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J Biol Chem, Vol. 274, Issue 15, 9962-9968, April 9, 1999
B Transcription Factor and c-Jun
N-terminal Kinase*
,,,,,, and¶
From the We have previously reported on the death effector
domain containing E8 gene product from equine
herpesvirus-2, designated FLICE inhibitory protein
(v-FLIP), and on its cellular homologue, c-FLIP, which inhibit the
activation of caspase-8 by death receptors. Here we report on the
structure and function of the E10 gene product of equine herpesvirus-2,
designated v-CARMEN, and on its cellular homologue, c-CARMEN, which
contain a caspase-recruiting domain (CARD) motif. c-CARMEN is highly
homologous to the viral protein in its N-terminal CARD motif but
differs in its C-terminal extension. v-CARMEN and c-CARMEN interact
directly in a CARD-dependent manner yet reveal different
binding specificities toward members of the tumor necrosis factor
receptor-associated factor (TRAF) family. v-CARMEN binds to TRAF6 and
weakly to TRAF3 and, upon overexpression, potently induces the c-Jun
N-terminal kinase (JNK), p38, and nuclear factor (NF)- The ability to undergo apoptosis is an inherent property of all
somatic cells. Apoptosis can be triggered by a variety of stimuli, such
as ligands of the tumor necrosis factor family, cytotoxic drugs, growth
factor starvation, and infectious agents such as viruses. Viruses are
faced with the need to productively replicate within a receptive
intracellular environment and thus have evolved strategies to
counteract the death signaling machinery (1, 2). Documented viral
apoptosis inhibitors include proteins that have a bcl-2-like function
or those that directly interfere with caspase activity. We and others
(3-5) have recently characterized a family of viral gene products,
collectively called v-FLIPs,1
that are produced by many Recently, the existence of a third related protein-protein interaction
domain, designated the caspase-recruiting domain (CARD), was revealed
(7). The prototype CARD is found in Apaf-1, a mitochondrial protein
related to the Caenorhabditis elegans protein CED-4 (8).
Activation of Apaf-1 by cytochrome c leads to the recruitment of the CARD-containing caspase-9 and to subsequent apoptosis (9). Additional CARD-dependent protein
interactions have been identified. The CARD-containing adaptor molecule
RAIDD recruits caspase-2 to the tumor necrosis factor receptor 1 (10), whereas the CARD-containing kinase CARDIAK/RIP-2 may mediate both the
recruitment and activation of caspase-1 by CD40 and the activation of
JNK and NF- We have previously reported on a gene product from equine herpesvirus
type 2 (EHV-2), designated E10, that comprises a CARD motif (7).
Because the E8 gene, which is found in the same region of
the EHV-2 genome, encodes the potent apoptosis inhibitor v-FLIP, we
undertook a study to investigate whether E10 may also be implicated in
the modulation of apoptosis.
Cloning of Viral, Human, and Mouse CARMEN cDNA--
The
complete ORF of viral E10 was amplified from viral EHV-2 DNA
(a kind gift of A. J. Davison, Glasgow, United Kingdom). The
amplified E10 ORF is longer than the originally published E10 ORF (after resequencing of the respective region of the
viral genome, we had to correct the originally reported E10
sequence (15) that predicted a shorter ORF). EST clones encoding a
related human and mouse CARD-containing protein were identified in the dbEST data base at the National Center for Biotechnology Information (EST clones 703916 and 574273) by performing a data base search using a
generalized profile method (16) based on the sequence homology among
other CARD-containing proteins (7).
Northern Blot Analysis--
Northern blot analysis was performed
by probing a murine multiple tissue Northern blot
(CLONTECH), according to the manufacturer's instructions, with a 32P-labeled antisense RNA probe
encompassing the complete ORF of murine CARMEN cDNA.
Expression Vectors--
cDNAs encoding CARMEN proteins or
fragments thereof were amplified by standard polymerase chain reaction
methods using Pwo polymerase (Boehringer Mannheim) and specific primers
containing suitable restriction sites on the 5'- and 3'-end on cDNA
templates from the following sources. Full-length human
CARMEN (amino acids 2-233), a deletion construct
encompassing the N-terminal CARD (amino acids 2-89, h-CARMEN-NT) or
lacking the CARD (amino acids 85-233, h-CARMEN-CT), was amplified on
EST clone 703916; full-length murine CARMEN (amino acids
2-233) was amplified on EST clone 574273; and full-length
v-CARMEN was amplified on EHV-2 DNA. An internal BamHI site at nucleotide 412 of v-CARMEN was used
for the construction of a C-terminally truncated v-CARMEN
encompassing the N-terminal CARD (amino acids 1-139, v-CARMEN-NT). A
deletion construct lacking the CARD (amino acids 109-311, v-CARMEN-CT)
was amplified on cloned full-length v-CARMEN. Amplified
products were cloned into pCRblunt (Invitrogen) and sequenced.
Subcloning into expression vectors derived from pCR-3 (Invitrogen)
yielded expression constructs with an N-terminal FLAG, hemagglutinin
(HA), or vesicular stomatitis virus (VSV) tag. For the yeast two-hybrid
interaction assay, sequenced constructs of v-CARMEN,
h-CARMEN, and their above described N-terminally truncated
versions were subcloned into pGBT-9 or pGAD10
(CLONTECH), yielding GAL4-DNA-binding proteins or
GAL4-activation-domain fusion proteins, respectively.
The following expression plasmids were obtained from the indicated
sources: NF- Transfection, Immunoprecipitation, Mitogen-activated Protein
Kinase, and NF- Two-hybrid Interaction Assay--
Protein-protein interactions
were analyzed by cotransforming a plasmid encoding a
v-CARMEN-GAL4-DNA-binding (GAL4-DB) fusion protein with plasmids
encoding various v/h-CARMEN-GAL4-activation-domain fusion protein
constructs (2.5 µg of each plasmid) into the Saccharomyces cerevisiae strain Y190 and subsequent filter lift assays for
colony color development according to the manufacturer's instructions (CLONTECH, yeast protocols handbook). Controls were
performed by using the respective vectors without insert.
To study the possible physiological role of the viral E10 gene
product, designated v-CARMEN (for CARD-containing
molecule enhancing NF- Next we tested whether v-CARMEN was able to stimulate activation of JNK
by coexpressing v-CARMEN with JNK in 293T cells. Activation of JNK
leads to its phosphorylation by upstream kinases, which can be detected
by antibodies specifically recognizing the phosphorylated but not the
unphosphorylated form of JNK. Compared with the vector control,
v-CARMEN potently induced JNK activation (Fig.
1A). Activation of the kinase
appeared to be dependent on the CARD motif, because overexpression of
the C-terminal part of v-CARMEN (lacking the CARD) did not result in
increased JNK activation, whereas a C-terminally truncated construct
encompassing the CARD (v-CARMEN-NT) was able to induce some JNK
activation. v-CARMEN-induced JNK activation was not inhibited by
dominant negative versions of TRAF2 or apoptosis signal-regulating
kinase 1 (ASK 1) (data not shown), indicating that v-CARMEN acts
downstream or independently of these mediators of tumor necrosis
factor-induced JNK activation (19). v-CARMEN also activated the stress
kinase p38 in a CARD-dependent manner (Fig. 1B).
In contrast, no activation of the MAP kinase ERK-1 was seen by the
overexpression of the viral protein (Fig. 1C).
The ability of v-CARMEN to activate an NF- Activation of NF- CARDs are known to serve as protein-protein interaction motifs (9, 10).
It was therefore likely that v-CARMEN exerted its JNK and NF- Institute of Biochemistry,
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B
transcriptional pathways. c-CARMEN or truncated versions thereof do not
appear to induce JNK and NF-B activation by themselves, nor do they
affect the JNK and NF-B activating potential of v-CARMEN. Thus, in
contrast to the cellular homologue, v-CARMEN may have additional
properties in its unique C terminus that allow for an autonomous
activator effect on NF-B and JNK. Through activation of NF-B,
v-CARMEN may regulate the expression of the cellular and viral genes
important for viral replication.
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-herpesviruses and by the molluscum contagiosum virus. The striking structural feature of the viral FLIPs
is the presence of a tandem repeat of a so-called death effector domain
(DED). The DED has structural homology to a motif called the death
domain, which is present in the cytoplasmic part of death receptors
such as Fas. The death domain of Fas interacts with the C-terminal
death domain of FADD, which in turn induces the binding of the
N-terminal DED of FADD to the DED-containing prodomain of caspase-8.
The recruitment and activation of caspase-8 by Fas result in the
processing of downstream caspases and the induction of apoptosis (6).
The DED-containing v-FLIPs interfere with the FADD-caspase-8
interaction and hence block apoptosis (3). Thus, the DED and the
death domain are important protein-protein interaction modules
implicated in cell death signaling.
B (11, 12). The respective recruiting/regulatory proteins
of other CARD-containing caspases (caspase-4, -5, -11, and -12), are
currently not known. Other CARD-containing proteins, i.e.
ARC (13), c-IAP1, and c-IAP2 (14), are involved in the regulation of apoptosis.
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BLuc (V. Jongeneel, Lausanne, Switzerland); FLAG-tagged
JNK (C. Widmann, Denver, CO); HA-tagged p38 (J. S. Gutkind, NIDR,
Bethesda, MD); ERK-1 (J. Pouysségur, Nice, France); dominant
negative (DN) GFP-TRAF2 (amino acids 266-501) (H. Wajant, Stuttgart, Germany); DN TRAF6, wild type, and DN IKK2 (S. Whiteside and
A. Israël, Paris, France); v-19 ras (E. Reichmann, Lausanne, Switzerland).
B Activation Assays--
These techniques were
performed essentially as described before (11, 17, 18). Activation of
p38 and ERK-1 was detected using phosphospecific antibodies that detect
the active form of the respective mitogen-activated protein kinases
(New England Biolabs).
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B, see
below), we assessed effector functions that have been described for
other CARD-containing proteins such as modulation of apoptosis and
activation of JNK and NF-B. Expression constructs encoding v-CARMEN
and a number of proapoptotic proteins were transfected into 293T cells,
and the presence of apoptotic cells was subsequently analyzed. Although
overexpression of v-CARMEN was very weakly cytotoxic, expression of
Fas, DR-3/TRAMP, TRAIL-R1, or TRAIL-R2 lead to extensive cell death,
which was neither inhibited nor enhanced by the coexpression of
v-CARMEN (data not shown). Stable transfection of Jurkat cells with
v-CARMEN or a construct lacking the CARD motif did not alter the
cells' susceptibility to Fas or staurosporine-induced apoptosis
(data not shown).
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Fig. 1.
Activation of JNK, p38, and
NF- B by v-CARMEN. Panels A and
B, 293T cells (2 × 105) were transfected
with 3 µg of a JNK or a p38 expression construct in combination with
plasmids encoding full-length v-CARMEN, its C-terminal portion lacking
the CARD (v-CARMEN-CT, amino acids 109-311), or the N-terminal CARD
alone (v-CARMEN-NT, amino acids 1-139). 24 h after transfection,
JNK or p38 activation was determined by Western blotting using
antibodies specifically detecting the active phosphorylated kinases.
The expression levels of the various FLAG-tagged v-CARMEN constructs,
FLAG-tagged JNK, and HA-tagged p38 were determined using anti-FLAG and
anti-HA antibodies, respectively. Panel C, analogous
experiments were done with ERK-1 by using an HA-tagged ERK-1 construct.
Overexpression of active Ras (v-19) was used as a positive control for
ERK-1 activation. Panels D and E, 293T cells were
cotransfected with 1 µg of an NF-B luciferase reporter plasmid
(pNF-BLuc), 0.5 µg of 
-galactosidase expression vector (pCMV
-gal), the indicated v-CARMEN constructs, and an empty vector to
give 5.5 µg of total DNA. Luciferase activities were determined
24 h after transfection and normalized on the basis of
-galactosidase values as described previously (17). Values shown are
averages for representative experiments in which each transfection was
carried out in duplicate. Panel F, inhibition of
v-CARMEN-induced NF-B activation by DN IKK2. 293T cells were
cotransfected with 1 µg of pNF-BLuc, 0.5 µg of pCMV -gal, 1.5 µg of v-CARMEN expression vector and/or the indicated IKK2 expression
vectors, and an empty vector to give 6 µg of total DNA. Samples were
analyzed for luciferase activity as in panel D.
B luciferase reporter
plasmid was next investigated. Expression of v-CARMEN in 293T cells
resulted in a dose-dependent activation of the reporter gene, reaching an approximately 10-fold increase in luciferase activity
as compared with the vector control (Fig. 1, D and
E). Induction of NF-B activity by v-CARMEN was almost as
strong as that seen with the adaptor protein MyD88 (Fig.
1D), which links interleukin-1R and toll receptors to
NF-B signaling pathways (17, 20-22). Similar to the requirement for
JNK activation, the initiation of NF-B signals by v-CARMEN was
dependent on the presence of the CARD motif.
B is dependent on the formation of a multiprotein
complex, which is comprised of TRAFs, the NF-B-inducing kinase
(NIK), IKK1, IKK2, the NF-B essential modulator (NEMO), IB
,
IB, and the IKK-complex-associated protein (ICAP) (23). Dominant
negative versions of some of these proteins can block NF-B-activating signals triggered by upstream receptors. Indeed, DN
IKK2, but not DN TRAF2 or DN TRAF6, inhibited v-CARMEN-mediated NF-B
activation, indicating that the overexpression of the viral protein
initiated a signal cascade downstream of TRAFs but upstream of IKK2 in
the NF-B signaling complex (Fig. 1F and data not shown).
B
activating effects through association with another CARD-containing
protein. In this regard, by screening public data bases with a CARD
sequence profile (7, 16) we discovered the presence of a novel CARD
protein with high homology to the CARD motif of v-CARMEN, which we call
c-CARMEN (Fig. 2A). v-CARMEN
corresponds to a 311-amino acid protein with an N-terminal CARD motif
followed by a C-terminal, glycine-rich extension of approximately 200 amino acid residues. After the resequencing of this region of the viral
genome, we had to correct the original E10 sequence
deposited in the data base, which predicted a shorter ORF corresponding
to only 210 amino acids (15). The predicted protein size of the
corrected 311-amino acid v-CARMEN (34 kDa) agrees well with the 36-kDa
protein detectable after expression in 293T cells (see Fig. 1).
c-CARMEN (the cellular homologue of v-CARMEN) consists of an N-terminal
CARD followed by a C-terminal extension of approximately 130 amino
acids with a predicted molecular size of 26 kDa. The CARD of v-CARMEN
shows 47 and 46% sequence identity with mouse and human c-CARMEN,
respectively, but only approximately 20-25% sequence identity with
other CARD-containing proteins (Fig. 2B). Little sequence
identity is found in the C-terminal extensions of the viral and the
cellular CARMEN, the latter of which lacks the glycine-rich regions.
Neither of the C-terminal extensions has significant homology to
protein sequences currently found in public data bases.
View larger version (75K):
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Fig. 2.
Panel A, structure and predicted amino
acid sequence of viral, human, and mouse CARMEN. CARMENs contain a
highly homologous CARD motif followed by an unrelated region of
approximately 130-200 amino acids. Panel B, the CARD motif
of CARMENs is aligned to the CARDs of RAIDD, caspase-1, -2, -4, -5, -9, -11, and -12, c-IAP1, c-IAP2, Apaf-1, ARC, CED-3, and CED-4
(7). For each block of aligned sequences, black boxes
indicate >50% amino acid sequence identity and gray
shading indicates >50% sequence similarity through conservative
amino acid substitutions.
Northern blot analysis revealed that murine CARMEN
(m-CARMEN) was expressed in all mouse tissues as a single
transcript of approximately 2.4 kilobases (Fig.
3), suggesting that the protein is of
functional relevance in many cell types.
|
The potential interaction of c-CARMEN with other CARD-containing
proteins was examined by coexpression of the different FLAG-tagged CARD
proteins with HA-tagged human CARMEN (h-CARMEN) in 293T cells followed
by co-immunoprecipitation studies. Using this technique, an interaction
was noted only between v-CARMEN and h-CARMEN, whereas caspase-1, -2, -4, and -9, RAIDD, or CARDIAK did not interact with h-CARMEN (Fig.
4A). We also did not detect an
interaction with the CARD motif of Apaf-1, cIAP-1, or cIAP-2 (data not
shown). A truncated version of v-CARMEN lacking the CARD motif
(v-CARMEN-CT) did not interact with either human or mouse c-CARMEN,
indicating that binding was mediated through the CARD motif (Fig.
4B). An analysis of this interaction in the yeast two-hybrid
system confirmed a direct and CARD-dependent interaction of
v-CARMEN with h-CARMEN (Table I).
Interestingly, c-CARMEN of human and mouse origin also formed
CARD-dependent homodimers in 293T cells (Fig.
4B). We were unable to detect homodimers of v-CARMEN in 293T
cells, although a homodimeric interaction of v-CARMEN was detected in the yeast two-hybrid system (Table I). Interestingly, the interaction between v-CARMEN and its cellular homologue lead to an altered electrophoretic mobility of the c-CARMENs (Fig. 4B). Human
and murine CARMEN migrated slightly slower by SDS-polyacrylamide gel electrophoresis in the presence of v-CARMEN, suggesting that the cellular homologue may undergo a post-translational modification such
as phosphorylation upon interaction with the viral homologue. Whether
this is because of the JNK/IKK kinase-inducing activity of v-CARMEN
(potentially recruiting kinases to the complex of viral/cellular
CARMEN) remains to be seen.
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Because v-CARMEN was a potent activator of the JNK and NF-B
signaling pathways, we anticipated a similar function for the cellular
homologue. However, overexpression of either full-length c-CARMEN or of
domains thereof was not capable of activating these signaling pathways
in 293T cells (Fig. 5, A and
B, and data not shown). c-CARMEN and its N- or C-terminal
deletion constructs also did not inhibit NF-B or JNK signals induced
by v-CARMEN or by triggering the receptors for tumor necrosis factor or
interleukin-1 (data not shown), indicating that the cellular homologue
is not essential to these pathways.
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We considered that the difference in signaling by v-CARMEN
versus c-CARMEN might be because of their ability to
interact with specific TRAF molecules, because members of the TRAF
family of adaptor proteins have been shown to be implicated in the
activation of transcription through JNK- and
NF-B-dependent pathways (reviewed in Ref. 24). We
therefore tested the ability of c-CARMEN and v-CARMEN to bind to
specific members of the TRAF family by coexpression of the respective
proteins in 293T cells. The result of the co-precipitation study shown
in Fig. 5 revealed a clear difference in the TRAF binding specificity
of c-CARMEN and v-CARMEN; human CARMEN bound specifically to TRAF1 and
TRAF5, whereas the v-CARMEN had a clear binding preference for TRAF6
and, to a smaller degree, for TRAF3 (Fig. 5, C and
D).
EHV-2 is a slow growing, cytopathogenic -herpesvirus, which appears
to be ubiquitous in the equine population (15). However, its precise
role as a pathogen remains uncertain. In infected horses, the virus can
induce chronic pharyngitis associated with lymphoid proliferation (25).
The virus is persistent in peripheral blood lymphocytes, suggesting
that it copes well with apoptotic processes occurring in the host. We
have previously identified its DED-containing E8 gene product (v-FLIP)
as a potent inhibitor of the death receptor-signaling pathways (3).
Moreover, EHV-2 also has a predicted bcl-2 gene homologue in
its genome (2). Although its biological activity has not yet been
verified, it is predicted that the gene product of this viral
bcl-2 homologue inhibits apoptotic signals originating from
the Apaf-1/caspase-9 pathway. In this report we have characterized the
EHV-2 protein E10, designated v-CARMEN, as a potent inducer of the
NF-B and JNK pathways. Cellular gene products induced by the NF-B
transcription factor are known to inhibit apoptosis by a variety of
means (26, 27). Thus, in addition to the E8-FLIP and the bcl-2
homologue, the E10/CARMEN gene product of EHV-2 may provide the virus
with a third anti-apoptotic mechanism. In addition, NF-B induction by v-CARMEN may serve to control the expression of viral genes with an
NF-B promotor in the course of viral replication (28).
We have identified a cellular homologue and binding partner of v-CARMEN
as c-CARMEN, which is highly homologous to the viral protein in its
N-terminal CARD motif. v-CARMEN and c-CARMEN interact directly in a
CARD-dependent manner yet reveal different binding specificities toward members of the TRAF family. When overexpressed in
293T cells, v-CARMEN is a potent inducer of the JNK, p38, and NF-B
transcriptional pathways, whereas c-CARMEN or truncated versions
thereof do not appear to activate these pathways by themselves nor do
they affect the JNK and NF-B activating potential of v-CARMEN. c-CARMEN may therefore act upstream of v-CARMEN in an as yet
unidentified NF-B/JNK-activating pathway. Alternatively, c-CARMEN
may interfere with NF-B/JNK activation only upon a
post-translational regulatory event, such as phosphorylation, or upon
interaction with a third component lacking in our cellular system.
Finally, we cannot exclude the possibility that c-CARMEN mediates yet
another NF-B/JNK-unrelated function of v-CARMEN and that the
observed CARD-dependent NF-B/JNK activation through
v-CARMEN is mediated by an as yet unidentified CARD-containing protein.
Interestingly, mutation of a novel gene (Bcl10) identical to
c-CARMEN was recently reported to be associated with B-cell
lymphomas of mucosa-associated lymphoid tissue and other tumor types
(29). Further study of the molecular mechanism of v-CARMEN function may
help in the understanding of the physiological role of its cellular
homologue and its potential implication in tumor development.
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ACKNOWLEDGEMENTS |
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We thank Dr. Ralph Budd for careful reading of the manuscript and Jean-Luc Bodmer for help with the submission of sequences to GenBankTM.
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FOOTNOTES |
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* This work was supported by grants from the Swiss National Science Foundation (to J. T.) and the European Molecular Biology Organization (to M. T.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EMBL Data Bank with accession number(s) AF100338 for the human CARMEN, AF100339 for the mouse CARMEN, and AF100340 for the viral CARMEN (EHV-2 ORF E10).
¶ To whom correspondence should be addressed. Tel.: 41 21 692 5738; Fax: 41 21 692 5705; E-mail: jurg.tschopp{at}ib.unil.ch.
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ABBREVIATIONS |
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The abbreviations used are:
FLIP, FLICE
inhibitory protein;
CARD, caspase-recruiting domain;
CARMEN, CARD-containing molecule enhancing NF-B;
DED, death effector domain;
EHV-2, equine herpesvirus-2;
ERK, extracellular signal-regulated
kinase;
IKK, IB kinase;
JNK, c-Jun N-terminal kinase;
NF, nuclear
factor;
TRAF, tumor necrosis factor receptor-associated factor;
ORF, open reading frame;
DN, dominant negative;
HA, hemagglutinin;
EST, expressed sequence tag;
VSV, vesicular stomatitis virus.
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ABSTRACT
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H. Liu, H. Ye, A. Dogan, R. Ranaldi, R. A. Hamoudi, I. Bearzi, P. G. Isaacson, and M.-Q. Du T(11;18)(q21;q21) is associated with advanced mucosa-associated lymphoid tissue lymphoma that expresses nuclear BCL10 Blood, August 15, 2001; 98(4): 1182 - 1187. [Abstract] [Full Text] [PDF]
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P. Desreumaux, L. Dubuquoy, S. Nutten, M. Peuchmaur, W. Englaro, K. Schoonjans, B. Derijard, B. Desvergne, W. Wahli, P. Chambon, et al. Attenuation of Colon Inflammation through Activators of the Retinoid X Receptor (RXR)/Peroxisome Proliferator-activated Receptor {{gamma}} (PPAR{{gamma}}) Heterodimer: A Basis for New Therapeutic Strategies J. Exp. Med., April 2, 2001; 193(7): 827 - 838. [Abstract] [Full Text] [PDF]
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V. Rochat-Steiner, K. Becker, O. Micheau, P. Schneider, K. Burns, and J. Tschopp FIST/HIPK3: a Fas/FADD-interacting Serine/Threonine Kinase that Induces FADD Phosphorylation and Inhibits Fas-mediated Jun NH2-terminal Kinase Activation J. Exp. Med., October 16, 2000; 192(8): 1165 - 1174. [Abstract] [Full Text] [PDF]
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M.-Q. Du, H. Peng, H. Liu, R. A. Hamoudi, T. C. Diss, T. G. Willis, H. Ye, A. Dogan, A. C. Wotherspoon, M. J. S. Dyer, et al. BCL10 gene mutation in lymphoma Blood, June 15, 2000; 95(12): 3885 - 3890. [Abstract] [Full Text] [PDF]
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T. Yoneda, K. Imaizumi, M. Maeda, D. Yui, T. Manabe, T. Katayama, N. Sato, F. Gomi, T. Morihara, Y. Mori, et al. Regulatory Mechanisms of TRAF2-mediated Signal Transduction by Bcl10, a MALT Lymphoma-associated Protein J. Biol. Chem., April 6, 2000; 275(15): 11114 - 11120. [Abstract] [Full Text] [PDF]
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C. Guiet and P. Vito Caspase Recruitment Domain (CARD)-dependent Cytoplasmic Filaments Mediate bcl10-induced NF-{kappa}B Activation J. Cell Biol., March 20, 2000; 148(6): 1131 - 1140. [Abstract] [Full Text] [PDF]
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E. Macintyre, D. Willerford, and S. W. Morris Non-Hodgkin's Lymphoma: Molecular Features of B Cell Lymphoma Hematology, January 1, 2000; 2000(1): 180 - 204. [Abstract] [Full Text] [PDF]
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G. Camarda, G. Spinetti, G. Bernardini, C. Mair, N. Davis-Poynter, M. C. Capogrossi, and M. Napolitano The Equine Herpesvirus 2 E1 Open Reading Frame Encodes a Functional Chemokine Receptor J. Virol., December 1, 1999; 73(12): 9843 - 9848. [Abstract] [Full Text]
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) indicates no color development even after 6 h.
Controls were performed using the respective expression vectors without
insert.
