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Executioner Caspase-3, -6, And -7 Perform Distinct, Non-redundant Roles During The Demolition Phase Of Apoptosis*
E. Slee, C. Adrain, S. Martin
Published 2001 · Biology, Medicine
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Apoptosis is orchestrated by a family of cysteine proteases known as the caspases. Fourteen mammalian caspases have been identified, three of which (caspase-3, -6, and -7) are thought to coordinate the execution phase of apoptosis by cleaving multiple structural and repair proteins. However, the relative contributions that the “executioner” caspases make to the demolition of the cell remains speculative. Here we have used cell-free extracts immuno-depleted of either caspase-3, -6, or -7 to examine the caspase requirements for apoptosis-associated proteolysis of 14 caspase substrates as well as nuclear condensation, chromatin margination, and DNA fragmentation. We show that caspase-3 is the primary executioner caspase in this system, necessary for cytochromec/dATP-inducible cleavage of fodrin, gelsolin, U1 small nuclear ribonucleoprotein, DNA fragmentation factor 45 (DFF45)/inhibitor of caspase-activated DNase (ICAD), receptor-interacting protein (RIP), X-linked inhibitor of apoptosis protein (X-IAP), signal transducer and activator of transcription-1 (STAT1), topoisomerase I, vimentin, Rb, and lamin B but not for cleavage of poly(ADP-ribose) polymerase (PARP) or lamin A. In addition, caspase-3 was also essential for apoptosis-associated chromatin margination, DNA fragmentation, and nuclear collapse in this system. Surprisingly, although caspase-6 and -7 are considered to be important downstream effector caspases, depletion of either caspase had minimal impact on any of the parameters investigated, calling into question their precise role during the execution phase of apoptosis.
This paper references
Caspases: Intracellular Signaling by Proteolysis
G. Salvesen (1997)
Catalytic properties of the caspases
HR Stennicke (1999)
Caspase-3 Is Required for α-Fodrin Cleavage but Dispensable for Cleavage of Other Death Substrates in Apoptosis*
R. Jänicke (1998)
Specific cleavage of the 70-kDa protein component of the U1 small nuclear ribonucleoprotein is a characteristic biochemical feature of apoptotic cell death.
L. Casciola-Rosen (1994)
Apoptosis: A Basic Biological Phenomenon with Wide-ranging Implications in Tissue Kinetics
J. Kerr (1972)
Ordering the Cytochrome c–initiated Caspase Cascade: Hierarchical Activation of Caspases-2, -3, -6, -7, -8, and -10 in a Caspase-9–dependent Manner
E. Slee (1999)
Defects in regulation of apoptosis in caspase-2-deficient mice.
L. Bergeron (1998)
STAT1 Is Inactivated by a Caspase*
P. King (1998)
Caspase structure, proteolytic substrates, and function during apoptotic cell death
Dw Nicholson (1999)
Suicidal Tendencies: Apoptotic Cell Death by Caspase Family Proteinases*
Beni B Wolf (1999)
Death receptors: signaling and modulation.
A. Ashkenazi (1998)
Mechanisms mediating caspase activation in cell death
S. Kumar (1999)
Protease Involvement in Fodrin Cleavage and Phosphatidylserine Exposure in Apoptosis*
D. Vanags (1996)
Serial killers: ordering caspase activation events in apoptosis
EA Slee (1999)
Caspases: the executioners of apoptosis.
G. Cohen (1997)
Degradation of lamin B1 precedes oligonucleosomal DNA fragmentation in apoptotic thymocytes and isolated thymocyte nuclei.
N. Neamati (1995)
Caspase activation: the induced-proximity model.
G. Salvesen (1999)
Cleavage of the death domain kinase RIP by caspase-8 prompts TNF-induced apoptosis.
Y. Lin (1999)
Essential contribution of caspase 3/CPP32 to apoptosis and its associated nuclear changes.
M. Woo (1998)
Induction of Apoptotic Program in Cell-Free Extracts: Requirement for dATP and Cytochrome c
X. Liu (1996)
Autoactivation of procaspase-9 by Apaf-1-mediated oligomerization.
S. Srinivasula (1998)
Cell‐free reconstitution of Fas‐, UV radiation‐ and ceramide‐induced apoptosis.
S. J. Martin (1995)
The 40-kDa subunit of DNA fragmentation factor induces DNA fragmentation and chromatin condensation during apoptosis.
X. Liu (1998)
A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD
M. Enari (1998)
Caspase-mediated Cleavage of DNA Topoisomerase I at Unconventional Sites during Apoptosis*
K. Samejima (1999)
Caspase-3 Is Required for DNA Fragmentation and Morphological Changes Associated with Apoptosis*
R. Jänicke (1998)
Studies of the lamin proteinase reveal multiple parallel biochemical pathways during apoptotic execution.
Y. Lazebnik (1995)
Caspases: enemies within.
N. Thornberry (1998)
Decreased apoptosis in the brain and premature lethality in CPP32-deficient mice
K. Kuida (1996)
Apaf-1, a Human Protein Homologous to C. elegans CED-4, Participates in Cytochrome c–Dependent Activation of Caspase-3
H. Zou (1997)
Calpain activation is upstream of caspases in radiation-induced apoptosis
N. Waterhouse (1998)
Calcium/Calmodulin-dependent Protein Kinase IV Is Cleaved by Caspase-3 and Calpain in SH-SY5Y Human Neuroblastoma Cells Undergoing Apoptosis*
K. McGinnis (1998)
Caspase-3-generated fragment of gelsolin: effector of morphological change in apoptosis.
S. Kothakota (1997)
A Combinatorial Approach Defines Specificities of Members of the Caspase Family and Granzyme B
N. Thornberry (1997)
Cleavage of CAD inhibitor in CAD activation and DNA degradation during apoptosis
H. Sakahira (1998)
Changes in nuclear morphology during apoptosis correlate with vimentin cleavage by different caspases located either upstream or downstream of Bcl‐2 action
N. Morishima (1999)
Proteolysis of Fodrin (Non-erythroid Spectrin) during Apoptosis (*)
S. J. Martin (1995)
Induction of endonucleolytic DNA cleavage in human acute myelogenous leukemia cells by etoposide, camptothecin, and other cytotoxic anticancer drugs: a cautionary note.
S. Kaufmann (1989)
The CED-3/ICE-like Protease Mch2 Is Activated during Apoptosis and Cleaves the Death Substrate Lamin A*
K. Orth (1996)
Cytochrome c and dATP-Dependent Formation of Apaf-1/Caspase-9 Complex Initiates an Apoptotic Protease Cascade
Peng Li (1997)
Purification and catalytic properties of human caspase family members
M. García-Calvo (1999)
The cytotoxic cell protease granzyme B initiates apoptosis in a cell‐free system by proteolytic processing and activation of the ICE/CED‐3 family protease, CPP32, via a novel two‐step mechanism.
S. J. Martin (1996)
Caspase-3 controls both cytoplasmic and nuclear events associated with Fas-mediated apoptosis in vivo.
T. Zheng (1998)
Cleavage of lamin A by Mch2 alpha but not CPP32: multiple interleukin 1 beta-converting enzyme-related proteases with distinct substrate recognition properties are active in apoptosis.
A. Takahashi (1996)
Specific cleavage of the retinoblastoma protein by an ICE‐like protease in apoptosis.
R. Jänicke (1996)
Caspase knockouts: matters of life and death
Ts Zheng (1999)
Phosphatidylserine Externalization during CD95-induced Apoptosis of Cells and Cytoplasts Requires ICE/CED-3 Protease Activity*
S. J. Martin (1996)
Apoptotic Pathways The Roads to Ruin
D. Green (1998)
Degradation of Retinoblastoma Protein in Tumor Necrosis Factor- and CD95-induced Cell Death*
X. Tan (1997)
Specific proteolytic cleavage of poly(ADP-ribose) polymerase: an early marker of chemotherapy-induced apoptosis.
S. Kaufmann (1993)
Mammalian caspases: structure, activation, substrates, and functions during apoptosis.
W. Earnshaw (1999)
Protease activation during apoptosis: Death by a thousand cuts?
S. Martin (1995)
Caspase-3 Is the Primary Activator of Apoptotic DNA Fragmentation via DNA Fragmentation Factor-45/Inhibitor of Caspase-activated DNase Inactivation*
Beni B Wolf (1999)
Non-erythroid alpha-spectrin breakdown by calpain and interleukin 1 beta-converting-enzyme-like protease(s) in apoptotic cells: contributory roles of both protease families in neuronal apoptosis.
R. Nath (1996)
DFF, a Heterodimeric Protein That Functions Downstream of Caspase-3 to Trigger DNA Fragmentation during Apoptosis
X. Liu (1997)
Selective cleavage of nuclear autoantigens during CD95 (Fas/APO-1)- mediated T cell apoptosis
C. Casiano (1996)
Cleavage of human inhibitor of apoptosis protein XIAP results in fragments with distinct specificities for caspases
Q. Deveraux (1999)
Cleavage of BID during cytotoxic drug and UV radiation-induced apoptosis occurs downstream of the point of Bcl-2 action and is catalysed by caspase-3: a potential feedback loop for amplification of apoptosis-associated mitochondrial cytochrome c release
E. Slee (2000)
Activation of intracellular proteases is an early event in TNF-induced apoptosis.
C. Voelkel-Johnson (1995)
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Knockdown of BAG3 sensitizes bladder cancer cells to treatment with the BH3 mimetic ABT-737
J. Mani (2015)
How melanoma cells evade trail-induced apoptosis
P. Hersey (2001)
Das therapeutische Potential der pharmakologischen Interferenz mit dem Renin-Angiotensin-System im in vitro Modell der diabetischen Retinopathie
Marie Horlbeck (2014)
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J. Schlezinger (2008)
Wirkung des HSP90-Inhibitors AUY922 in Ewing-Sarkomzellen
Marc Schaarschmidt (2020)
Induction of apoptosis by Hax‐1 siRNA in melanoma cells
W. Li (2009)
Identification of FDA‐approved drugs as novel allosteric inhibitors of human executioner caspases
R. N. V. Krishna Deepak (2018)
MicroRNA-455-3p Inhibits Tumor Cell Proliferation and Induces Apoptosis in HCT116 Human Colon Cancer Cells
J. Zheng (2016)
Overexpression of Annexin II Receptor-Induced Autophagy Protects Against Apoptosis in Uveal Melanoma Cells.
Yuelu Zhang (2016)
Apoptosis: Implications in Viral and Mycobacterium tuberculosis infections
Gorakh Raj Giri (2017)
Picornaviruses and Apoptosis: Subversion of Cell Death
Sarah Croft (2017)
TRIBUTYLTIN INDUCES HUMAN NEUTROPHIL APOPTOSIS AND SELECTIVE DEGRADATION OF CYTOSKELETAL PROTEINS BY CASPASES
V. Lavastre (2002)
KCC 2 loss induces apoptosis in mature neurons 1 KCC 2 is required for the survival of mature neurons but not for their development
Pituitary adenylate cyclase activating polypeptide (PACAP1-38) exerts both pro and anti-apoptotic effects on postnatal retinal development in rat
N. Zsolt (2018)
An in vitro and in vivo study of a novel zinc complex, zinc N-(2-hydroxyacetophenone)glycinate to overcome multidrug resistance in cancer.
Ruma Dey Ghosh (2011)
Analysis of the anti-cancer activity of novel indigenous algal compounds in breast cancer: towards the development of a model for screening anti-cancer stem cell activity
J. Lawson (2010)
Experimental Infection of Bar-Headed Geese (Anser indicus) and Ruddy Shelducks (Tadorna ferruginea) With a Clade 2.3.2 H5N1 Highly Pathogenic Avian Influenza Virus
N. Nemeth (2013)
Nuclear lamins: laminopathies and their role in premature ageing.
J. Broers (2006)
Mice overexpressing human caspase 3 appear phenotypically normal but exhibit increased apoptosis and larger lesion volumes in response to transient focal cerebral ischaemia
L. E. Kerr (2004)
Apoptosis measurement by annexin v staining.
E. Miller (2004)
ZEB1 Links p63 and p73 in a Novel Neuronal Survival Pathway Rapidly Induced in Response to Cortical Ischemia
T. Bui (2009)
Effects of Hypoxic Conditions on Skeletal Myoblasts
Shuai Zhao (2016)
Red clover flavonoids protect against oxidative stress-induced cardiotoxicity in vivo and in vitro
M. Wang (2014)
Proteinase-activated Receptor 2 (PAR2) Decreases Apoptosis in Colonic Epithelial Cells*
V. Iablokov (2014)
Mechanisms of tolvaptan-induced toxicity in HepG2 cells.
Yuanfeng Wu (2015)
Grb7 and Hax1 may colocalize partially to mitochondria in EGF‐treated SKBR3 cells and their interaction can affect Caspase3 cleavage of Hax1
L. Qian (2016)
Mechanisms of Caspase-3 Regulation in the Execution of Cell Death
Yadira Malavez (2012)
Activated protein C and its potential applications in prevention of islet β-cell damage and diabetes.
M. Xue (2014)
Roles of c-FLIP in Apoptosis, Necroptosis, and Autophagy
A. Safa (2013)
Parallel synthesis and biological evaluation of 837 analogues of procaspase-activating compound 1 (PAC-1).
Danny C. Hsu (2012)
Effects of propofol-dexmedetomidine combination on ischemia reperfusion-induced cerebral injury.
Z. Wang (2014)
Protective effect of ginsenoside Rg1 on lidocaine-induced apoptosis
H. Li (2014)See more