Chapter 18
Apoptosis
Copyright © Garland Science 2008
M18.1
Apoptosis
건강한 성인: Billions of cells die every hour
Programmed cell death(PCD): idea in 1970s acceptance (20년)
:apoptosis (PCD의 한종류)
Two distinct forms of cell death
apoptosis
Cell shrinks, Cytoskeletin collapses, 핵막 분해,
DNA 절단
Apoptic body-chemically altered:macrophage
necrosis
Swell
Burst
Spilling their contents
Eliciting inflammatory response
Programmed cell death
morphology in tobacco cells.
Programmed cell death eliminates unwanted cells
Sculpting the digits in the developing mouse paw by apotosis
1.
2.
3.
4.
불필요 세포/조직/기관제거
세포수 조절 (간세포 분열/phenobarbital)
Quality control: B-/T-lymphocyte cell 제거
골수세포: 백혈구 제거
Figure 18-2 Molecular Biology of the Cell (© Garland Science 2008)
Apoptotic Cells Are Biochemically Recognizable
Markers of apoptosis
TUNEL technique
Phosphatidylserine: 세포막 안쪽
바깥: Annexin V로 검출
“eat me” signal
“Don’t eat me” signal
Figure 18-4a Molecular Biology of the Cell (© Garland Science 2008)
Apoptotic Cells Are Biochemically Recognizable
Markers of apoptosis
Positively charged 형광색소
: 미토콘도리아 inner membrane 의 안쪽
Cytochrome C: released from the
intermembrane space of mitochondria
Figure 18-4b Molecular Biology of the Cell (© Garland Science 2008)
Apoptosis Depends on an Intracellular Proteolytic
Cascade That Is Mediated by Caspases
Caspase:
Procaspase activation during apoptosis
Figure 18-5a Molecular Biology of the Cell (© Garland Science 2008)
Apoptosis Depends on an Intracellular Proteolytic
Cascade That Is Mediated by Caspases
Procaspase activation during apoptosis
Caspase recruitment
domain: activation complex
Cytoskeleton
Cell-cell adhesion proteins
endonuclease
Figure 18-5b Molecular Biology of the Cell (© Garland Science 2008)
Cell-Surface Death Receptors Activate the
Extrinsic Pathway of Apoptosis
The extrinsic pathway of apoptosis activated through Fas death receptors
Tumor necrosis fctor
receptor familiy
Figure 18-6 Molecular Biology of the Cell (© Garland Science 2008)
DISC: Death-inducing signaling complex
Decoy receptor
FLIP blocking protein
The Intrinsic Pathway of Apoptosis Depends on
Mitochondria
Release of cytochrome c from mitochondria during apoptosis
bind procaspase-activating adapter protein(Apaf) apoptosome 형성
 Recruit initiator procaspase proteins (procaspase-9)
Figure 18-7 Molecular Biology of the Cell (© Garland Science 2008)
The Intrinsic Pathway of Apoptosis Depends on
Mitochondria
The intrinsic pathway of apoptosis
Figure 18-8 Molecular Biology of the Cell (© Garland Science 2008)
Apoptosis
효소?
Bcl2 Proteins Regulate the Intrinsic Pathway of
Apoptosis
The three classes of Bcl2
Figure 18-9 Molecular Biology of the Cell (© Garland Science 2008)
Bcl2 Proteins Regulate the Intrinsic Pathway of
Apoptosis
The role of BH123 pro-apoptotic Bcl2 proteins(mainly Bax and Bak) in
the release of mitochondrial intermembrane proteins in the intrinsic
pathway of apoptosis
Figure 18-10 Molecular Biology of the Cell (© Garland Science 2008)
Bax, Bak
• Bax
– Bound to mitochondrial outer membrane
• Bak
– Located in cytosol, transport into mitochondira
after apoptotic signaling
• Both work on ER and nuclear membrane,
activated by ER stress release Ca++ and
intrinsic apoptotic pathway
Bcl2 Proteins Regulate the Intrinsic Pathway of
Apoptosis
How pro-apoptotic BH3-only and anti-apoptotic Bcl2 proteins regulate
the intrinsic pathway of apoptosis
Figure 18-11a Molecular Biology of the Cell (© Garland Science 2008)
Bcl2 Proteins Regulate the Intrinsic Pathway of
Apoptosis
How pro-apoptotic BH3-only and anti-apoptotic Bcl2 proteins regulate
the intrinsic pathway of apoptosis
Figure 18-11b Molecular Biology of the Cell (© Garland Science 2008)
Bid is the link between the two pathways
• Death receptor extrinsic pathway
• The initiator caspase, caspase-8 cleasve
Bid producing tBid
• tBid translocates to mitochondria inhibit
bcl2
Bid: a proapoptotic BHS-3-only protein
IAPs Inhibit Caspases
A proposed model for the roles of IAPs and anti-IAPs in the control of
apoptosis in mammalian cells
IAP: Inhibitor of apoptosis
first identified from vaculovirus.
Figure 18-12a Molecular Biology of the Cell (© Garland Science 2008)
IAPs Inhibit Caspases
A proposed model for the roles of IAPs and anti-IAPs in the control of
apoptosis in mammalian cells
Figure 18-12b Molecular Biology of the Cell (© Garland Science 2008)
Extracellular Survival Factors Inhibit Apoptosis in
Various Ways
The role of survival factors and cell death in adjusting the number of
developing nerve cells to the amount of target tissue
Figure 18-13 Molecular Biology of the Cell (© Garland Science 2008)
Extracellular Survival Factors Inhibit Apoptosis in
Various Ways
Three ways that extracellular survival factors can inhibit apoptosis
Figure 18-14 Molecular Biology of the Cell (© Garland Science 2008)
Bak/bax double mutant in mouse
• Cannot activate intrinsic apoptosis
• But without survival signal, nutrient import
is not efficient
• Autophagedie from starvation
Figure Q18-1 Molecular Biology of the Cell (© Garland Science 2008)
UV illumination to human Hela Cells
 within 24h apoptosis in all cells
 from 6 h after illumination to 24 h
Slow apoptosis?
or
Gradual apoptosis in cell population?
Figure Q18-2 Molecular Biology of the Cell (© Garland Science 2008)
Apoptosis (2010) 15:249–256
Apoptotic-like regulation of programmed
cell death in plants
• Protoplast condensation, nuclear condensation,
fragmentation
• A central regulatory role for the mitochondria
• The degradation of the cell and its contents by PCD
associated proteases.
• Caspase-like
– Study using caspase inhibitor, substrate
– Lack in caspase ortholog from Arabidopsis genome
• No evidence that cyt c can directly activate AL-PCD
proteases.
• No Bcl2 family homologs identified
• Involvement of chloroplast?
Schematic representation of AL-PCD
MMP: mitochondrial membrane permeablization
PTP: the perability transition pore
Caspase-independent DNA
degradation
• Endo G
– No homolog in plant
– Mito IMS contain strong Mg2+ dependent
nuclease activity
• AIF/monodehydroascorbate reductase
– 5 homologs in Arabidospsis
– Antioxidant pathway
– DNA-binding defective AIF fails to induce cell
death
Metacaspases
• 9 metacaspases in Arabidopsis
• Arginine instead of Aspartic acid
• No caspase substrate clevage, no inhibition by
caspase inhibitors
• Involvement in PCD of Arabidopsis
• Natural substrates?
– TSN(Tudor staphylococcal nuclease) in Norway spruce
(유럽가문비)
– hTSN: caspase substrate, involved in PCD