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Departments of Pathology [E. W., G-Q. W., A. A., H. R.], Pharmacology [D. E. J.], Medicine [D. E. J., S. M. D.], and Otolaryngology [B. R. G.], University of Pittsburgh School of Medicine, University of Pittsburgh Mass Spectrometry Facility [A. A.], and University of Pittsburgh Cancer Institute [D. E. J., H. R.], Pittsburgh, Pennsylvania 15123
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ABSTRACT |
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 Top ABSTRACT IntroductionMaterials and MethodsResults and DiscussionREFERENCES |
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Introduction |
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TopABSTRACTIntroductionMaterials and MethodsResults and DiscussionREFERENCES |
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A number of intracellular proteins that negatively regulate apoptosis execution, primarily by interfering with the caspase cascade, have been identified. Antiapoptotic members of the Bcl-2 protein family act to prevent release of cytochrome c from the mitochondria (11 , 12) and can also bind and incapacitate Apaf-1 (13 , 14) , a critical cytoplasmic protein involved in cytochrome c-mediated activation of caspase-9 (8 , 15) . c-FLIP, a death effector domain-containing protein, prevents association of caspase-8 with cell surface death receptors, thereby blocking caspase-8 activation (16) . More recently, it has been shown that members of the IAP (17) protein family bind and inhibit specific caspases (18, 19, 20) .
Human IAP proteins, including hILP/XIAP (21 , 22) , c-IAP1, c-IAP2, NAIP, survivin, and Bruce, are characterized by the presence of one to three copies of a 70-amino acid motif, the BIR domain, which bears homology to sequences found in the baculovirus IAP proteins (reviewed in Ref. 17 ). The hILP, c-IAP1, and c-IAP2 proteins also contain COOH-terminal RING finger domains. hILP, c-IAP1, and c-IAP2 bind and inhibit the activated forms but not the proenzyme forms of caspase-3 and -7 (18, 19, 20) . In addition, hILP, c-IAP1, and c-IAP2 bind procaspase-9, preventing processing and activation of this enzyme (18) . These inhibitors also inhibit active caspase-9. However, despite demonstrations that hILP, c-IAP1, and c-IAP2 can bind and inhibit caspases, the molecular mechanism(s) of this inhibition remains unclear. Two caspase inhibitor proteins that are unrelated to IAPs, cowpox viral CrmA (23) and baculovirus p35 (24 , 25) , also bind directly to caspases (25) . CrmA and p35 have been shown to be suicide inactivators of caspases (26, 27, 28) . After binding, CrmA and p35 are proteolytically cleaved, and the cleaved products remain associated with the caspase to inhibit enzyme activity.
The hILP protein consists of three BIR domains and one RING finger domain and appears to be a more potent inhibitor of caspase-3 and -7 than c-IAP1 or c-IAP2 (19 , 20) . The RING finger domain is not essential for hILP binding to caspase-3 and -7, but it is important for binding to the cytoplasmic domain of bone morphogenetic protein type I receptor and may mediate functions of hILP unrelated to apoptosis (29) . Of the three hILP BIR domains, the second BIR domain, but not the first or third domains, is sufficient for binding and inhibition of caspase-3 and -7 (30) . Thus, only a portion of the molecule is needed for caspase inhibition and suppression of apoptosis.
In this report, we demonstrate that cellular hILP is cleaved by a caspase protease after treatment of cells with a variety of apoptotic stimuli. Similar hILP cleavage was seen in vitro using recombinant caspase-3 or -7 and in vitro translated hILP as a substrate. The cleavage products were found to remain associated with caspase-3 and -7 and were detected in peripheral blood T cells from healthy individuals stimulated to undergo AICD3 and detected in vivo in TALs. These findings demonstrate that hILP is a substrate of caspases and may act as a suicide inactivator of these enzymes.
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Materials and Methods |
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6ß4 mAb (A9) was
a generous gift from Dr. T. E. Carey (University of Michigan, Ann
Arbor, MI). Inhibitors of apoptosis, including Z-VAD.FMK and
Z-DEVD.FMK, were purchased from Enzyme Systems (Livermore, CA).
Recombinant caspase-3 and caspase-7 were purchased from PharMingen (San
Diego, CA). A mAb specific for hILP was purchased from Transduction
Laboratories (San Diego, CA). Rabbit anti-caspase-3 Ab and murine
anti-caspase-7 mAb were purchased from PharMingen. Anti-CD3 mAb was
purchased from DAKO (Carpinteria, CA).
Cell Lines.
Jurkat T leukemic cell line was obtained from American Type Culture
Collection (Manassas, VA). Jurkat cells were grown in RPMI 1640
containing 10% FCS, 2 mM L-glutamine, and 100
units/ml each of penicillin and streptomycin (complete medium). The
generation of stable cell lines expressing epitope-tagged CrmA or Bcl-2
proteins has been described previously (31)
. Transfected
cell lines were maintained in complete medium supplemented with 0.5
mg/ml G418 (Life Technologies, Inc.).
Induction of Apoptosis.
Jurkat cells plated at 0.5–1 x 106 cells/ml in complete medium were treated with
VP-16 (20 µM), agonistic anti-Fas Ab (200 ng/ml), or
staurosporin (0.5 µM) at 37°C for varying lengths of
time, as indicated for each experiment. To induce AICD, 48-well plates
were precoated with anti-CD3 (5 µg/ml) in 50 mM Tris (pH
9.0). PBL-T cells (1 x 106
cells/ml) were plated in wells precoated with anti-CD3 mAb in complete
medium in the presence of PMA and ionomycin at concentrations of 50
ng/ml and 0.5 µg/ml, respectively (32)
.
Western Blot Analysis.
To generate whole cell extracts, cells were lysed in 1% NP40, 20
mM Tris-base (pH 7.4), 137 mM NaCl, 10%
glycerol, 1 mM phenylmethylsulfonyl fluoride, 10 µg/ml
leupeptin, and 10 µg/ml aprotinin. Proteins were resolved by SDS-PAGE
using 15% polyacrylamide gels and transferred to PVDF membranes as
described previously (33)
. The protein bands were detected
by enhanced chemiluminescence (Pierce, Rockford, IL) after probing with
a specific primary Ab and a horseradish peroxidase-conjugated secondary
Ab.
In Vitro Translation.
Human hILP cDNA cloned in pcDNA3 vector was a generous gift from Colin
S. Duckett (NIH, Bethesda, MD). Plasmid DNA was translated in the TNT
T7 transcription-translation-coupled reticulocyte lysate system
(Promega). Each coupled transcription-translation reaction contained 1
µg of plasmid DNA in a final volume of 50 µl in a methionine-free
amino acid mixture supplemented with
[35S]methionine according to the
manufacturer’s instructions. After incubation at 30°C for 90 min,
the reaction products were stored at -70°C.
In Vitro Cleavage Reaction.
In vitro cleavage reactions were performed in a buffer
containing 20 mM HEPES (pH 7.4), 10
mM KCl, 1.5 mM
MgCl2, 1 mM EDTA, 1
mM EGTA, 20% glycerol, 1
mM phenylmethylsulfonyl fluoride, 10 µg/ml
leupeptin, and 10 µg/ml aprotinin for 1 h at 30°C with 4 µl
of 35S-labeled hILP protein in the presence or
absence of recombinant caspases and peptide inhibitors of caspases in a
total volume of 20 µl/reaction. Reactions were terminated by the
addition of SDS loading buffer and boiling for 5 min. Products of the
cleavage reactions were resolved on 15% SDS-PAGE, transferred to PVDF
membranes, and detected by autoradiography. Alternatively, the reaction
products were detected by Western blotting with anti-hILP mAb.
Patients.
Ascitic fluids were obtained from patients with OvCA at Magee Women’s
Hospital, University of Pittsburgh Medical Center (Pittsburgh, PA). The
ovary was the primary site of malignancy for all patients. The patients
were untreated at the time of specimen collection. The study was
approved by the Institutional Review Board for human use at the
University of Pittsburgh Medical Center.
Isolation of TAL-T or PBL-T Cells.
Ascitic fluid cells were washed twice in RPMI 1640, placed on
Ficoll-Hypaque discontinuous density gradients, and centrifuged to
harvest TAL and tumor cells as described previously (34)
.
To select for T lymphocytes, TALs were incubated in the presence of
anti-CD14, anti-CD16, anti-CD19 (10 µg/ml; DAKO) and
anti-6ß4 mAbs (50 µg/ml) for 30 min at
0°C. The cells were then washed twice and incubated with magnetic
beads coated with goat antimouse immunoglobulins (1 cell:30 beads;
PerSeptive Diagnostics, Cambridge, MA) for 30 min at 0°C. After each
of two successive incubations with magnetic beads, a magnet was used to
collect beads containing attached cells. T cells from peripheral blood
on normal donors were purified by a similar procedure. As assessed by
flow cytometry, the negatively selected T cells were 99% CD3 positive.
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Results and Discussion |
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TopABSTRACTIntroductionMaterials and MethodsResults and DiscussionREFERENCES |
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). After 16 h of stimulation with anti-Fas Ab, the
level of full-length hILP was significantly reduced. Even more apparent
was the appearance of a 29-kDa fragment recognized by the anti-hILP
mAb. The 29-kDa fragment was first detected after 2 h of
stimulation, and its levels continued to increase thereafter.
Stimulation of Jurkat cells with anti-Fas Ab also resulted in the
processing of procaspase-3 (32 kDa) to active subunits of 20 and 17 kDa
(Fig. 1B
). Activation of caspase-3 was first detected after
2 h of treatment but was far more substantial after 8 h of
treatment. Thus, cleavage of hILP occurred concurrently with caspase-3
activation.
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). The 29-kDa fragment was first detected after
4 h of treatment with VP-16 and after 2 h of treatment with
staurosporin. Processing of caspase-3 coincided with production of the
hILP fragment.
Inhibition of hILP Cleavage by Z-VAD.FMK.
A number of intracellular proteins are cleaved by caspase proteases
during apoptosis, including the antiapoptotic molecules Bcl-2 and
Bcl-XL (35, 36, 37, 38)
. In addition, the
CrmA and p35 proteins, which directly bind and inhibit caspases, have
been shown to be caspase substrates (26, 27, 28)
. Because hILP
is known to bind and inhibit caspase-3 and -7, we sought to determine
whether hILP cleavage in apoptotic cells was mediated by a caspase
protease. To address this question, Jurkat cells were treated with
anti-Fas, staurosporin, or VP-16 in the absence or presence of
Z-VAD.FMK, a potent general inhibitor of caspases. As shown in Fig. 2A
, Z-VAD.FMK completely abrogated production of the
29-kDa-hILP fragment in response to all three stimuli. This indicated
that hILP cleavage was caspase mediated.
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Jurkat cells engineered to overexpress Bcl-2 or CrmA (31)
were treated with anti-Fas Ab, staurosporin, or VP-16, followed by
immunoblot analysis with anti-hILP (Fig. 3
). As a control, cells transfected with vector alone (Neo)
were also analyzed. Bcl-2 overexpression completely abrogated hILP
cleavage in response to VP-16 treatment. Considerably less protection
was seen in Bcl-2/Jurkat cells treated with anti-Fas or staurosporin.
CrmA, on the other hand, dramatically inhibited hILP cleavage in the
anti-Fas- and staurosporin-treated cells but had little impact in
VP-16-treated cells. Taken together, these results support the
conclusion that cleavage of hILP in apoptotic cells is mediated by a
caspase protease.
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). Production of the cleavage fragments
was inhibited by the caspase inhibitor Z-DEVD.FMK. It appears that
in vitro translated hILP is more accessible to recombinant
caspases than the endogenous hILP is to endogenous caspases because
additional proteolytic fragments were detected in vitro.
However, like the endogenous fragment, the p29 cleavage fragment
generated from in vitro translated hILP was detected by
anti-hILP mAb (Fig. 4, C and D
).
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, the p29 fragment was not only immunoprecipitated by anti-hILP Ab but
was also coimmunoprecipitated with either caspase-3 or caspase-7. These
results demonstrate that although hILP is cleaved by caspases, the p29
product remains associated with the cleaving enzyme. Thus, hILP may
function in a fashion similar to that of CrmA and p35, with the cleaved
products remaining bound to the enzyme and inhibiting the caspase
activity. Alternatively, hILP may behave like Bcl-2, losing its
antiapoptotic activity after cleavage and perhaps even becoming
proapoptotic (37)
.
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, Lane 1), but not in control cells stimulated with only PMA
and ionomycin (Fig. 6A
, Lane 4). Interestingly, in human
peripheral blood T cells, an additional p45 hILP protein was detected
in cells treated with anti-CD3, VP-16, or staurosporin, suggesting that
hILP may be subjected to cleavage before production of the p29
fragment. In T lymphocytes pretreated with the pan-caspase inhibitor
Z-VAD.FMK before stimulation of AICD, no cleavage products of hILP were
detected (data not shown).
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). These results demonstrate that the cleavage of hILP
occurs in an in vivo setting where the loss or gain of
inhibitory function may have significant biological consequences. In summary, we have shown that endogenous hILP is cleaved by a caspase protease during cellular apoptosis. The fact that hILP cleavage is seen after Fas stimulation or treatment with VP-16 or staurosporin indicates that the caspase responsible is active in both death receptor- and drug-mediated apoptotic pathways. The observation that the hILP cleavage products remain associated with active subunits of caspase-3 and -7 suggests that hILP, like CrmA and p35, may act as a suicide inactivator of caspases, undergoing cleavage as a part of its mechanism. However, it is also possible that the cleavage products exhibit some unique cellular function. In this regard, it is interesting to note that sequences in the RING finger domain of hILP promote association of hILP with the cytoplasmic domain of bone morphogenetic protein type I receptor (29) . If the hILP cleavage products dissociate from caspases inside the cell, then it is likely that they may act as dominant-negative inhibitors of normal hILP function. Future studies will be needed to thoroughly investigate these possibilities. Our observations that hILP cleavage products are found in peripheral blood T cells undergoing AICD and also in TALs demonstrate that hILP proteolysis occurs in vivo. Thus, hILP cleavage may be fundamentally important to the process of apoptosis in both normal and pathological in vivo settings.
Note Added in Proof:
While this manuscript was under review, a similar pattern of
caspase-mediated hILP/XIAP cleavage was reported by Deveraux et
al. (Q. L. Devereaux et al., EMBO J., 18:5242–5251, 1999).
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FOOTNOTES |
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1 Supported by NIH Grant CA66044 (to D. E. J.),
National Cancer Institute Grant PO1DE 12321-01 (to H. R.), a grant
from The Pittsburgh Foundation (to H. R.), American Cancer Association
Grant RPG-98-288-01-CIM (to H. R.), and a grant from the Department of
Defense (to H. R.). 
2 To whom requests for reprints should be
addressed, at University of Pittsburgh Cancer Institute, W952
Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15213.
Phone: (412) 624-0289; Fax: (412) 624-7737; E-mail: rabinow+{at}pitt.edu
3 The abbreviations used are: AICD,
activation-induced cell death; Ab, antibody; mAb, monoclonal antibody;
PBL, peripheral blood lymphocyte; TAL, tumor-associated lymphocyte;
PMA, phorbol 12-myristate 13-acetate; PVDF, polyvinylidene difluoride;
OvCA, ovarian carcinoma.
Received 10/18/99. Accepted 2/16/00.
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1) death signal. J. Biol. Chem., 273: 4345-4349, 1998.
B. J. Biol. Chem., 274: 987-992, 1999.
chain. Cancer Res., 59: 1422-1427, 1999.This article has been cited by other articles:
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