Programmed Cell Death - Tocris Bioscience · Programmed Cell Death ... ASK1 NQDI 1 Bcl-2 Family...
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www.tocris.com Programmed Cell Death Bram van Raam 1 and Guy Salvesen 2 1 VIB/UGent Department for Molecular Biomedical Research, Technologiepark 927, 9052 Ghent, Belgium. Email: [email protected] 2 Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA. Email: [email protected] TNF-α TNFR1 TRADD TRAF2 IKKα IκBα NF-κB Active XBP1 mRNA splicing eIF2α ATF4 cFLIP L /Caspase-8 heterodimer Caspase-8 homodimer Caspase-6 Apoptosome Caspase-3-7 Caspase-9 (Active) Caspase-9 (Inactive) Apaf-1 XIAP SMAC Omi Calcium release Phosphatidylserine exposure Phosphatidylserines Phosphatidylcholines ATP Scramblase Flippase ADP Ca 2+ Ca 2+ Ca 2+ Cytochrome c cIAP1/2 EndoG Calpains Calcium efflux Calcium buffering NOXA PUMA NOXA PUMA Lamin Lamin degradation Nucleus DNA AIF FADD RIPK3 NEMO FADD FADD Fas RIPK1 Inhibited by: CYLD Caspase-6 Caspase-8 Caspase-10 cFLIP L Golgi apparatus Mitochondrion Proteolytic cleavage Breakdown of nuclear envelope Transcription of cFLIP Transcription of UPR, ERAD genes DNA cleavage Loss of DNA repair Cleaved ATF6α ATF6α PERK IRE1 IP 3 R Ca 2+ ER P Fas ligand Necroptotic Cell Death Apoptotic Cell Death Cell Survival p53 MDM2 Bid tBid Bax Bak Mcl-1 Bcl-2 Bcl-2 IKKβ PARP-1 Cleaved PARP-1 RIPK3 RIPK1 FADD Caspase-8 homodimer Caspase-8 homodimer Necroptosis Apoptosis Necroptosis Apoptosis Apoptosis RIPK3 RIPK1 FADD cFLIP S RIPK3 RIPK1 FADD Necroptosis cFLIP L /Caspase-8 heterodimer Cell survival Box 1: The influence of caspase-8 and cFLIP on cell fate following death receptor activation Caspase-8 homodimers induce apoptosis via activation of downstream caspases and also inhibit necroptotic signaling. Heterodimers of caspase-8 and cFLIP L cannot induce apoptosis but still inhibit necroptosis, resulting in cell survival. Inhibition of the caspase-8 homodimer (e.g. by cFLIP S ) prevents apoptosis and removes its inhibitory effects on RIPK1, activating necroptosis. Products available from Tocris ASK1 NQDI 1 Bcl-2 Family ARRY 520, AT 101, Bax channel blocker, Gambogic acid, iMAC2, SU 9516, TW 37 Calpains Acetyl-Calpastatin (184-210) (human), Calpeptin, MG 132, PD 150606 Caspases Apoptosis Activator 2, AZ 10417808, Z-DEVD-FMK, Z-VAD-FMK DAPK DAPK Substrate Peptide, TC-DAPK 6 eIF2α Salubrinal ERAD Eeyarestatin I IAPs Embelin IP 3 Receptors 2-APB, (-)-Xestospongin C IRE1 4μ8C, Kaempferol, STF 083010 NF-κB Signaling Caffeic acid phenethyl ester, IKK 16, IMD 0354, PF 184, TPCA-1 p53 HLI 373, Nutlin-3, Pifithrin-α, PRIMA-1 PARP-1 NU 1025, PJ 34 RIP1 Necrostatin-1 Glossary AIF Apoptosis inducing factor Apaf-1 Apoptotic peptidase activating factor 1 ATF Activating transcription factor Bak Bcl2 homologous antagonist killer Bax Bcl2-associated X protein Bid BH3-interacting domain death agonist cFLIP L Cellular FLICE-like inhibitory protein (long) cFLIP S Cellular FLICE-like inhibitory protein (short) cIAP Cellular inhibitor of apoptosis CYLD Protein encoded by the Cylindromatosis gene DAPK Death-associated protein kinase eIF2α Eukaryotic translation initiation factor 2 alpha EndoG Endonuclease G ERAD Endoplasmic reticulum-associated protein degradation FADD Fas-associated protein with death domain IκBα Inhibitor of κB alpha IKK Inhibitor of κB kinase IRE1 Inositol-requiring protein 1 MDM2 Mouse double minute 2 protein NEMO NF-κB essential modulator PERK PRKR-like endoplasmic reticulum kinase RIPK Receptor-interacting protein kinase SMAC Second mitochondria-derived activator of caspases tBid Truncated BH3-interacting domain death agonist TNF- α Tumor necrosis factor- α TNFR1 Tumor necrosis factor receptor type 1 TRADD Tumor necrosis factor receptor type 1-associated death domain TRAF2 Tumor necrosis factor receptor-associated factor 2 UPR Unfolded protein response XBP X-box-binding protein XIAP X-linked inhibitor of apoptosis NF-κB Nuclear factor-κB Two main forms of programmed cell death (PCD) are currently recognized: apoptosis and necroptosis. Apoptosis, a clean form of cellular demise that results in the quiet phagocytosis of unwanted cells, is the best known form of PCD and is executed through the sequential activation of a family of cysteine proteases, the caspases. Necroptosis, on the other hand, depends on activation of the RIP kinases and is a messy form of PCD wherein the cell’s contents are spilled into the environment, resulting in sterile inflammation. 1,2 Caspase-8 activation at the Death Receptors prevents necroptotic signaling, while favoring either apoptosis or survival. Caspase-8 differentiates between these two tasks by forming either a homodimer or heterodimer with its inactive homolog FLIP L (see Box 1). Heterodimer formation is preferred, but limited to the amount of available FLIP L . 3 Apoptosis is further regulated by the Bcl-2 family of proteins. Upon activation, the pro-apoptotic members of this family promote the release of pro-apoptotic factors from the mitochondria, resulting in the activation of downstream caspases and the execution of apoptosis. 4 Finally, the intracellular free Ca 2+ balance plays an important role in the regulation of apoptosis. 5 Elevated free Ca 2+ levels can lead to the activation of Ca 2+ -dependent proteases, the calpains, which influence the apoptotic process at several levels. In addition, intracellular free Ca 2+ regulates the activity of the cell membrane enzymes responsible for maintaining membrane asymmetry. This results in the net exposure of phosphatidylserine, an ‘eat me’ signal, on the outer membrane of apoptotic cells. 6 References 1. Green et al (2011) RIPK-dependent necrosis and its regulation by caspases: a mystery in five acts. Mol. Cell. 44 9. 2. Martin et al (2012) A perspective on mammalian caspases as positive and negative regulators of inflammation. Mol. Cell. 46 387. 3. van Raam and Salvesen (2012) Proliferative versus apoptotic functions of caspase-8 Hetero or homo: the caspase-8 dimer controls cell fate. Biochim. Biophys. Acta 1824 113. 4. Kale et al (2012) Shedding light on apoptosis at subcellular membranes. Cell 151 1179. 5. Decrock et al (2013) IP 3 , a small molecule with a powerful message. Biochim. Biophys. Acta Jan 2. 6. Ravichandran (2011) Beginnings of a good apoptotic meal: the find-me and eat-me signaling pathways. Immunity 35 445. For copies of this poster, please visit www.tocris.com © 2013 Tocris Cookson, Ltd. Tocris is a Bio-Techne brand
Transcript of Programmed Cell Death - Tocris Bioscience · Programmed Cell Death ... ASK1 NQDI 1 Bcl-2 Family...
www.tocris.com
Programmed Cell DeathBram van Raam1 and Guy Salvesen2
1VIB/UGent Department for Molecular Biomedical Research, Technologiepark 927, 9052 Ghent, Belgium. Email: [email protected] Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA. Email: [email protected]
TNF-α
TNFR1
TRADD
TRAF2
IKKα
IκBα
NF-κB
Active XBP1
mRNA splicing
eIF2α
ATF4
cFLIPL/Caspase-8 heterodimer
Caspase-8homodimer
Caspase-6
Apoptosome
Caspase-3-7
Caspase-9(Active)
Caspase-9(Inactive)
Apaf-1
XIAP
SMACOmi
Calcium release
Phosphatidylserine exposure
PhosphatidylserinesPhosphatidylcholines
ATP
ScramblaseFlippase
ADP
Ca2+
Ca2+
Ca2+
Cytochrome c
cIAP1/2
EndoG
Calpains
Calciumefflux
Calciumbuffering
NOXAPUMA
NOXA
PUMA
Lamin Lamindegradation
Nucleus
DNAAIF
FADD
RIPK3
NEMO
FADD FADD
Fas
RIPK1
Inhibited by:CYLDCaspase-6Caspase-8Caspase-10cFLIPL
Golgi apparatus
MitochondrionProteolyticcleavage
Breakdownof nuclearenvelope
Transcription of cFLIP
Transcription of UPR, ERAD genes
DNA cleavage
Loss of DNA repair
Cleaved ATF6α
ATF6α
PERK
IRE1
IP3R
Ca2+
ER
P
Fas ligand
NecroptoticCell Death
ApoptoticCell Death
Cell Survival
p53
MDM2
Bid
tBid
Bax
Bak
Mcl-1
Bcl-2
Bcl-2
IKKβ
PARP-1
Cleaved PARP-1
RIPK3 RIPK1 FADD
Caspase-8homodimer
Caspase-8homodimer
NecroptosisApoptosis Necroptosis Apoptosis
Apoptosis
RIPK3 RIPK1 FADDcFLIPS RIPK3 RIPK1 FADD
Necroptosis
cFLIPL/Caspase-8heterodimer
Cell survival
Box 1: The influence of caspase-8 and cFLIP on cell fate following death receptor activationCaspase-8 homodimers induce apoptosis via activation of downstream caspases and also inhibit necroptotic signaling. Heterodimers of caspase-8 and cFLIPL cannot induce apoptosis but still inhibit necroptosis, resulting in cell survival. Inhibition of the caspase-8 homodimer (e.g. by cFLIPS) prevents apoptosis and removes its inhibitory effects on RIPK1, activating necroptosis.
Products available from Tocris
ASK1 NQDI 1
Bcl-2Family
ARRY 520, AT 101, Bax channel blocker, Gambogic acid, iMAC2, SU 9516, TW 37
Calpains Acetyl-Calpastatin (184-210) (human), Calpeptin, MG 132, PD 150606
Caspases Apoptosis Activator 2, AZ 10417808, Z-DEVD-FMK, Z-VAD-FMK
DAPK DAPK Substrate Peptide, TC-DAPK 6
eIF2α Salubrinal
ERAD Eeyarestatin I
IAPs Embelin
IP3 Receptors
2-APB, (-)-Xestospongin C
IRE1 4μ8C, Kaempferol, STF 083010
NF-κB Signaling
Caffeic acid phenethyl ester, IKK 16, IMD 0354, PF 184, TPCA-1
p53 HLI 373, Nutlin-3, Pifithrin-α, PRIMA-1
PARP-1 NU 1025, PJ 34
RIP1 Necrostatin-1
GlossaryAIF Apoptosis inducing factorApaf-1 Apoptotic peptidase activating factor 1ATF Activating transcription factorBak Bcl2 homologous antagonist killerBax Bcl2-associated X proteinBid BH3-interacting domain death agonistcFLIPL Cellular FLICE-like inhibitory protein (long)
cFLIPS Cellular FLICE-like inhibitory protein (short)cIAP Cellular inhibitor of apoptosisCYLD Protein encoded by the Cylindromatosis
geneDAPK Death-associated protein kinaseeIF2α Eukaryotic translation initiation factor 2
alphaEndoG Endonuclease GERAD Endoplasmic reticulum-associated protein
degradationFADD Fas-associated protein with death domainIκBα Inhibitor of κB alphaIKK Inhibitor of κB kinaseIRE1 Inositol-requiring protein 1 MDM2 Mouse double minute 2 proteinNEMO NF-κB essential modulator
PERK PRKR-like endoplasmic reticulum kinaseRIPK Receptor-interacting protein kinaseSMAC Second mitochondria-derived activator of
caspasestBid Truncated BH3-interacting domain death
agonistTNF-α Tumor necrosis factor- αTNFR1 Tumor necrosis factor receptor type 1 TRADD Tumor necrosis factor receptor type
1-associated death domainTRAF2 Tumor necrosis factor receptor-associated
factor 2UPR Unfolded protein responseXBP X-box-binding proteinXIAP X-linked inhibitor of apoptosis
NF-κB Nuclear factor-κB
Two main forms of programmed cell death (PCD) are currently recognized: apoptosis and necroptosis. Apoptosis, a clean form of cellular demise that results in the quiet phagocytosis of unwanted cells, is the best known form of PCD and is executed through the sequential activation of a family of cysteine proteases, the caspases. Necroptosis, on the other hand, depends on activation of the RIP kinases and is a messy form of PCD wherein the cell’s contents are spilled into the environment, resulting in sterile inflammation.1,2 Caspase-8 activation at the Death Receptors prevents necroptotic signaling, while favoring either apoptosis or survival. Caspase-8 differentiates between these two tasks by forming either a homodimer or heterodimer with its inactive homolog FLIPL (see Box 1). Heterodimer formation is preferred, but limited to the amount of available FLIPL.
3 Apoptosis is further regulated by the Bcl-2 family of proteins. Upon activation, the pro-apoptotic members of this family promote the release of pro-apoptotic factors from the mitochondria, resulting in the activation of downstream caspases and the execution of apoptosis.4 Finally, the intracellular free Ca2+ balance plays an important role in the regulation of apoptosis.5 Elevated free Ca2+ levels can lead to the activation of Ca2+-dependent proteases, the calpains, which influence the apoptotic process at several levels. In addition, intracellular free Ca2+ regulates the activity of the cell membrane enzymes responsible for maintaining membrane asymmetry. This results in the net exposure of phosphatidylserine, an ‘eat me’ signal, on the outer membrane of apoptotic cells.6
References1. Green et al (2011) RIPK-dependent necrosis and its regulation by caspases: a mystery in five acts. Mol. Cell. 44 9.2. Martin et al (2012) A perspective on mammalian caspases as positive and negative regulators of inflammation. Mol. Cell. 46 387.3. van Raam and Salvesen (2012) Proliferative versus apoptotic functions of caspase-8 Hetero or homo: the caspase-8 dimer controls cell fate. Biochim. Biophys. Acta 1824 113.4. Kale et al (2012) Shedding light on apoptosis at subcellular membranes. Cell 151 1179.5. Decrock et al (2013) IP3, a small molecule with a powerful message. Biochim. Biophys. Acta Jan 2.6. Ravichandran (2011) Beginnings of a good apoptotic meal: the find-me and eat-me signaling pathways. Immunity 35 445.
For copies of this poster, please visit www.tocris.com
© 2013 Tocris Cookson, Ltd.Tocris is a Bio-Techne brand
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