BIO 5068Fundamentals of Molecular and Cell
Biology
ApoptosisDecember 1/6, 2005
Dr. Robert H. [email protected] 747-4681
The emergent integrated circuit of the cellThe emergent integrated circuit of the cell
2003 03230Hanahan and Weinberg (2000). Cell 100:57-70
The emergent integrated circuit of the cellThe emergent integrated circuit of the cell
2003 0330Hanahan and Weinberg (2000). Cell 100:57-70
2004 0481
Cell proliferation - apoptosis = homeostasisCell proliferation - apoptosis = homeostasis
proliferation apoptosis
disorders ofcell accumulation
disorders ofcell loss
homeostasis
time
Apoptosis: A basic biological phenomenon Apoptosis: A basic biological phenomenon with wide-ranging implications…with wide-ranging implications…
2003 0331
“The term apoptosis is proposed for a hitherto little recognized mechanism of controlled cell deletion, which appears to play a complementary but opposite role to mitosis in the regulation of animal cell populations. Its morphological features suggest that it is an active, inherently programmed phenomenon, and it has been shown that it can be initiated or inhibited by a variety of environmental stimuli, both physiological and pathological…”
Kerr, Wyllie, and Currie (1972). Br. J. Cancer 26:239-57
2003 0286
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Cell death-related publicationsCell death-related publications
Apoptosis (programmed cell death) – part IApoptosis (programmed cell death) – part II
2003 0329
first described by Kerr, Wyllie and Currie(Br. J. Cancer, 1972, 26:239)
Greek for “falling off” or “dropping off”
describes the molecular and morphological processes leading to controlled cellular self-destruction
stereotypical morphological changes: shrinkage, vacuoloation, loss of contact to ECM, chromatin condensation, fragmentation into apoptotic bodies
active and defined process that plays a crucial role in regulation of tissue homeostasis
2004 0477
Morphologic features ofMorphologic features ofnormal, apoptotic and necrotic cellsnormal, apoptotic and necrotic cells
1
6
3
5
2
4
Vitale et al. Purdue Cytometry CD-ROM Series, Vol. 4
necrosisnecrosis cell swelling nuclear disintegration
membrane dissolution annexin V+/PI+
2004 0478
Apoptosis vs. necrosisApoptosis vs. necrosis
apoptosisapoptosis cell shrinkage nuclear condensation,
apoptotic bodies cytoplasmic blebbing annexin V+/PIˉ single or few cells no inflammation
GITR crosslinking does not inhibitGITR crosslinking does not inhibitactivation-induced cell deathactivation-induced cell death
2004 0459
PI
annexV
0.00 mg/ml anti-CD3
0.02 mg/ml anti-CD3
I II
III
-- GITR + GITR
Esp
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necrosisnecrosis cell swelling nuclear disintegration
membrane dissolution annexin V+/PI+
whole organs inflammation
2004 0478
Apoptosis vs. necrosisApoptosis vs. necrosis
apoptosisapoptosis cell shrinkage nuclear condensation,
apoptotic bodies cytoplasmic blebbing annexin V+/PIˉ single or few cells no inflammation
stimuli include signaling triggered by:cell surface receptors, growth factor withdrawal, hypoxia, heat shock, DNA damage, viral infection, chemotherapeutic agents
involved in many physiologic events:embryogenesis, differentiation, homeostasis, aging, removal of defect and/or harmful cells
cause for a variety of pathologic disorders:neurodegenerative disease, immunodeficiency,auto-immune disease, and cancer
stimuli include signaling triggered by:cell surface receptors, growth factor withdrawal, hypoxia, heat shock, DNA damage, viral infection, chemotherapeutic agents
involved in many physiologic events:embryogenesis, differentiation, homeostasis, aging, removal of defect and/or harmful cells
cause for a variety of pathologic disorders:neurodegenerative disease, immunodeficiency,auto-immune disease, and cancer
stimuli include signaling triggered by:cell surface receptors, growth factor withdrawal, hypoxia, heat shock, DNA damage, viral infection, chemotherapeutic agents
involved in many physiologic events:embryogenesis, differentiation, homeostasis, aging, removal of defect and/or harmful cells
cause for a variety of pathologic disorders:neurodegenerative disease, immunodeficiency,auto-immune disease, and cancer
stimuli include signaling triggered by:cell surface receptors, growth factor withdrawal, hypoxia, heat shock, DNA damage, viral infection, chemotherapeutic agents
involved in many physiologic events:embryogenesis, differentiation, homeostasis, aging, removal of defect and/or harmful cells
cause for a variety of pathologic disorders:neurodegenerative disease, immunodeficiency,auto-immune disease, and cancer
Apoptosis (programmed cell death) – part IIApoptosis (programmed cell death) – part II
2003 0329
2004 0479
Apoptosis vs. ‘programmed cell death’Apoptosis vs. ‘programmed cell death’
‘programmed cell death’ and apoptosis are often used as synonyms, but the terms are not identical
‘programmed cell death’ is a genetically defined process during development of multicellular organisms, e.g., Caenorhabditis elegans:1090 cells are generated during development,exactly 131 of these cells undergo apoptosis
‘programmed cell death’ is mediated by apoptosis
2004 0480
Caenorhabditis elegansCaenorhabditis elegans::a model for apoptosis researcha model for apoptosis research
CED-9
CED-4
CED-3
EGL-1
apoptosis
2004 0491
The Nobel PrizeThe Nobel Prizein Physiology and Medicine 2002in Physiology and Medicine 2002
"for their discoveries concerning 'genetic regulation of organ development and programmed cell death'"
Sydney Brenner H. Robert Horvitz John E. Sulston
1/3 of the prize 1/3 of the prize 1/3 of the prize
United Kingdom USA United Kingdom
The Molecular Sciences Institute Berkeley, CA, USA
Massachusetts Institute of Technology (MIT) Cambridge, MA, USA
The Wellcome Trust Sanger Institute Cambridge, United Kingdom
b. 1927(in Union of South Africa)
b. 1947 b. 1942
http://nobelprize.org/medicine/laureates/2002/
Regulation of caspase activity:Regulation of caspase activity:C. elegans vs. higher eukaryotesC. elegans vs. higher eukaryotes
2001 0221
Ced-4
Ced-9
Ced-3
Apaf-1
Bcl-2Bcl-xL
cyto c
BaxBad
caspases
c-IAPsmodified from Arch and Thompson (1999).Ann. Rev. Cell Dev. Biol. 15:113-40
2004 0482
Biochemical features of apoptosisBiochemical features of apoptosis
proteolytic cleavage of cytoskeleton
proteolytic cleavage of nuclear proteins
endonucleolytic cleavage of genomic DNA
crosslinking of proteins by transglutaminase
exposure of phoshpatidyl serine on the cell surface
2004 0483
Proposed functions of biochemical Proposed functions of biochemical changes during apoptosischanges during apoptosis
changes of cytoskeleton and cell volume→ separation of cells from their environment
degradation of nuclear proteins and genomic DNA→ destruction of genetic material and interference
with DNA repair mechanisms
Transglutaminase activity→ packaging cell content
Plasma membrane changes→ activation of phagocytes
changes of cytoskeleton and cell volume→ separation of cells from their environment
degradation of nuclear proteins and genomic DNA→ destruction of genetic material and interference
with DNA repair mechanisms
Transglutaminase activity→ packaging cell content
Plasma membrane changes→ activation of phagocytes
changes of cytoskeleton and cell volume→ separation of cells from their environment
degradation of nuclear proteins and genomic DNA→ destruction of genetic material and interference
with DNA repair mechanisms
Transglutaminase activity→ packaging cell content
Plasma membrane changes→ activation of phagocytes
changes of cytoskeleton and cell volume→ separation of cells from their environment
degradation of nuclear proteins and genomic DNA→ destruction of genetic material and interference
with DNA repair mechanisms
Transglutaminase activity→ packaging cell content
Plasma membrane changes→ activation of phagocytes
changes of cytoskeleton and cell volume→ separation of cells from their environment
degradation of nuclear proteins and genomic DNA→ destruction of genetic material and interference
with DNA repair mechanisms
Transglutaminase activity→ packaging cell content
Plasma membrane changes→ activation of phagocytes
Cell-extrinsic and cell-intrinsicCell-extrinsic and cell-intrinsicapoptotic signaling pathwaysapoptotic signaling pathways
2003 0280Ash
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2002
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TNFR signaling and apoptosisTNFR signaling and apoptosis
2003 0295
“death receptors” induce p53-independent apoptosis
TNF was identified as a tumoricidal serum compound (Carswell et al. 1975).
TNFR was identified years later(Rubin et al. 1985, Kull et al. 1985).
TNF and TNFR belong to superfamilies(Aggarwal et al. 1985).
TNFR superfamily can be divided based on the presence of a death domain in some of the receptors.
2003 0344
Ashkenazi (2002). Nature Reviews Cancer Vol 2:420-30
TNFR and TNF superfamiliesTNFR and TNF superfamilies
Signaling triggered by TNFR family membersSignaling triggered by TNFR family members
2005 0529mod
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999)
.A
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Rev
. Cel
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:113
-40
Therapeutic strategies utilizing death receptorsTherapeutic strategies utilizing death receptors
2003 0278Ash
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2002
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Death receptor-induced signalingDeath receptor-induced signaling
2003 0276Ash
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Targeting of the FADD geneTargeting of the FADD gene
2003 0268Yeh et al. (1998). Science 279:1954-8
Defective apoptotic pathwaysDefective apoptotic pathwaysin FADDin FADD-/--/- MEFs MEFs
2003 0296Yeh et al. (1998). Science 279:1954-8
Apoptotic pathways in FADDApoptotic pathways in FADD-/--/- fibroblasts fibroblasts
2003 0297Yeh et al. (1998). Science 279:1954-8
10 ng TNF- + chx c-myc adenovirus c-myc adenovirus
adriamycinE1B-neg adenovirus
● FADD+/+
■ FADD-/-
Death receptor-induced signalingDeath receptor-induced signaling
2003 0276Ash
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Caspases (part I)Caspases (part I)
2003 0301
cysteine proteases with specificity for aspartic acid.
related to Caenorhabditis elegans gene ced-3.
constitutively and ubiquitously expressed as catalytically inactive pro-enzymes (zymogens).
N-terminal pro-domain, large and small subunit.
activation requires proteolysis of the zymogen at specific Asp residues resulting in removal of thepro-domain and formation of heterodimers
active caspases are tetramers composed of two heterodimers
2004 0484
Mechanism of caspase activationMechanism of caspase activation
catalytic domain requires amino acids from large and small subunits
zymogen
active caspase
prodomain smalllarge
prodomainautoproteolysis,other caspases
Asp Asp
Caspases (part II)Caspases (part II)
2003 0301
differences in length and sequence of pro-domain:long pro-domain [casp 1, 2, 4, 5, 8, 9, 10, 11, 12, 13]short pro-domain [casp 3, 6, 7, 14]
long pro-domains mediate protein-protein interaction:death effector domain (DED) mediates interactionwith death receptors [casp 8, 10]casp recruitment domain (CARD) also found in Ced-4, Apaf-1 and RAIDD [casp 1, 2, 4, 5, 9, 11, 12, 13]
arranged in proteolytic cascades that amplify signals.
initiator caspases (instigators) cleaveeffector caspases (terminators).
Caspase-3, -8, and -9 knockoutsCaspase-3, -8, and -9 knockouts
2003 0320
caspase-8: embryonically lethal (>E11.5)death receptor (Fas, TNFR, DR3) pathway
caspase-9: perinatally lethal<2% survive and develop normallyneuroepithelial progenitors; mitochondrial pathways (dexamethasone, staurosporin, etoposide, -irradiation)
caspase-3: perinatally lethaldepends on genetic backgroundneuroepithelial progenitors; lack of or delayed morphological changes and DNA fragmentation
Apoptotic signaling pathwaysApoptotic signaling pathways
2003 0280Ash
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Apoptotic pathways in caspase-3Apoptotic pathways in caspase-3-/--/- ES cells ES cells
2003 0317Woo et al. (1998). Genes Dev. 12:806-19
Some examples of caspase substratesSome examples of caspase substratesCategory Substrate Caspase Effect proposed role in apoptosis
Structural Nuclear Lamins 6 Degraded Disassembly of nuclear matrix
FAK 7,6 Inactivated Disassembly of focal adhesionsGelsolin 3 Activated Disassembly of actin filaments,
blebbing, DNA cleavageActin 3,1 Degraded Disassembly of actin filamentsb-catenin 3 Degraded Disassembly of cell-cell contacts
Signaling MEKK1 3 Activated Activation of SAPKAkt-1 ? Inactivated Inhibition of survival pathway
Cell cycle DNA replication complex C
3 Inactivated Inhibition of DNA replication
mdm2 3 Altered Inhibition of p53Rb 3 Inactivated Release of E2F-1
DNA repair /damage
PARP 3 Inactivated DNA nicks not recognized
iCAD 3 Inactivated Degradation of genomic DNADNA-PK 3 Inactivated Inhibition of DNA repair
2004 0485
DNA fragmentation in apoptosisDNA fragmentation in apoptosis
DNA fragmentation
chromatin
DNA
core histonenucleosome
180bp
endonucleolytic
agarose gel electrophoresis
Abnormal chromatin condensation andAbnormal chromatin condensation andlack of DNA degradation in caspase-3lack of DNA degradation in caspase-3-/--/- cells cells
2003 0318Woo et al. (1998). Genes Dev. 12:806-19
Abnormal chromatin condensationAbnormal chromatin condensationin caspase-3in caspase-3-/--/- MEFs MEFs
2003 0319Woo et al. (1998). Genes Dev. 12:806-19
Lethal effect of anti-Fas mAbLethal effect of anti-Fas mAbin caspase-deficient animalsin caspase-deficient animals
2003 0321Zheng et al. (2000). Nature Med. 6:1241-7
Apoptotic signaling pathwaysApoptotic signaling pathways
2003 0280Ash
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Cytochrome c release, Bid translocation and Cytochrome c release, Bid translocation and caspase activation triggered by anti-Fas mAbcaspase activation triggered by anti-Fas mAb
2003 0322Zheng et al. (2000). Nature Med. 6:1241-7
*
I +Bcl-2Bcl-xL
BaxBakBadtBid
cytochrome cSmac/DIABLO
Interactions betweenInteractions betweenprocaspase-9, Apaf-1, and cytochrome cprocaspase-9, Apaf-1, and cytochrome c
2003 0325Zou et al. (1999). J. Biol. Chem. 274:11549-56
*
I +Bcl-2Bcl-xL
BaxBakBadtBid
cytochrome cSmac/DIABLO
The apoptosomeThe apoptosome
2003 0324Zou et al. (1999). J. Biol. Chem. 274:11549-56
Phenotypes of Apaf1Phenotypes of Apaf1-/--/- embryos embryos
2003 0302Yoshida et al. (1998). Cell 94:739-50
Apaf-1-/-
Apaf-1+/+
Apoptotic pathways in Apaf1Apoptotic pathways in Apaf1-/--/- ES and EF cells ES and EF cells
2003 0303Yoshida et al. (1998). Cell 94:739-50
ES cells EF cells
cellular IAPscellular IAPs – family of cytoplasmic proteins that interfere with caspase activation but are also involved in receptor-induced signal transduction pathways.
Bcl-2/Bcl-xBcl-2/Bcl-xLL – family of pro- and anti-apoptotic proteins that act as sensor for cellular damage or stress.
p53 – transcription factor that senses DNA damage and regulates cell proliferation and apoptosis.
PI-3K and Akt/PKBPI-3K and Akt/PKB – lipid and protein kinases that integrate signals from growth factor receptor to regulate multiple pathways of cell survival and apoptosis.
cellular IAPscellular IAPs – family of cytoplasmic proteins that interfere with caspase activation but are also involved in receptor-induced signal transduction pathways.
Bcl-2/Bcl-xBcl-2/Bcl-xLL – family of pro- and anti-apoptotic proteins that act as sensor for cellular damage or stress.
p53 – transcription factor that senses DNA damage and regulates cell proliferation and apoptosis.
PI-3K and Akt/PKBPI-3K and Akt/PKB – lipid and protein kinases that integrate signals from growth factor receptor to regulate multiple pathways of cell survival and apoptosis.
cellular IAPscellular IAPs – family of cytoplasmic proteins that interfere with caspase activation but are also involved in receptor-induced signal transduction pathways.
Bcl-2/Bcl-xBcl-2/Bcl-xLL – family of pro- and anti-apoptotic proteins that act as sensor for cellular damage or stress.
p53 – transcription factor that senses DNA damage and regulates cell proliferation and apoptosis.
PI-3K and Akt/PKBPI-3K and Akt/PKB – lipid and protein kinases that integrate signals from growth factor receptor to regulate multiple pathways of cell survival and apoptosis.
cellular IAPscellular IAPs – family of cytoplasmic proteins that interfere with caspase activation but are also involved in receptor-induced signal transduction pathways.
Bcl-2/Bcl-xBcl-2/Bcl-xLL – family of pro- and anti-apoptotic proteins that act as sensor for cellular damage or stress.
p53 – transcription factor that senses DNA damage and regulates cell proliferation and apoptosis.
PI-3K and Akt/PKBPI-3K and Akt/PKB – lipid and protein kinases that integrate signals from growth factor receptor to regulate multiple pathways of cell survival and apoptosis.
cellular IAPscellular IAPs – family of cytoplasmic proteins that interfere with caspase activation but are also involved in receptor-induced signal transduction pathways.
Bcl-2/Bcl-xBcl-2/Bcl-xLL – family of pro- and anti-apoptotic proteins that act as sensor for cellular damage or stress.
p53 – transcription factor that senses DNA damage and regulates cell proliferation and apoptosis.
PI-3K and Akt/PKBPI-3K and Akt/PKB – lipid and protein kinases that integrate signals from growth factor receptor to regulate multiple pathways of cell survival and apoptosis.
Regulators of apoptosisRegulators of apoptosis
2004 0494
2004 0486
Bcl-2 proteins as regulators of Bcl-2 proteins as regulators of apoptosisapoptosis
inner membraneintermembranespace
outer membrane
Cytochrome crelease
caspaseactivation
*I +Bcl-2Bcl-xL
BaxBak BadtBid
Smac/DIABLOrelease
X-IAPinhibition
Smac/DIABLO deficiencySmac/DIABLO deficiencyimpairs caspase 3 cleavage impairs caspase 3 cleavage in vitroin vitro
2003 0311Okada et al. (2002). Mol. Cell. Biol. 22:3509-17
*
I +Bcl-2Bcl-xL
BaxBakBadtBid
cytochrome cSmac/DIABLO
2004 0500
Role of X-IAP in exogenous and endogenous Role of X-IAP in exogenous and endogenous cell death pathwayscell death pathways
Lis
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80
2004 0491
Bcl-2 family membersBcl-2 family members
Chan and Yu (2004). Clin. Exp. Pharm. Phys. 31:119-28
Bcl-2 inhibits cytochrome c release and Bcl-2 inhibits cytochrome c release and apoptotic changes in a cell-free systemapoptotic changes in a cell-free system
2003 03256Kluck et al. (1997). Science 275:1132-6
*
I +Bcl-2Bcl-xL
BaxBak BadtBid
cytochrome cSmac/DIABLO
Cytochrome c bypassesCytochrome c bypassesthe inhibitory effects of Bcl-2 on apoptosisthe inhibitory effects of Bcl-2 on apoptosis
2003 03258
*
I +Bcl-2Bcl-xL
BaxBakBadtBid
cytochrome cSmac/DIABLO
Kluck et al. (1997). Science 275:1132-6
2004 0497
Interactions of Bcl-2 family membersInteractions of Bcl-2 family members
Chan and Yu (2004). Clin. Exp. Pharm. Phys. 31:119-28
Gross Anatomical PhenotypesGross Anatomical Phenotypesof bax-/- bak-/- miceof bax-/- bak-/- mice
2003 0306
*
I +Bcl-2Bcl-xL
BaxBakBadtBid
cytochrome cSmac/DIABLO
Lindsten et al. (2000). Molecular Cell 6:1389-99
Lymphoid abnormalitiesLymphoid abnormalitiesof bax-/- bak-/- miceof bax-/- bak-/- mice
2003 0307Lindsten et al. (2000). Molecular Cell 6:1389-99
*
I +Bcl-2Bcl-xL
BaxBak BadtBid
cytochrome cSmac/DIABLO
2004 0498
Role of p53 in cell survival and apoptosisRole of p53 in cell survival and apoptosis
p53
DNA damage
cell cycle arrest
DNA repair
other mechanisms
Fas
Bax
Bcl-2
2005 0538
Functional domains of p53Functional domains of p53
Yee and Vousden (2005). Carcinogenesis 26:1317-22
2005 0540
Transcriptional targets of p53Transcriptional targets of p53mediate its different biological outcomesmediate its different biological outcomes
Har
ris
and
Lev
ine
(200
5). O
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24:2
899-
908
2005 0539
Models p53 function as BH3-only proteinModels p53 function as BH3-only protein
Yee and Vousden (2005). Carcinogenesis 26:1317-22
Bad
2004 0499
Role of PKB/Akt in apoptosisRole of PKB/Akt in apoptosis
P P
P P P PP
P PP
P PPPI-3K
PKBPDK1
growthfactor
activatedtyrosine kinase
PI(4,5)P2 PI(3,4,5)P3
P P
P PP
14-3-3
Bcl-2
P
IKKFKHRL1caspase 9
ICAD/CADp53
PARP
MAPK
AP-1
NF-B
tBid
caspase-3
Fas DR5TNFR-I DR4DR3 DR6
FADDTRADD
caspase-8
2004 0487
Regulators of apoptosisRegulators of apoptosis
c-IAPs
Akt/PKB
cytochrome cSmac/DIABLO
Bcl-xL
BadBcl-2
Bax
caspase-9
APAF-1
Bak
AIFendo-G
granzymes
extrinsic
intrinsic
2004 0488
Apoptosis in developmentApoptosis in developmentElimination of unwanted or supernumerary cellsElimination of unwanted or supernumerary cells
active C. elegans: neurons through induction of Egl-1 Drosophila: through ectdysone induction of rpr vertebrate: interdigital webs, cells in wrong organs,
infected cells, transformed cellspassive
vertebrate: T cells with no self-recognition
Enforced selection of appropriate cellsEnforced selection of appropriate cellsactive
positive selection of lymphocytes XBP1 required for plasma cell development
passive role of Bcl-xL in hematopoiesis role of IL-7 in early thymocyte development
Apoptosis in the adult organismApoptosis in the adult organism
2004 0492
EyeEye – the lens of the eye, which forms during embryonic development consist of apoptotic cells that have replaced their content with the clear protein crystallin.
IntestineIntestine – cells composing the finger-like projections of the intestinal wall arise at the bottom of the crypts, travel to the tips, undergo apoptosis and are sloughed off.
SkinSkin – cells migrating from the deepest layers to the epithelial layer undergo apoptosis and form the protective epithelium.
ThymusThymus – most developing T cells undergo apoptosis because they lack a functional T cell receptor or are autoreactive.
UterusUterus – cells of the uterine wall undergo apoptosis and are sloughed off during menstruation.
OtherOther – virally infected and transformed cells undergo apoptosis; deregulation of the process often causes cancer.
2004 0490
Apoptosis in inflammatory responsesApoptosis in inflammatory responsesPathogens inhibit apoptosisPathogens inhibit apoptosis
E1B-19k bcl-2 homologuep35 IAPcrm A caspase inhibitor
Release of inflammatory mediatorsRelease of inflammatory mediators
IL-1, IL-1b, and IL-18 lack secretory sequences
IL-1b and IL-18 must be activated by caspase 1
GranzymesGranzymesserine proteaseseffectively released into target cells by lymphocytesdirectly activate caspases or substrates (granzyme B)Initiate bcl-2 family-independent mitochondrial lesion
2004 0489
Apoptosis in cancerApoptosis in cancerInitiation and selectionInitiation and selection
overexpression of anti-apoptotic genes (bcl-2, IAPs)loss of anchorage-dependent growth (PTEN, PI-3K, PKB/Akt)failure to suppress pro-apoptotic genes (PKB/Akt)suppression of Apaf-1 (melanoma and leukemia)suppression of caspase 8 (neuroblastoma)TRAIL-R1 and TRAIL-R2 mutations in breast cancer
Resistance to chemotherapyResistance to chemotherapychemotherapy damages genome or cytoskeletonchemotherapy activates intrinsic and extrinsic pathwaysp53 mutations allow escape of damaged cellsmutations suppress responses
Apoptosis: A basic biological phenomenon Apoptosis: A basic biological phenomenon with wide-ranging implications…with wide-ranging implications…
2003 0331
“The term apoptosis is proposed for a hitherto little recognized mechanism of controlled cell deletion, which appears to play a complementary but opposite role to mitosis in the regulation of animal cell populations. Its morphological features suggest that it is an active, inherently programmed phenomenon, and it has been shown that it can be initiated or inhibited by a variety of environmental stimuli, both physiological and pathological…”
Kerr, Wyllie, and Currie (1972). Br. J. Cancer 26:239-57