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Chapter 18Apoptosis
Chapter 18Apoptosis
Copyright © Garland Science 2008
Apoptosis
Two distinct forms of cell death
건강한 성인 : Billions of cells die every hourProgrammed cell death(PCD): idea in 1970s acceptance (20 년 )
:apoptosis (PCD 의 한종류 )
M18.1
apoptosis necrosis
Cell shrinks, Cytoskeletin collapses, 핵막 분해 , DNA 절단Apoptic body-chemically altered:macrophage
SwellBurstSpilling their contentsEliciting inflammatory response
Programmed cell death morphology in tobacco cells.
Figure 18-2 Molecular Biology of the Cell (© Garland Science 2008)
Sculpting the digits in the developing mouse paw by apotosis
Programmed cell death eliminates unwanted cells
1. 불필요 세포 /조직 /기관제거2. 세포수 조절 ( 간세포 분열 /phenobarbital)3. Quality control: B-/T-lymphocyte cell 제거4. 골수세포 : 백혈구 제거
Figure 18-4a Molecular Biology of the Cell (© Garland Science 2008)
Apoptotic Cells Are Biochemically RecognizableMarkers of apoptosis
TUNEL techniquePhosphatidylserine: 세포막 안쪽 바깥 : Annexin V 로 검출
“eat me” signal“Don’t eat me” signal
Figure 18-4b Molecular Biology of the Cell (© Garland Science 2008)
Apoptotic Cells Are Biochemically RecognizableMarkers of apoptosis
Positively charged 형광색소: 미토콘도리아 inner membrane 의 안쪽
Cytochrome C: released from the intermembrane space of mitochondria
Figure 18-5a 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 18-5b Molecular Biology of the Cell (© Garland Science 2008)
Apoptosis Depends on an Intracellular Proteolytic Cascade That Is Mediated by Caspases
Procaspase activation during apoptosis
endonuclease
CytoskeletonCell-cell adhesion proteins
Caspase recruitment domain: activation complex
Figure 18-6 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
DISC: Death-inducing signaling complexDecoy receptorFLIP blocking protein
Figure 18-7 Molecular Biology of the Cell (© Garland Science 2008)
The Intrinsic Pathway of Apoptosis Depends on Mitochondria
Release of cytochrome c from mitochondria during apoptosisbind procaspase-activating adapter protein(Apaf) apoptosome 형성
Recruit initiator procaspase proteins (procaspase-9)
Figure 18-8 Molecular Biology of the Cell (© Garland Science 2008)
The Intrinsic Pathway of Apoptosis Depends on Mitochondria
The intrinsic pathway of apoptosis
Apoptosis
효소 ?
Figure 18-9 Molecular Biology of the Cell (© Garland Science 2008)
Bcl2 Proteins Regulate the Intrinsic Pathway of Apoptosis
The three classes of Bcl2
Figure 18-10 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
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
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)
Bcl2 Proteins Regulate the Intrinsic Pathway of Apoptosis
How pro-apoptotic BH3-only and anti-apoptotic Bcl2 proteins regulate the intrinsic pathway of apoptosis
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
Figure 18-12a Molecular Biology of the Cell (© Garland Science 2008)
IAPs Inhibit CaspasesA 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 18-12b Molecular Biology of the Cell (© Garland Science 2008)
A proposed model for the roles of IAPs and anti-IAPs in the control of apoptosis in mammalian cells
IAPs Inhibit Caspases
Figure 18-13 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 18-14 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
Bak/bax double mutant in mouse
• Cannot activate intrinsic apoptosis
• But without survival signal, nutrient import is not efficient
• Autophagedie 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)
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?
Apoptosis (2010) 15:249–256
Schematic representation of AL-PCD
MMP: mitochondrial membrane permeablizationPTP: 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
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