis

 Entosis: cell death as a result of becoming

engulfed by a neighboring cell   PARP-1-mediated cell death: PARP-1-

dependent but caspase-independent cell death

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 Autophagy: s elf-eating

Cell Cycle 2010, 9:17, 3470-3478

 Autophagy-induced cell death

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Introduction to apoptosis

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 Apoptosis, one of the PCD,

describes the orchestrated collapse

of a cell, staging membrane

blebbing, cell shrinkage, proteinfragmentation, chromatin

condensation and DNA degradation

followed by rapid engulfment of 

corpses by neighboring cells

Nature 407 12 October 2000

 Apoptosis (Greek,   “falling away”)

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The highly conserved apoptotic pathway

 Apoptosis Dec 24, 2009

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 Apoptosis:

a historical view

In 1800 ’   s 

Normal cell death observed during amphibian metamorphosis

Observation of epithelial lining of regressive ovarian

follicles with broken nuclei which eventually disappear 

In 1914 

Gapher proposed that there must be an amitotic mechanism to

counterbalance mitosis

In 1951 

Glucksmann described physiological cell death in the embryo

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 Apoptosis:

a historical view

In 1960 

Concept of cell suicide emerged; individual cell death for 

the benefit of the whole organism

In 1964 , Lockshin and WilliamsProgrammed cell death used to describe the cell deaths

that occur in predictable places and at predictable times

during development

In 1972, Kerr, Wyllie, and Currie

 Apoptosis is proposed for controlled cell deletion, and

presented morphological evidence distinguishing

apoptosis

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 Apoptosis observed by microscopy

Nat Rev Mol Cell Biol 2008,  8:231

Daunorubicin-treated HeLa

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 Apoptosis shapes life

Formation of structure   Control of cell numbers

Deletion of structures   Elimination of abnormal cells

. Nat Rev. Mol. Cell Biol. 2002,  3:779

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Why has evolution favored such a system of 

self destruction?

Where and when did this system originate?

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The origin of programmed cell death (PCD)

The PCD is not restricted in multicellular organisms

It is found in several unicellular organisms, including

Kinetoplastid parasites: Trypanosoma cruzi and

Trypanosoma brucei

The free-living slime mold Dictyostelium discoideum

The free-living ciliate Tetrahymena thermophila

Yeast

Bacteira: streptomyces

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Programmed cell death in the evolution

Eubacteria

Archaebacteria

Kinetoplastids

Between 1.5 and 2

billion years ago

Slime moldsRed algae

Ciliates

Around 1 billion

years ago

Fungi

Multicellular 

animals

Multicellular 

plants

0.7 billion years ago

 Adapted from Science,1996, 272:1278-1279

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Origin and evolution of PCD

Cell death and differ. 2002, 9:394-404

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Selection for killer genes (encoding toxin) in bacteria for 

offensive through evolution

Selection for induction of killer genes in adverse

environmental conditions, providing a selective

advantage to the best-adapted offspring

JC Ameisen’s hypothesis

PCD and bacterial origin

Selection for genes encoding antidotes for defensive purpose

Multistep theory---

Science 272, 1278

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Since the eukaryote cell is a symbiont that arose

from fusion of different bacteria species,

suggesting that PCD may have evolved from aresolution of conflict between heterogeneous

genomes within a cell

JC Ameisen’s hypothesis on PCD’s bacterial origin, cont.

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Why has evolution favored such a system of 

self destruction?

PCD

For constant selection for the fittest cell in the colony

For optimal adaptation of cell numbers to the environment

For tight regulation of the cell cycle and differentiation

For stable relation between host and parasite

For forming multicellular body from undifferentiated

unicellular cell

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The mitochondrial change during PCD

 A striking feature of cells undergoing PCD is that they

suffer alterations in their mitochondrial structure and

function before nuclear structures are affected

The alterations of mitochondria are manifested by

the reduction in the mitochondrial transmembrane

potential (m)

The reduction of  m is likely to be the opening of mitochondrial permeability transition pores

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Why Is Mitochondrion as the central

control point of apoptosis

Outer membrane

Inner membrane

Matrix

Intermembrane space

Mitochondrial outer membrane

Mitochondrial inner 

membrane

PORIN/VDAC

 ANT  (adenine nucleotide translocator)  22 

Endosymbiotic genesis of mitochondria as the

origin of eukaryotic PCD

Theory of JM Frade et al.

In eukaryotic evolution, former invasive bacteria may

have used porin-type channels to enter their host and

to induce its death when the levels of its cytoplasmicpurine nucleotides were dropped

The appearance of adenosine nucleotide translocators in

the primitive eukaryotes, which permitted usage of the

oxidative metabolism of the invaders, provided the basis

for the permeability transition phenomena

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 Assignment

  Describe at least one example of host and bacteria

invader relationship to support the theory of programmed

cell death derived from Endosymbiotic genesis of 

mitochondria proposed by JM Frade et al