Caspases are a group of cysteine proteases critical for apoptosis of eukaryotic cells. Deletion of genes that encode murine caspases suggests that caspases are involved not only in apoptosis but also in cytokine maturation and cell growth and differentiation. Among them, caspase-1 and caspase-11 are primarily involved in the processing of pro-inflammatory cytokines. Caspase-3 and caspase-9 are essential for apoptosis during brain development. Caspase-8 is required for the development of heart muscle, cell proliferation in the hematopoietic lineage and death-receptor-mediated apoptosis. These studies suggest that caspases function in cell signaling events including apoptosis, cell growth and differentiation.

REFERENCES

Alnemri
E. S.
,
Livingston
D. J.
,
Nicholson
D. W.
,
Salvesen
G.
,
Thornberry
N. A.
,
Wong
W. W.
,
Yuan
J.
(
1996
).
Human ICE/CED-3 protease nomenclature.
Cell
87
,
171
–.
Bergeron
L.
,
Perez
G. I.
,
Macdonald
G.
,
Shi
L.
,
Sun
Y.
,
Jurisicova
A.
,
Varmuza
S.
,
Latham
K. E.
,
Flaws
J. A.
,
Salter
J. C.
,
Hara
H.
,
Moskowitz
M. A.
,
Li
E.
,
Greenberg
A.
,
Tilly
J. L.
,
Yuan
J.
(
1998
).
Defects in regulation of apoptosis in caspase-2-deficient mice.
Genes Dev
12
,
1304
1314
Cryns
V.
,
Yuan
J.
(
1998
).
Proteases to die for.
Genes Dev
12
,
1551
1570
Fantuzzi
G.
,
Puren
A. J.
,
Harding
M. W.
,
Livingston
D. J.
,
Dinarello
C. A.
(
1998
).
Interleukin-18 regulation of interferon gamma production and cell proliferation as shown in interleukin-1beta-converting enzyme (caspase-1)-deficient mice.
Blood
91
,
2118
2125
Fisher
G. H.
,
Rosenberg
F. J.
,
Straus
S. E.
,
Dale
J. K.
,
Middleton
L. A.
,
Lin
A. Y.
,
Strober
W.
,
Lenardo
M. J.
,
Puck
J. M.
(
1995
).
Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome.
Cell
81
,
935
946
Ghayur
T.
,
Banerjee
S.
,
Hugunin
M.
,
Butler
D.
,
Herzog
L.
,
Carter
A.
,
Quintal
L.
,
Sekut
L.
,
Talanian
R.
,
Paskind
M.
,
Wong
W.
,
Kamen
R.
,
Tracey
D.
,
Allen
H.
(
1997
).
Caspase-1 processes IFN-gamma-inducing factor and regulates LPS-induced IFN-gamma production.
Nature
386
,
619
623
Gu
Y.
,
Kuida
K.
,
Tsutsui
H.
,
Ku
G.
,
Hsiao
K.
,
Fleming
M. A.
,
Hayashi
N.
,
Higashino
K.
,
Okamura
H.
,
Nakanishi
K.
,
Kurimoto
M.
,
Tanimoto
T.
,
Flavell
R. A.
,
Sato
V.
,
Harding
M. W.
,
Livingston
D. J.
,
Su
M. S.
(
1997
).
Activation of interferon-gamma inducing factor mediated by interleukin-1beta converting enzyme.
Science
275
,
206
209
Hakem
R.
,
Hakem
A.
,
Duncan
G. S.
,
Henderson
J. T.
,
Woo
M.
,
Soengas
M. S.
,
Elia
A.
,
de la Pompa
J. L.
,
Kagi
D.
,
Khoo
W.
,
Potter
J.
,
Yoshida
R.
,
Kaufman
S. A.
,
Lowe
S. W.
,
Penninger
J. M.
,
Mak
T. W.
(
1998
).
Differential requirement for caspase 9 in apoptotic pathways in vivo.
Cell
94
,
339
352
Kuida
K.
,
Lippke
J. A.
,
Ku
G.
,
Harding
M. W.
,
Livingston
D. J.
,
Su
M. S.
,
Flavell
R. A.
(
1995
).
Altered cytokine export and apoptosis in mice deficient in interleukin-1 beta converting enzyme.
Science
267
,
2000
2003
Kuida
K.
,
Zheng
T. S.
,
Na
S.
,
Kuan
C.
,
Yang
D.
,
Karasuyama
H.
,
Rakic
P.
,
Flavell
R. A.
(
1996
).
Decreased apoptosis in the brain and premature lethality in CPP32-deficient mice.
Nature
384
,
368
372
Kuida
K.
,
Haydar
T. F.
,
Kuan
C. Y.
,
Gu
Y.
,
Taya
C.
,
Karasuyama
H.
,
Su
M. S.
,
Rakic
P.
,
Flavell
R. A.
(
1998
).
Reduced apoptosis andcytochrome c-mediated caspase activation in mice lacking caspase 9.
Cell
94
,
325
337
Li
H.
,
Zhu
H.
,
Xu
C. J.
,
Yuan
J.
(
1998
).
Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis.
Cell
94
,
491
501
Li
P.
,
Allen
H.
,
Banerjee
S.
,
Franklin
S.
,
Herzog
L.
,
Johnston
C.
,
McDowell
J.
,
Paskind
M.
,
Rodman
L.
,
Salfeld
J.
,
Towne
E.
,
Tracey
D.
,
Wardwell
S.
,
Wei
F.
,
Wong
W.
,
Kamen
R.
,
Seshadri
T.
(
1995
).
Mice deficient in IL-1 beta-converting enzyme are defective in production of mature IL-1 beta and resistant to endotoxic shock.
Cell
80
,
401
411
Luo
X.
,
Budihardjo.
I.
,
Zou.
H.
,
Slaughter.
C.
,
Wang
X.
(
1998
).
Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors.
Cell
94
,
481
490
Nicholson
D. W.
,
Ali
A.
,
Thornberry
N. A.
,
Vaillancourt
J. P.
,
Ding
C. K.
,
Gallant
M.
,
Gareau
Y.
,
Griffin
P. R.
,
Labelle
M.
,
Lazebnik
Y. A.
,
Munday
N. A.
,
Raju
S. M.
,
Smulson
M. E.
,
Yamin
T.-T.
,
Yu
V. L.
,
Miller
D. K.
(
1995
).
Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis.
Nature
376
,
37
43
Nicholson
D. W.
,
Thornberry
N. A.
(
1997
).
Caspases: killer proteases.
Trends Biochem. Sci
22
,
299
306
Pan
G.
,
Ni
J.
,
Wei
Y. F.
,
Yu
G.
,
Gentz
R.
,
Dixit
V. M.
(
1997
).
An antagonist decoy receptor and a death domain-containing receptor for TRAIL.
Science
277
,
815
818
Rieux-Laucat
F.
,
Le Deist
F.
,
Hivroz
C.
,
Roberts
I. A.
,
Debatin
K. M.
,
Fischer
A.
,
de Villartay
J. P.
) (
1995
).
Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity.
Science
268
,
1347
1349
Rotonda
J.
,
Nicholson
D. W.
,
Fazil
K. M.
,
Gallant
M.
,
Gareau
Y.
,
Labelle
M.
,
Peterson
E. P.
,
Rasper
D. M.
,
Ruel
R.
,
Vaillancourt
J. P.
,
Thornberry
N. A.
,
Becker
J. W.
(
1996
).
The three-dimensional structure of apopain/CPP32, a key mediator of apoptosis.
Nat. Struct. Biol
3
,
619
625
Salvesen
G. S.
,
Dixit
V. M.
(
1997
).
Caspases: intracellular signaling by proteolysis.
Cell
91
,
443
446
Salvesen
G. S.
,
Dixit
V. M.
(
1999
).
Caspase activation: the induced-proximity model.
Proc. Nat. Acad. Sci. USA
96
,
10964
10967
Sneller
M. C.
,
Wang
J.
,
Dale
J. K.
,
Strober
W.
,
Middelton
L. A.
,
Choi
Y.
,
Fleisher
T. A.
,
Lim
M. S.
,
Jaffe
E. S.
,
Puck
J. M.
,
Lenardo
M. J.
,
Straus
S. E.
(
1997
).
Clincial, immunologic and genetic features of an autoimmune lymphoproliferative syndrome associated with abnormal lymphocyte apoptosis.
Blood
89
,
1341
1348
Srinivasula
S. M.
,
Ahmad
M.
,
Fernandes-Alnemri.
T.
,
Litwack
G.
,
Alnemri
E. S.
(
1996
).
Molecular ordering of the Fas-apoptotic pathway: the Fas/APO-1 protease Mch5 is a CrmA-inhibitable protease that activates multiple Ced-3/ICE-like cysteine proteases.
Proc. Nat. Acad. Sci. USA
93
,
14486
14491
Thornberry
N. A.
,
Rano
T. A.
,
Peterson
E. P.
,
Rasper
D. M.
,
Timkey
T.
,
Garcia-Calvo
M.
,
Houtzager
V. M.
,
Nordstrom
P. A.
,
Roy
S.
,
Vaillancourt
J. P.
,
Chapman
K. T.
,
Nicholson
D. W.
(
1997
).
A combinatorial approach defines specificities of members of the caspase family and granzyme B. Functional relationships established for key mediators of apoptosis.
J Biol Chem
272
,
17907
17911
Thornberry
N. A.
,
Lazebnik
Y.
(
1998
).
Caspases: enemies within.
Science
281
,
1312
1316
Varfolomeev
E. E.
,
Schuchmann
M.
,
Luria
V.
,
Chiannilkulchai
N.
,
Beckmann
J. S.
,
Mett
I. L.
,
Rebrikov
D.
,
Brodianski
V. M.
,
Kemper
O. C.
,
Kollet
O.
,
Lapidot
T.
,
Soffer
D.
,
Sobe
T.
,
Avraham
K. B.
,
Goncharov
T.
,
Holtmann
H.
,
Lonai
P.
,
Wallach
D.
(
1998
).
Targeted disruption of the mouse Caspase 8 gene ablates cell death induction by the TNF receptors, Fas/Apo1 and DR3 and is lethal prenatally.
Immunity
9
,
267
276
Vincenz
C.
,
Dixit
V. M.
(
1997
).
Fas-associated death domain protein interleukin-1beta-converting enzyme 2 (FLICE2), an ICE/Ced-3 homologue, is proximally involved in CD95-and p55-mediated death signaling.
J. Biol. Chem
272
,
6578
6583
Walker
N. P.
,
Talanian
R. V.
,
Brady
K. D.
,
Dang
L. C.
,
Bump
N. J.
,
Ferenz
C. R.
,
Franklin
S.
,
Ghayur
T.
,
Hackett
M. C.
,
Hammill
L. D.
(
1994
).
Crystal structure of the cysteine protease interleukin-1 beta-converting enzyme: a (p20/p10)2 homodimer.
Cell
78
,
343
352
Wang
J.
,
Lenardo
M. J.
(
1997
).
Molecules involved in cell death and peripheral tolerance.
Curr. Opin. Immunol
9
,
818
825
Wang
J.
,
Zheng
L.
,
Lobito
A.
,
Chan
F. K.
,
Dale
J.
,
Sneller
M.
,
Yao
X.
,
Puck
J. M.
,
Straus
S. E.
,
Lenardo
M. J.
(
1999
).
Inherited human Caspase 10 mutations underlie defective lymphocyte and dendritic cell apoptosis in autoimmune lymphoproliferative syndrome type II.
Cell
98
,
47
58
Wang
S.
,
Miura
M.
,
Jung
Y. K.
,
Zhu
H.
,
Li
E.
,
Yuan
J.
(
1998
).
Murine caspase-11, an ICE-interacting protease, is essential for the activation of ICE.
Cell
92
,
501
509
Wilson
K. P.
,
Black
J. A.
,
Thomson
J. A.
,
Kim
E. E.
,
Griffith
J. P.
,
Navia
M. A.
,
Murcko
M. A.
,
Chambers
S. P.
,
Aldape
R. A.
,
Raybuck
S. A.
,
Livingston
D. J.
(
1994
).
Structure and mechanism of interleukin-1 beta converting enzyme.
Nature
370
,
270
275
Woo
M.
,
Hakem
R.
,
Soengas
M. S.
,
Duncan
G. S.
,
Shahinian
A.
,
Kagi
D.
,
Hakem
A.
,
McCurrach
M.
,
Khoo
W.
,
Kaufman
S. A.
,
Senaldi
G.
,
Howard
T.
,
Lowe
S. W.
,
Mak
T. W.
(
1998
).
Essential contribution of caspase 3/CPP32 to apoptosis and its associated nuclear changes.
Genes Dev
12
,
806
819
Wu
J.
,
Wilson
J.
,
He
J.
,
Xiang
L.
,
Schur
P. H.
,
Mountz
J. D.
(
1996
).
Fas ligand mutation in a patient with systemic lupus erythematosus and lymphoproliferative disease.
J. Clin. Invest
98
,
1107
1113
Yeh
W. C.
,
Pompa
J. L.
,
McCurrach
M. E.
,
Shu
H. B.
,
Elia
A. J.
,
Shahinian
A.
,
Ng
M.
,
Wakeham
A.
,
Khoo
W.
,
Mitchell
K.
,
El-Deiry
W. S.
,
Lowe
S. W.
,
Goeddel
D. V.
,
Mak
T. W.
(
1998
).
FADD:essential for embryo development and signaling from some, but not all, inducers of apoptosis.
Science
279
,
1954
1958
Yin
X. M.
,
Wang
K.
,
Gross
A.
,
Zhao
Y.
,
Zinkel
S.
,
Klocke
B.
,
Roth
K. A.
,
Korsmeyer
S. J.
(
1999
).
Bid-deficient mice are resistant to Fas-induced hepatocellular apoptosis.
Nature
400
,
886
891
Yuan
J.
,
Shaham
S.
,
Ledoux
S.
,
Ellis
H. M.
,
Horvitz
H. R.
(
1993
).
The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1 beta-converting enzyme.
Cell
75
,
641
652
Zhang
J.
,
Cado
D.
,
Chen
A.
,
Kabra
N. H.
,
Winoto
A.
(
1998
).
Fas-mediated apoptosis and activation-induced T-cell proliferation are defective in mice lacking FADD/Mort1.
Nature
392
,
296
300
Zheng
T. S.
,
Schlosser
S. F.
,
Dao
T.
,
Hingorani
R.
,
Crispe
I. N.
,
Boyer
J. L.
,
Flavell
R. A.
(
1998
).
Caspase-3 controls both cytoplasmic and nuclear events associated with Fas-mediated apoptosis in vivo.
Proc. Nat. Acad. Sci. USA
95
,
13618
13623
Zou
H.
,
Henzel
W. J.
,
Liu
X.
,
Lutschg
A.
,
Wang
X.
(
1997
).
Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3.
Cell
90
,
405
413
This content is only available via PDF.