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doi:10.1111/j.1745-7270.2005.00108.x |
Caspase Family Proteases and
Apoptosis
Ting-Jun FAN1*,
Li-Hui HAN2, Ri-Shan CONG1, and Jin
LIANG1
1 College
of Marine Life Sciences, Division of Life Science and Technology, Ocean
University of China, Qingdao 266003, China;
2
College of Chemistry & Chemical Engineering, Ocean University of China,
Qingdao 266003, China
Received: July 27,
2005
Accepted: September
27, 2005
This work was
supported by a grant from the Imbursement Project for Studied Abroad Returnees from
the Ministry of Education of China (No. 980418)
*Corresponding
author: Tel, 86-532-82031637; Fax, 86-532-82031637; E-mail, [email protected]
Abstract Apoptosis, or programmed
cell death, is an essential physiological process that plays a critical role in
development and tissue homeostasis. The progress of apoptosis is regulated in
an orderly way by a series of signal cascades under certain circumstances. The
caspase-cascade system plays vital roles in the induction, transduction and
amplification of intracellular apoptotic signals. Caspases, closely associated
with apoptosis, are aspartate-specific cysteine proteases and members of the
interleukin-1b-converting enzyme family. The
activation and function of caspases, involved in the delicate caspase-cascade
system, are regulated by various kinds of molecules, such as the inhibitor of
apoptosis protein, Bcl-2 family proteins, calpain, and Ca2+.
Based on the latest research, the members of the caspase family,
caspase-cascade system and caspase-regulating molecules involved in apoptosis
are reviewed.
Key words caspase; apoptosis;
interleukin-1b-converting enzyme family;
inhibitor of apoptosis protein; Bcl-2 family
Apoptosis is a type of cell death regulated in an orderly way by a
series of signal cascades under certain situations. It plays an essential role
in regulating growth, development and immune response, and clearing redundant
or abnormal cells in organisms. It is also an important way by which organisms
can maintain a constant amount of cells in order to live successfully. The
induction and execution of apoptosis require the cooperation of a series of
molecules including signal molecules, receptors, enzymes and gene regulating
proteins. Among them, the caspase-cascade signaling system, regulated by
various molecules such as the inhibitor of apoptosis protein (IAP), Bcl-2
family proteins, and calpain, is vital in the process of apoptosis [1].
Based on the latest research in caspase family proteases, we
reviewed the properties of caspases, the activation of the caspase-cascade
signaling system, and the regulatory factors.
Molecular Properties of
Caspases
Caspases, the interleukin-1b-converting enzyme family proteases, are
highly homologous to Caenorhabditis elegans cell death gene CED-3.
Fourteen caspases have been identified so far, all of which share some common
properties: they are all aspartate-specific cysteine proteases; they all have a
conservative pentapeptide active site ‘QACXG’ (X can be R, Q or D); their
precursors are all zymogens known as procaspases. The N-terminal of the
prodomain in procaspases contains a highly diverse structure required for
caspase activation; and they are all capable of autoactivating as well as
activating other caspases, to produce a heterodimer with a big and a small
subunit, and two heterodimers form an enzymatic active heterotetramer [1].
Based on their homology in amino acid sequences, caspases are divided into
three subfamilies, as shown in Table 1.
Except for procaspase-14, unique for its proteolytic processing
which has been principally associated with epithelial cell differentiation
rather than apoptosis or inflammation, the procaspases of the inflammatory
mediator caspases and apoptosis activator caspases all have long prodomains in
procaspases [2,3]. The long prodomain contains the death effector domain (DED)
in procaspase-8 and -10, or the caspase recruitment domain (CARD) in
procaspase-2 and procaspase-9. DED and CARD, the death domain family members,
are involved in procaspase activation and downstream caspase-cascade
regulation through protein-protein interactions. A similar pyrin domain was
found in the prodomain of zebra fish procaspase. The three domains all contain
a common 3-D structure known as the death domain fold, composed of six
antiparallel a-helices arranged in a Greek key conformation. However, the shorter
prodomains in the procaspases of apoptosis executioner caspases are not
involved in protein-protein interactions [3].
Procaspase Activation
Generally, there are two pathways through which the caspase family
proteases can be activated: one is the death signal-induced, death
receptor-mediated pathway; the other is the stress-induced,
mitochondrion-mediated pathway (i.e. a caspase-9-dependent pathway).
Death receptor-mediated
procaspase-activation pathway
Death receptor-dependent procaspase-activation pathway of
caspase-8/caspase-10 Cell death signals, such as Fas ligand (FasL)
and tumor necrosis factor (TNF)-2, can be specifically recognized by their
corresponding death receptors, such as Fas or TNF receptor (TNFR)-1, in the
plasma membrane. Their binding will in turn activate the death receptors. Fas
can bind to the Fas-associated death domain (FADD) (or TNFR-associated death
domain, TRADD) and cause FADD aggregation and the emergence of DEDs. These
exposed DEDs interact with the DEDs in the prodomain of procaspase-8, which
will induce the oligomerization of procaspase-8 localized on the cytosolic
side of the plasma membrane. Then a massive molecule complex known as the
death-inducing signal complex (DISC) is formed. In DISC, two linear subunits of
procaspase-8 compact to each other followed by procaspase-8 autoactivation to
caspase-8. The activation of the downstream pathways of caspase-8 varies with
different cell types (Fig. 1). In Type I cells (cells of some lymphoid
cell lines), caspase-8 is vigorously activated and can directly activate the
downstream procaspases (e.g. procaspase-3). In Type II cells (other than Type I
cells), caspase-8 is only mildly activated and unable to activate procaspase-3
directly. However, it can activate the mitochondrion-mediated pathway by
truncating Bid (a pro-apoptotic Bcl-2 family member), a kind of proapoptotic
protein in the cytosol, into its active form, tBid. tBid will trigger the
activation of the mitochondrion pathway: cytochrome c, apoptosis-inducing
factor (AIF) and other molecules are released from mitochondria, and apoptosis
will be induced [4–7].
The activation pathway mediated by procaspase-10, with a
DED-containing prodomain, is similar to that mediated by procaspase-8.
Caspase-10 functions mainly in the apoptosis of lymphoid cells [8]. It can
function independently of caspase-8 in initiating Fas- and TNF-related
apoptosis. Moreover, Fas crosslinking in primary human T cells leads to the
recruitment and activation of procaspase-10.
Although caspase-8 and caspase-10 both interact with the DED of FADD
in death receptor signaling, they may have different apoptosis substrates and
therefore potentially function distinctly in death receptor signaling or other
cellular processes [8,9].
Death receptor-dependent procaspase-activation pathway of caspase-2 Once death signals bind to their corresponding death receptors on
the plasma membrane, death receptors will be activated. The activated receptors
recruit procaspase-2 by adaptors, such as receptor-interacting protein (RIP),
RIP-associated ICH-1/CED-3 homologous protein with a death domain and TRADD, by
means of the prodomain of procaspase-2. Procaspase-2 is activated after the
recruitment (Fig. 2). Very little has been understood so far concerning
the downstream substrates of caspase-2 [10].
Mitochondrion-mediated
procaspase-activation pathway
Mitochondrion-mediated procaspase-activation pathway of
caspase-8 Apart from being recruited to form a DISC complex after
autoactivation, procaspase-8 could also be activated through a cytochrome c-dependent
pathway. After cytochrome c is released from mitochondria to the cytosol,
caspase-6 is the only cytosolic caspase with the ability to activate
procaspase-8, which depends solely on procaspase-6 activation by prodomain
cleaving. It means that, in the cytochrome c-dependent pathway, the activation
of procaspase-8 requires neither the interaction with FADD nor the formation of
a DISC complex [9].
Mitochondrion-mediated procaspase-activation pathway of
caspase-9 When cellular stress (e.g. DNA damage) occurs, proapoptotic proteins
in the cytosol will be activated, which will in turn induce the opening of
mitochondrion permeability transition pores (MPTPs). As a result, cytochrome c
localized in mitochondria will be released to the cytosol. With the presence
of cytosolic dATP (deoxyadenosine triphosphate) or ATP, apoptotic protease
activation factor-1 (Apaf-1) oligomerizes. Together with cytosolic
procaspase-9, dATP and cytochrome c, oligomerized Apaf-1 can result in the
formation of a massive complex known as apoptosome. The N-terminal of Apaf-1
and the prodomain of procaspase-9 both have CARDs, with complementary shapes
and opposite charges. They interact with each other by CARDs and form a complex
in the proportion of 1:1 [5,11]. Activated caspase-9 can in turn activate
procaspase-3 and procaspase-7. The activated caspase-3 will then activate
procaspase-9 and form a positive feedback activation pathway (Fig. 3).
In the mitochondrion-mediated activation pathway, Apaf-1 is a
central component of the apoptosome. Apaf-1 has three distinct domains: an
N-terminal CARD, a nucleotide-binding domain and 1213 repeats of WD40 near its
C-terminal. At least four different isoforms of Apaf-1 have been found, all of
which contain the three domains resulted from the alternative splicing of
Apaf-1 pre-mRNA. CARD is responsible for binding the prodomain of
procaspase-9, thus it is important in procaspase-9 recruitment and activation.
The sequence of the nucleotide-binding domain is very similar to CED-4 in C.
elegans. For this reason, the domain is also referred to as the
CED-4-homologous domain. This domain is responsible for Apaf-1 oligomerization
in the presence of cytochrome c and dATP. The dATP-binding ability of Apaf-1
alone is poor, but with cytochrome c it can be greatly enhanced. Procaspase-9
also has a synergic promotion to the binding [12]. WD40 repeats are involved in
the interaction of Apaf-1 and cytochrome c [13,14].
Recently, there have been many reports concerning the activation of
caspase-9, which have challenged traditional ideas. Under normal physiological
conditions, inactive caspase-9 exists in the form of a monomer. When caspase-9
is artificially crystallized or is recruited by Apaf-1 in vivo, the
formation of a caspase-9 dimer results in the activation of caspase-9 [15]. In
murine embryonic fibroblast cells, the activation of procaspase-9 was
independent of cytochrome c release, the presence of Apaf-1 or reactive oxygen
intermediates in apoptosis triggered by Sendai virus infection [16].
Costantini et al. [17] reported both procaspase-9 and caspase-9 exist in
mitochondria isolated from liver, brain, kidney, spleen and heart. Procaspase-9
translocated from mitochondria to the cytosol and the nucleus in apoptosis
because of changes in the permeability of the mitochondrion membrane [17].
According to these new results, alternative ideas have been brought
forward about how procaspase-9 is activated and what molecules are required
during the activation. One view generally held is that, although the prodomain
of procaspase-9 is cleaved, the formation of the caspase-9 (or procaspase-9)
dimer, rather than the cleavage, is essential to the activation of caspase-9.
However, under some circumstances, the activation of procaspase-9 may be
independent of mitochondrial factors, such as cytochrome c.
Downstream Substrates of
Caspases
Once activated, apoptosis activator caspases such as caspase-2, -8
and/or -10 will activate other downstream apoptosis executioner caspases
including caspase-3, -6, and -7. Furthermore, active caspase 8 can cleave Bid
to tBid, which translocates to the mitochondrial membrane and triggers
cytochrome c release and activation of the mitochondrial apoptotic pathway
[18]. The activated executioner caspases can subsequently cleave distinct
cellular proteins such as PARP [poly(ADP-ribose) polymerase], lamin, fodrin,
and also Bcl-2, leading to the characteristic morphological changes. The
downstream substrates of inflammatory mediator caspases, such as caspase-1, -4
and -5, include pro-IL-1b, pro-IL-18, IL-1F7b and NOD-LRR (nucleotide-binding oligomerization
domain-leucine-rich repeat) members such as Ipaf (interleukin-1b-converting-enzyme
protease-activating factor), LRR and pyrin proteins, etc. [19,20].
Caspase-3, caspase-6 and
caspase-7
Caspase-3, a key factor in apoptosis execution, is the active form
of procaspase-3. The latter can be activated by caspase-3, caspase-8, caspase-9,
caspase-10, CPP32 activating protease, granzyme B (Gran B), and others. The
downstream substrates of caspase-3 include procaspase-3, procaspase-6,
procaspase-9, DNA-PK, PKCg, PARP, D4-GDI (D4 GDP-dissociation inhibitor), steroid response
element-binding protein, U1-70kD, inhibitor of
caspase-activated deoxyribonuclease (ICAD) and so on. Except for a-fodrin and
topoisomerase I, all of the substrates can be cleaved during the apoptosis in
caspase-3–/– cells,
from which we can see that caspase-3 is not the only apoptosis executioner
caspase [3]. Because all substrates of caspase-3 contain DEVD sequences in
common, artificially synthesized tetra peptides Ac-DEVE-AMC and Ac-DEVE-CHO are
usually used as the specific substrate and inhibitor of caspase-3,
respectively.
Through alternative splicing, caspase-3 pre-mRNA can be translated
into a short caspase-3 (caspase-3S), which lacks the conservative �QACXG sequence in the catalyzing
site, and is co-expressed with caspase-3 in all human tissues. In HEK293 cells,
overexpressed caspase-3S could protect cells from apoptosis induced by
proteosome inhibition [3].
Caspase-6 and caspase-7 are highly homologous to caspase-3.
Procaspase-6 can be activated by caspase-3 but not Gran B. Caspase-6 can also
activate procaspase-3 by a positive feedback pathway. The substrates of
caspase-6 include PARP, lamin and procaspase-3. Procaspase-7, whose substrates
include PARP, procaspase-6 and steroid response element-binding protein, can
be activated by Gran B [9,21].
Other downstream substrates of
caspases
The downstream substrates of caspases, such as PARP, DNA-PK and U1-70kD, are also involved in DNA repair. Once these substrates have
been inactivated by the cleavage of caspases, DNA degradation will ensue.
Caspase-activated deoxyribonuclease (CAD) is a kind of constitutive,
magnesium-dependent endonuclease that can be activated by caspases. CAD plays
an important role in DNA degradation in the apoptosis of mammals. In normal
cells, CAD resides in the nucleus, binding with its specific inhibitor, ICAD,
to form a complex. ICAD is not only the inhibitor but also the molecular
chaperone of CAD, essential for the proper folding of CAD. In apoptosis,
caspase-9 damages the nuclear pores in an unknown fashion so that caspase-3
can enter the nucleus to cleave ICAD. This releases the CAD from the complex,
which can result in DNA degradation (Fig. 4).
Lamin A and fodrin are essential components of the nuclear skeleton and
cytosolic skeleton, respectively. The cleavage of lamin by caspases in
apoptosis can lead to the condensation of chromatins and the decomposition of
the nuclear membrane. The cleavage of fodrin by caspases in apoptosis can
result in apoptotic body formation.
When all kinds of caspase substrates are activated, the cell will go
through a series of changes, including the activation of related genes, a
decrease in DNA damage repair ability, the activation of zymogens or
inactivation of enzymes, cytoskeleton disassembly, and chromatin fragmentation.
The cell inevitably undergoes apoptosis.
Functions of Caspase-2
Caspase-2 is the earliest identified caspase in mammals. This enzyme
is unique for its features of both initiator and effector caspases. Caspase-2
appears to be necessary for the onset of apoptosis triggered by several
insults, including DNA damage, administration of TNF, and different pathogens
and viruses [22]. Both caspase-2 and caspase-9 are similar to CED-3 in C.
elegans, all of them with a CARD. Caspase-2 widely distributes in most
tissues and cell types. It can be found in the nucleus as well as the
cytoplasm, with a considerable portion in the Golgi complex.
Many studies have shown that caspase-2 serves as an apoptosis
inducer in some types of cells. Read et al. [10] reported the
spontaneous recruitment of procaspase-2 into a protein complex without
cytochrome c or Apaf-1 in some cells. The complex formed through the
recruitment was enough to activate procaspase-2. In this case, procaspase-2
might be activated upstream of procaspase-9 activation, the release of
cytochrome c and other apoptosis factors inside the mitochondria [10]. In the
same year, the research results of Paroni et al. [23] showed that in
the early phase of apoptosis, caspase-2 inside the nucleus could cause
mitochondrial dysfunction without entering the cytosol. The release of
cytochrome c was not accompanied by any obvious alteration in nuclear pores.
Only in the late phase of apoptosis, caspase-2 entered the cytosol because of
an increase in the diffusion limits of the nuclear pores. Guo et al.
[24] reported that purified caspase-2 at physiological levels could cleave
cytosolic Bid into tBid, which could induce the release of mitochondrial
cytochrome c. Furthermore, caspase-2 could induce the release of cytochrome c,
AIF and second mitochondrial activators of caspases/direct IAP binding protein
with low pI (Smac/DIABLO) from
mitochondria, independent of Bid or other cytosolic factors [6]. Mitochondrial
cytochrome c released by caspase-2 was sufficient to activate apoptosome in
vitro [24]. In 2002, Lassus et al. [25] found that in
caspase-2-deficient cells, the translocation of Bax from the cytosol to
mitochondria, induced by etoposide, was inhibited. The reports cited above put
forward a new question: In the mitochondrion-mediated activation pathway of
apoptosis, which caspase is the first to be activated, caspase-2 or caspase-9?
These new results also gave rise to the new proposal that Bcl-2 may act as
CED-9, inhibiting apoptosis through inhibiting the activation of procaspase-2
rather than, as previously known, through inhibiting the release of
mitochondrial proapoptotic factors and maintaining the normal MPTPs [26,27]. In
addition, it was found that not only was caspase-2 associated with the
activation of procaspase-9, but caspase-2L could also promote the formation of
DISC to help with the activation of procaspase-8 in Fas-mediated apoptosis
[28].
In 2002, Mendelsohn et al. [29] found that cyclin D3, a
positive cell cycle regulator, could interact with caspase-2 and stabilize it.
The interaction implies the important roles that cyclin D3 and caspase-2 may
play in coordinating the balance of cell division and apoptosis.
Caspase-12 and Endoplasmic
Reticulum (ER) Stress-induced Apoptosis
Caspase-1, caspase-4, caspase-5, caspase-11 and caspase-12 are
highly homologous [30,31].
Caspase-12 localizes in ER and mediates apoptosis under ER stress.
It plays a key role in many nervous system diseases, such as Alzheimer‘s disease. ER stress is mainly
caused by the accumulation of proteins, particularly unfolded and malfolded ones, in ER lumen and/or the
perturbation of calcium ion homeostasis. Thapsigargin, tunicamycin, calcium
ionophores, brefeldin-A and cisplatin can all induce ER stress.
It has been proved in some cell types that ER stress can lead to
apoptosis in which caspase-12 is involved. In apoptosis caused by tunicamycin,
the processing of procaspase-12 at its N-terminus was necessary not only for
the translocation of active caspase-12 into the nucleus but also for cell
apoptosis. Under ER stress, the activation of procaspase-12 could be induced by
other caspases. The stress inducers can lead to the translocation of caspase-7
from the cytosol to the ER surface. Caspase-7 activates procaspase-12 by
exsecting its prodomain through interaction. This activation manner may be
employed in all prolonged apoptosis caused by ER stress [32]. The functions of
mitochondria in this type of apoptosis varied with different reports. Morishima
et al. [31] reported that procaspase-12 was specifically activated as an
inducer caspase in apoptosis triggered by ER stress in murine myoblast cell
line C2C12. The activated caspase-12 then activates procaspase-9, and the
activated caspase-9 in turn activates procaspase-3, -6 and -7 (Fig. 5).
In these newly-found caspase-activation pathways, no cytochrome c was found to
be released from mitochondria, which implies that cytochrome c is not involved
in the activation of procaspase-9, and, in this case, procaspase-9 is the
downstream substrate of caspase-12 [31].
Caspase Family Protease
Regulating Factors
The activation and inactivation of caspases are regulated by
various proteins, ions and other factors, such as IAP, Bcl-2 family proteins, calpain,
Ca2+, Gran B and cytokine response modifier A (Crm A).
IAP
IAP was first identified in insect cells infected by the
baculovirus. Encoded by a viral gene, IAP can inhibit infected host cells from
executing the apoptotic program. So far, in humans, the identified members of
the IAP family include cIAP1, cIAP2, XIAP (X-linked mammalian inhibitor of
apoptosis protein), NAIP (neuronal apoptosis inhibitory protein), survivin and
livin. All members of the family
contain 1–3 N-terminal baculovirus IAP repeat (BIR) domains and one
conservative C-terminal RING (really interesting new gene) domain. The BIR
domains are zinc finger-like structures that can chelate zinc ions. These zinc
fingers can bind to the surface of caspases so that the amino acid sequences,
or linkers, between BIR domains can block the catalyzing grooves of caspases.
As a result, IAP can protect a cell from apoptosis by inhibiting the activity
of caspases. However, not all BIR-containing proteins are inhibitors of
apoptosis. Survivin, for example, containing only one BIR domain, may act as a
regulator of mitosis rather than apoptosis. The RING domain has the catalyzing
activity of ubiquitin ligase E3. It can catalyze the connection of ubiquitin
with the RING domain or with other proteins. It can be hypothesized that the
RING domain may facilitate the degradation of caspases that bind to IAP [34].
The activity of mammalian IAP can be inhibited by Smac/DIABLO
released from mitochondria. As the four-residue sequence (Ala1-Val2-Pro3-Ile4)
in the newly-formed N-terminus of Smac/DIABLO
can recognize and bind to the caspase-9-binding site of XIAP, so that XIAP will
be inactivated, its inhibiting effect on caspase-9 will in turn be relieved
[17]. IAP family proteins may also have other functions besides caspase
inhibition. As reported by Uren et al., IAP family members in yeast
could neither unite caspases nor induce apoptosis [35].
Bcl-2 family proteins
The members of the Bcl-2 family are a group of crucial regulatory
factors in apoptosis. According to functional and structural criteria, the
members can be divided into two groups. Group I proteins are all anti-apoptotic
proteins, including A1/Bfl1, Bcl-2, Bcl-w, Bcl-xL, Boo/Diva, Mcl-1, NR-13 and
Nrf3 in mammals, BHRF-1, E1B19K, Ks-Bcl-2, LMW5-HL and ORF16 in bacteria, and
Ced-9 in C. elegans [7,36,37]. They all have four short Bcl-2 homology
(BH) domains: BH1, BH2, BH3 and BH4. The most overt mechanism of their
anti-apoptotic functions is inhibiting proapoptotic proteins of the Bcl-2 family
by binding to them. Group II proteins are all proapoptotic proteins, including
Bad, Bak, Bax, Bcl-rambo, Bcl-xS, Bid, Bik, Bim, Blk, BNIP3, Bok/Mtd, Hrk and
Nip3 in mammals, and Egl-1 in C. elegans [36]. Bax and Bak, originally
localized in the cytoplasm, can translocate to the mitochondrial outer membrane
after an apoptotic program starts. Following the translocation, they will
undergo conformation changes, oligomerization and insertion into the
mitochondrial outer membrane to elevate the permeability of MPTPs. Group I
proteins can bind selectively to the active conformation of Bax to prevent it
from inserting into the mitochondrial outer membrane to maintain the normal
permeability of MPTPs, and prevent the release of mitochondrial proapoptotic factors,
such as cytochrome c, AIF and Smac/DIABLO [6,11]. Through cytochrome c, AIF,
and others, Bcl-2 family proteins can indirectly regulate the activity of
caspases in related apoptotic pathways [11].
Calpain and calcium ion
Calpain is a kind of ca2+-dependent cysteine protease of the papainase family. It is
generally believed that calpain is activated in both necrosis and apoptosis.
Calpain and caspase-3 share many common substrates, including fodrin, Ca2+-dependent protein kinase and ADP-ribosyltransferase/PARP [38]. In
apoptosis induced by ER stress, calpain’s functions are particularly salient
because of the perturbed Ca2+ homeostasis. In the
brain cells of rats suffering from unilateral hypoxia-ischemia, m-calpain first
cleaved procaspase-3 into 29 kDa fragments to facilitate its further cleavage
and activation [39]. Cisplatin, a kind of anticancer agent, can cause ER stress
and apoptosis. During this process, the activation of procaspase-12 by
cisplatin is dependent on Ca2+ and calpain [40]. In addition,
calpain can also cleave Bcl-xL in its loop region, which will convert Bcl-xL to
a proapoptotic molecule from an anti-apoptotic one [41].
Gran B, Crm A and p35
Gran B is a kind of serine protease with an important role in apoptosis
in cytotoxic T cells. Gran B can activate various procaspases, such as
procaspase-3, procaspase-7, procaspase-8, procaspase-9 and procaspase-10, to
initiate apoptosis [42]. In 2000, Barry et al. found that Gran B could
cleave Bid to initiate the mitochondrion-mediated activation pathway [43].
The activity of Gran B can be inhibited by Crm A, a kind of serpin
from the vaccinia virus. Crm A, a strong inhibitor of caspase-1 and caspase-8,
and a weak inhibitor of caspase-3 and caspase-6, can prevent the cross-link of
Fas and inactivate Gran B (Fig. 6).
Baculovirus p35, with the ability of binding to caspases to cleave
and inactivate them, is an effective inhibitor of caspases from caspase-1 to
caspase-8 [44].
However, the mechanisms through which the members of the caspase
family interact with each other, and how they interact with other proapoptotic
and antiapoptotic factors, are still uncertain. Studies on these problems in
apoptosis research are quite intense, and continual advances in this field will
give us further understanding about the caspase family and apoptosis. Apoptosis
is vital in normal embryonic genesis and development, the differentiation of
immune cells, autoimmunity, tumorigenesis and nervous system injuries. Caspase
family proteases are key factors in apoptosis, and the related research can
help us to obtain the essence of the above phenomena at the molecular level and
enable us to make breakthroughs in the therapy of tumors, immune system diseases
and nervous system diseases using the artificial control of apoptosis.
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