| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
*
Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany; and
Institute of Pathology, Universitätsklinikum Benjamin Franklin, Berlin, Germany
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
B activation, selectively desensitized and enhanced,
respectively, TNFR60-induced cell death in HeLa cells. However, upon
costimulation of TNFR80, which mediates activation of nuclear
factor-B and the c-Jun amino-terminal kinase via TRAF2, TNF-induced
cell death is drastically enhanced in parental and TRAF2-transfected,
but not in TRAF2 (87–501)-transfected cells. These data point to a
critical role of TRAF2 in the apoptotic TNFR cross talk, whereby the
TNFR80-dependent enhancement of TNFR60-induced cell death is due to
TNFR80-mediated negative regulation of TRAF2 function(s). An
interference with TRAF2 function was confirmed independently by
analysis of c-Jun amino-terminal kinase activation via TNFR60 upon
prestimulation of TNFR80. We propose that the apoptotic TNFR cross talk
is based on TNFR80-mediated abrogation of antiapoptotic TRAF2-dependent
signaling pathways initiated by TNFR60, but not Apo1/Fas or the
apoptotic TNF-related apoptosis-inducing ligand
receptors. |
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Until recently, the molecular mechanisms of intracellular signal
initiation by binding of TNF and TNF-related cytokines to their cognate
receptors remained undefined. In fact, none of the TNFR superfamily
members possesses sequences implying any known catalytic activity.
However, during the last 4 yr, a rapidly growing number of proteins has
been identified that directly or indirectly associate with the
cytoplasmic domains of the TNFR superfamily members. Most of these
associated factors belong to two groups of signal-transduction
molecules, the so-called death domain proteins and the TNFR-associated
factor (TRAF)4 family. Both
groups are defined by distinct sequence motifs that are involved in
further protein/protein interactions (reviewed in 4 . The death
domain has been defined originally as a part of the intracellular
regions of TNFR60 and Apo1/Fas, and is responsible for the generation
of the apoptotic signal by these receptors (5, 6). TRADD
(TNFR1-associated death domain protein; 7), FADD/MORT1 (Fas-associated
protein with death domain/mediator of receptor-induced toxicity;
8–10), and RIP (receptor-interacting protein; 11) are death
domain-containing proteins that have been identified by yeast
two-hybrid screens using the intracellular domain of TNFR60 or Apo1/Fas
as baits. Overexpression of these molecules leads to activation of
NF-B and/or induction of apoptosis (7, 8, 9, 10, 11). FADD/MORT1 is part of
the inducible Apo1/Fas death-inducing signaling complex (12), and is
believed to represent the physical link to proapoptotic proteases of
the caspase family (13, 14).
There are several lines of evidence that two TNFR60-signaling cascades
bifurcate at TRADD, one leading to the activation of NF-B and the
other coupling via FADD/MORT1 to the apoptotic caspase cascade (15, 16). The serine threonine kinase RIP is recruited to the
TNFR60-signaling complex in a ligand-dependent manner, and might also
be involved in the activation of NF-B as well as induction of cell
death (17), although the position of RIP within the signaling cascades
is yet rather unclear (18).
The TRAF protein family currently comprises six members that interact
with molecules of the TNFR superfamily or with the IL-1R. Rothe et al.
(19) have isolated the first two members of the TRAF protein family
based on their interaction with the cytoplasmic domain of TNFR80.
TRAF3, also designated as CD40bp, CAP-1, LAP1, or CRAF1, was identified
by its association with CD40 (20, 21, 22, 23) and TRAF5 by binding to the
LT-ßR (24). TRAF4, also termed CART1, was isolated by differential
screening of libraries of malignant and nonmalignant breast tissues
(25) and TRAF6 by homology screening of an expressed sequence tag
library (26). Overexpression studies and analysis of various deletion
mutants of members of the TNFR superfamily suggested that TRAF2, 5, and
6 are critically involved in the activation of NF-B by CD40 (27, 28), CD30 (29), LT-ßR (24), TNFR80 (27), and TNFR60 (15), as well as
the membrane receptor for IL-1 (26). The C-terminal TRAF domain of TRAF
proteins comprises about 230 amino acid residues, and can be divided in
the N- and C-TRAF domain. For most of the TRAF molecules, the
capability to interact with several members of the TNFR superfamily and
other TRAFs has been established (reviewed in 4 . Moreover, some
of the TRAF molecules bind to cytoplasmic proteins that are capable or
suspected to modulate TNF-initiated apoptosis or TNF-dependent
activation of NF-B. These include the inhibitors of apoptosis (IAP;
30), the antiapoptotic molecule A20 (31), and the molecule TANK (TNF
activator of NF-B)/I-TRAF (TRAF-interacting protein) (32, 33), as
well as the TRAF-interacting protein TRIP (34), respectively. In
particular, Hsu et al. (15) have shown that interaction of the death
domain protein TRADD with TRAF2 is critically involved in
TNFR60-dependent activation of NF-B.
The common usage of the above-described signal-transduction molecules by various members of the TNFR superfamily opens up the possibility of a complex pattern of receptor cross talk. In fact, we and others have recently described synergistic action of TNFR80, CD40, and TNFR60 in the induction of cell death (35, 36, 37). In this study, we demonstrate that TRAF2 is involved in the enhancement of TNFR60-mediated cell death by TNFR80. This apoptotic cross talk occurs upstream of FADD/MORT1 in the TNFR60-signaling pathway or at a pathway selectively used by TNFR60 because no interference with the apoptotic signaling induced by the cytokines Apo1/Fas and TRAIL/Apo2 ligand or with ceramide- and UV-induced cell death was observed.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The TNFR80-specific agonistic mAb MR2-1 was kindly provided by W. Buurman (University of Limburg, Maasstricht, The Netherlands). FITC-labeled goat anti-mouse IgG plus IgM Ab was obtained from Dianova (Hamburg, Germany). All other reagents were obtained from Sigma (Deisenhofen, Germany), if not otherwise stated. A 1:1 mixture of purified recombinant Flag-tagged human TRAIL (10 µg/ml) and anti-Flag M2 Ab (20 µg/ml; Kodak International Biotechnologies, New Haven, CT) was incubated at room temperature for 10 min and diluted to the final concentrations indicated in the figure legends.
Cells
HeLa cells and transfectants derived thereof were grown at 37°C in a humidified 5% CO2 incubator in Click RPMI 1640 medium supplemented with 5% heat-inactivated FCS, 2 mM L-glutamine, 50 U/ml penicillin, and 50 µg/ml streptomycin. Additionally, transfectants were permanently cultured in the presence of the appropriate selection drug.
DNA transfection
Cells were transfected by a standard electroporation procedure.
In brief, 5 x 106 cells were incubated in HEBS buffer
(135 mM NaCl, 5 mM KCl, 0.75 mM Na2HPO4, 5 mM
dextrose, and 20 mM HEPES, pH 7.05) with 10 to 20 µg of vector DNA
and, when necessary, 1 µg of a selection plasmid carrying the
Escherichia coli neomycin resistance gene (pMAMneo;
Clontech, Palo Alto, CA) or the Zeocin resistance gene (pZeoSV;
Invitrogen, San Diego, CA). Electroporation was performed by a prepulse
of 320 V, 3 µF capacitance, and 800 
; incubation for 5 min on ice;
and a final pulse of 220 V, 960 µF, and 400 (Gene Pulsar;
Bio-Rad, München, Germany). Transfected cells were selected in
culture medium containing 600 µg/ml G418 (Life Technologies,
Eggenheim, Germany), 500 µg/ml Zeocin (Invitrogen, San Diego, CA),
200 µg/ml hygromycin B (Boehringer Mannheim, Mannheim, Germany), or a
combination thereof. After 2 to 3 wk of selection, individual
drug-resistant colonies were isolated. Transfectants of receptor
constructs were pooled and enriched for high expressors by cell sorting
using a FACStarPlus (Becton Dickinson, San Jose, CA).
Transfectants overexpressing intracellular proteins were individually
expanded and characterized.
Cytotoxicity assay
HeLa cells and transfectants derived thereof were plated at a density of 1.5 x 104 cells/well in triplicates in 96-well microtiter plates in 100 µl of Click RPMI 1640 overnight at 37°C. On the next day, the reagents of interest were added in the presence of 2.5 µg/ml cycloheximide. The plates were incubated for additional 12- to 24-h culture, and cell viability was determined by crystal violet staining. Briefly, supernatants were discarded and the cells were washed once with PBS, followed by crystal violet staining (20% methanol, 0.5% crystal violet) for 15 min. The wells were washed with H2O and air dried. Residual dye was diluted with methanol for 15 min, and OD at 550 nm was measured with a R5000 ELISA plate reader (Dynatech, Guernsey, U.K.).
IL-6 assay
Cells were plated at a density of 1.5 x 104 cells/well in triplicates in 96-well microtiter plates in 100 µl of Click RPMI 1640 overnight at 37°C. On the next day, the cells were treated with the reagents of interest for additional 12 to 24 h. Finally, supernatants were removed and cleared by centrifugation at 15,000 rpm for 10 min, and IL-6 concentration was determined using a commercially available ELISA kit, according to the manufacturer’s recommendations (PharMingen, Hamburg, Germany).
Transfections, luciferase assays, and protein kinase assay
HeLa cells (0.8 x 105) were seeded in 24-well
tissue culture plates. On the following day, the cells were transfected
using the SuperFect reagent (Qiagen, Hilden, Germany) with a 3x
NF-B-luciferase reporter plasmid and a SV40 promoter-driven
ß-galactosidase expression plasmid to normalize the transfection
efficiency. After additional 24 h, the cells were harvested in
PBS, lysed in luciferase lysis buffer (Promega, Mannheim, Germany), and
assayed for luciferase and ß-galactosidase activities using a LUMAT
9501 Luminometer (Berthold, Bad Wildbad, Germany). JNK activity was
measured by immunocomplex kinase assay with
glutathione-S-transferase c-jun (1–79) as
substrate, as described elsewhere (38).
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
We have demonstrated recently a synergistic enhancement of
TNF/TNFR60 signaling by costimulation of TNFR80 by the membrane form of
TNF- or TNFR80-specific agonistic Abs (35, 37). To obtain insight into
the molecular mechanisms of this TNFR cooperation, we asked whether
similar cooperative mechanisms exist between TNFR80 and other
death-inducing members of the TNFR family. Whereas costimulation of
TNFR80 in HeLa cells transfected with TNFR80 (HeLa-TNFR80) resulted in
a strong enhancement of TNF-induced cell death (Fig. 1
A; 37 , no
enhancement of the cytotoxic effects induced by TRAIL/Apo2 ligand
(TRAIL/Apo2L), a member of the TNF ligand family (39, 40), or
stimulation of the Apo1/Fas Ag could be observed (Fig. 1, B
and C). This is remarkable because it has been shown that
TNF, TRAIL/Apo2L, and stimulation of Apo1/Fas can induce cell death
using similar pathways, including the molecule FADD and different
members of the caspase family (41, 42). Accordingly, in our cell
systems, cytotoxicity by the aforementioned stimuli could be inhibited
completely by the caspase inhibitor peptide z-VAD-fmk (Fig. 1D). Together, these data indicate that the TNFR80-dependent
enhancement of TNFR60-induced cytotoxicity modulates a signaling
pathway selectively used by TNFR60 or that the synergistic action of
TNFR80 occurs upstream of FADD/MORT1 and the apoptotic caspases engaged
by TNFR60, Apo1/Fas, and the receptors for TRAIL/Apo2L.
|
E,
ceramide-induced cell death was not enhanced by costimulation of
TNFR80. Likewise, the cytotoxic effects of daunorubicin, a drug that
has been suggested to induce apoptosis by elevating the intracellular
ceramide level (47, 48), were not modulated by TNFR80 stimulation (Fig. 1F). Moreover, neither ceramide- nor daunorubicin-induced
cell death was affected by the addition of z-VAD-fmk (Fig. 1, E and F), suggesting that ceramide acts
downstream of the caspase cascade or on a parallel pathway. TRAF2-mediated protection from TNFR60-induced cell death is antagonized in the context of TNFR80 coactivation
In a recent study, we have shown that the TRAF2 binding
domain of TNFR80 is essential for the TNFR80-mediated enhancement of
TNFR60-induced cell death (37). In fact, overexpression of wild-type
TRAF2 in HeLa-TNFR80 cells resulted in a reduced sensitivity to the
cytotoxic effects of TNF (Fig. 2A). Moreover, introduction of
a deletion mutant of TRAF2 (TRAF2 (87–501)) that is still capable of
associating with TNFR, but is deficient in the activation of
NF-B and JNK due to the lack of the RING finger domain (27),
resulted in a dramatic enhancement of TNFR60-mediated cytotoxicity
(Fig. 2A), with no change in the sensitivity toward
TRAIL/Apo2L-, UV-, ceramide-, and daunorubicin-induced cell death (data
not shown). Hence, upon stimulation of TNFR60, both apoptotic and
antiapoptotic pathways are activated simultaneously, with TRAF2 being
critically involved in the transduction of protective signals. To
evaluate the potential role of TRAF2 in the TNFR80-mediated enhancement
of TNFR60-induced apoptosis, the double transfectants HeLa-TNFR80-TRAF2
and HeLa-TNFR80-TRAF2 (87–501) were investigated under conditions of
specific coactivation of both TNFRs. Interestingly, HeLa-TNFR80-TRAF2
double transfectants, although less sensitive for TNF-induced
cytotoxicity (Fig. 2A), were still highly susceptible toward
TNFR80-mediated enhancement of TNFR60-induced apoptosis (Fig. 2B). Overexpression of TRAF2 (87–501) resulted in a
reduction of both the proliferation rate (Fig. 2C) and
TNF-induced gene induction (Fig. 2D), which is in good
accordance with a critical role of TRAF2 in TNF-induced activation of
NF-B and JNK. In the same cells, which show an increased sensitivity
against TNF, no further enhancement was noted upon costimulation of
TNFR80 (Fig. 2B). These data indicate that the TRAF2
(87–501) molecule interferes with the TRAF2-dependent induction of
antiapoptotic molecules (Fig. 2A). The TNF sensitivity of
TRAF2 (87–501) transfectants resembles the sensitivity of TNF in
wild-type cells after enhancement by costimulation of TNFR80.
Therefore, it appears that the TRAF2-dependent protective response
induced concomitantly with the apoptotic pathway is overruled in the
context of TNFR80 stimulation. It is important to note that TNF-induced
apoptosis only occurs in the presence of the protein synthesis
inhibitor cycloheximide in all of our HeLa transfectants, a fact that,
at the first view, is in conflict with NF-B-dependent induction of
antiapoptotic proteins. However, in our experiments, we used only 2.5
µg/ml cycloheximide, a concentration at which protein synthesis is
only reduced, but not prevented. We have confirmed this by
determination of IL-6 production and synthesis of a NF-B-dependent
reporter protein, which were reduced under these conditions only for
5–40% and 10%, respectively (Fig. 3).
|
|
A recent study has shown that transient cotransfection of TNFR80
and TRAF2 results in a rapid depletion of TRAF2 (49). It is tempting to
speculate that TNFR80-induced degradation/inactivation of TRAF2 and
possibly other associated proteins contributes to the apoptotic TNFR
cross talk investigated in our study. To test this hypothesis, we
analyzed the effect of TNFR80 costimulation on TNF-mediated JNK
activation since the TNF-induced JNK activation is indicative for TRAF2
action (50, 51). As shown in Figure 4,
prestimulation of TNFR80 strongly interferes with JNK activation by
TNF. TNF-induced JNK activation was reduced by approximately 50% after
prestimulation of TNFR80 for 0.5 h, and was almost completely
abrogated after 6-h prestimulation of TNFR80. In contrast, IL-1-induced
activation of JNK, which is independent of TRAF2, remained largely
unaffected upon TNFR80 prestimulation (Fig. 4).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
As shown in Figure 1, TNFR80 triggering enhances TNFR60-mediated,
but neither Apo1/Fas-mediated nor TRAIL/Apo2L-induced cell death.
FADD/MORT1 is a common component of the apoptotic pathways utilized by
TNFR60 and Apo1/Fas (15, 16, 52, 53). Hence, it is most likely that the
TNFR60-TNFR80 cross talk occurs upstream of FADD/MORT1 or on a separate
TNFR60-induced pathway, being distinct from, but coinitiated with the
FADD/MORT1-dependent apoptotic pathway. The existence of mechanisms
able to selectively modulate TNFR60- or Apo1/Fas-induced cell death at
a point at which both pathways have not merged, is also indicated by
the fact that a number of cellular systems have been described in which
TNF-sensitive cells are Apo1/Fas resistant and vice versa (54, 55, 56, 57). One
possible branching point is the cytoplasmic domain of TNFR60. It has
been shown recently that a nine-amino-acid binding motif outside the
death domain is required to couple the TNFR60 to neutral
sphingomyelinase (58, 59), whereas acidic sphingomyelinase, NF-B
activation, and induction of apoptosis have been assigned to the death
domain of the receptor (6, 60). Hsu et al. (15) have described an
additional bifurcation point downstream of the death domain of TNFR60,
namely the TNFR60-associated death domain protein TRADD. This molecule
directly associates in a ligand-dependent manner with TNFR60 (15) and
is critically involved in both NF-B and JNK activation as well as
induction of apoptosis (7, 61). In particular, amino acid residues
1–169 of TRADD are sufficient to associate with TRAF2, which is
involved in NF-B activation by TNFR60, TNFR80, and CD40 (27, 15).
The N-terminal death domain of TRADD (amino acid residues 195–312)
links to FADD/MORT1, which transduces the apoptotic signal to the
caspase cascade (13, 14).
TRAF2 is involved both in positive and negative regulation of TNF-induced apoptosis
In the HeLa-TNFR80 transfectants used in this study, no further
TNFR80-dependent enhancement of TNFR60-mediated cytotoxicity can be
detected in cells, in which a negative regulator of NF-B activation
(TRAF2 (87–501)) is expressed. These transfectants already display a
high susceptibility toward TNF in the absence of TNFR80 stimulation
(Fig. 2). Furthermore, we have shown recently that TNFR cross talk is
dependent on the TRAF2 binding site of TNFR80 (37). These data suggest
that TNFR80 exerts its proapoptotic capability by a TRAF2-dependent
interaction with a NF-B-dependent gene product. The interference of
a NF-B-dependent gene product with TNF-induced cytotoxicity is in
good accordance with recent results from several groups, demonstrating
that inhibition of NF-B activation increases the sensitivity toward
TNF-induced apoptosis (61, 62, 63, 64, 65). The fact that overexpression of TRAF2
(87–501) resulted in a dramatic enhancement of TNFR60-mediated
cytotoxicity (Fig. 2A), thus resembling the TNFR80-mediated
enhancement of TNF-induced cytotoxicity in cells overexpressing TRAF2
or only endogenous TRAF2 (Fig. 2B), can be explained by the
following hypothesis (Fig. 5).
|
B and JNK
activation, and 2) recruitment of these proteins to the TNFR60
death-signaling complex. In cells coexpressing TNFR80, however,
appropriate stimulation of this receptor results in binding and
degradation of TRAF2 and TRAF2-associated proteins, thereby reducing
the availability of protective factors at the TNFR60 death-signaling
complex. This promotes the apoptotic TNF response (Fig. 5). According
to this model, in the cellular system studied in this investigation,
exclusive stimulation of TNFR60 in HeLa-TNFR80 cells concomitantly
induces pro- and antiapoptotic pathways. As overexpression of TRAF2
(87–501) drastically enhances TNF sensitivity, but not responsiveness
to anti-Apo1 or TRAIL/Apo2L, an NF-B-dependent cell death
protective factor (NDPF) that is selective for TNF must be postulated
(Fig. 5A). In addition, the efficient activation of the
death proteases is counteracted by constitutively expressed,
cycloheximide-sensitive negative regulator(s), for example a cellular
homologue of the CrmA gene product. This is evident from the fact that
induction of cell death by TNF, anti-Apo1, and TRAIL/Apo2L in HeLa
cells can occur only when protein translation is reduced. Putative
candidates for this/these protective protein(s) are the IAP molecules
(30), TRAF-interacting protein (TRIP) (34), TRAF1 (19), cellular
FLICE-inhibitory protein/casper (66, 67), and A20 (31), because
these molecules are able to form complexes with TRAF2. In fact, Speiser
et al. (68) have shown recently in transgenic mice that overexpression
of TRAF1 inhibits Ag-induced apoptosis by CD8+ T
lymphocytes, a process in which TNF is critically involved (69, 70).
Moreover, Chu et al. (71) have shown that c-IAP2 counteracts
TNF-induced cell death. According to the model proposed in this work, a
rather balanced cellular response with intermediate sensitivity to cell
death induction will be shifted toward a vigorous apoptotic response
upon costimulation of TNFR80 due to TNFR80-dependent inactivation of
TRAF2: 1) TRAF2 will be recruited and/or degraded by this receptor,
thus reducing the production of NDPFs (e.g., TRAF1, A20, and c-IAP2);
2) NPDFs bound to TRAF2 may also be degraded; 3) still existing NDPFs
cannot be recruited sufficiently to their relevant site of action, the
apoptotic TNFR60-signaling complex, because of lack of the essential
adapter, the TRAF2 molecule.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 T.W. and M.G. contributed equally to this manuscript.
3 Address correspondence and reprint requests to Dr. H. Wajant, Institute of Cell Biology and Immunology, University of Stuttgart, Allmandring 31, 70569 Stuttgart, Germany. E-mail address:
4 Abbreviations used in this paper: TRAF, TNF receptor-associated factor; Apo2L, Apo2 ligand; FADD, Fas-associated protein with death domain; IAP, inhibitors of apoptosis; JNK, c-Jun amino-terminal kinase; MORT, mediator of receptor-induced toxicity; NDPF, nuclear factor-B-dependent cell death protective factor; RIP, receptor-interacting protein; TRADD, TNF receptor 1-associated death domain protein; TRAIL, TNF-related apoptosis-inducing ligand.
Received for publication December 31, 1997. Accepted for publication May 19, 1998.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
B activation. Cell 81:495.[Medline]
B and putative signal transducer for the lymphotoxin-ß receptor. J. Biol. Chem. 271:14661.B by TNF receptor 2 and CD40. Science 269:142.
B activation. Proc. Natl. Acad. Sci. USA 93:6721.B activation. Genes Dev. 10:963.B activation. J. Exp. Med. 185:1275.B activation and gene induction. Curr. Biol. 8:113.[Medline]
B activation, and increased sensitivity to TNF-induced cell death in TRAF2-deficient mice. Immunity 7:715.[Medline]
-B activation and regulates lymphocyte proliferation and survival. Immunity 7:703.[Medline]
B activation prevents cell death. Cell 87:565.[Medline]
B in preventing TNF-
-induced cell death. Science 274:782.B. Science 274:784.-induced apoptosis by NF-B. Science 274:787.B control. Proc. Natl. Acad. Sci. USA 94:10057.This article has been cited by other articles:
|
|
 |
|
  A. Krippner-Heidenreich, G. Walsemann, M. J. Beyrouthy, S. Speckgens, R. Kraft, H. Thole, R. V. Talanian, M. M. Hurt, and B. Luscher Caspase-Dependent Regulation and Subcellular Redistribution of the Transcriptional Modulator YY1 during Apoptosis Mol. Cell. Biol., May 1, 2005; 25(9): 3704 - 3714. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Till, P. Rosenstiel, A. Krippner-Heidenreich, S. Mascheretti-Croucher, P. J. P. Croucher, H. Schafer, P. Scheurich, D. Seegert, and S. Schreiber The Met-196 -> Arg Variation of Human Tumor Necrosis Factor Receptor 2 (TNFR2) Affects TNF-{alpha}-induced Apoptosis by Impaired NF-{kappa}B Signaling and Target Gene Expression J. Biol. Chem., February 18, 2005; 280(7): 5994 - 6004. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. F. Fischer, T. Harlander, J. Vier, and G. Hacker Protection against CD95-Induced Apoptosis by Chlamydial Infection at a Mitochondrial Step Infect. Immun., February 1, 2004; 72(2): 1107 - 1115. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. M. Toennies, J. M. Green, and R. H. Arch Expression of CD30 and Ox40 on T lymphocyte subsets is controlled by distinct regulatory mechanisms J. Leukoc. Biol., February 1, 2004; 75(2): 350 - 357. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. Mason, S. Xuan, I. Dragatsis, A. Efstratiadis, and J. E. Goldman Insulin-Like Growth Factor (IGF) Signaling through Type 1 IGF Receptor Plays an Important Role in Remyelination J. Neurosci., August 20, 2003; 23(20): 7710 - 7718. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. YANG and X. YU Regulation of apoptosis: the ubiquitous way FASEB J, May 1, 2003; 17(8): 790 - 799. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Schumann, K. Muhlen, A. K. Kiemer, A. M. Vollmar, and G. Tiegs Parenchymal, But Not Leukocyte, TNF Receptor 2 Mediates T Cell-Dependent Hepatitis in Mice J. Immunol., February 15, 2003; 170(4): 2129 - 2137. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Krippner-Heidenreich, F. Tubing, S. Bryde, S. Willi, G. Zimmermann, and P. Scheurich Control of Receptor-induced Signaling Complex Formation by the Kinetics of Ligand/Receptor Interaction J. Biol. Chem., November 8, 2002; 277(46): 44155 - 44163. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. R. Arron, Y. Pewzner-Jung, M. C. Walsh, T. Kobayashi, and Y. Choi Regulation of the Subcellular Localization of Tumor Necrosis Factor Receptor-associated Factor (TRAF)2 by TRAF1 Reveals Mechanisms of TRAF2 Signaling J. Exp. Med., October 7, 2002; 196(7): 923 - 934. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. J. Morrison and J. L. Marcinkiewicz Tumor Necrosis Factor {alpha} Enhances Oocyte/Follicle Apoptosis in the Neonatal Rat Ovary Biol Reprod, February 1, 2002; 66(2): 450 - 457. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Fotin-Mleczek, F. Henkler, D. Samel, M. Reichwein, A. Hausser, I. Parmryd, P. Scheurich, J. A. Schmid, and H. Wajant Apoptotic crosstalk of TNF receptors: TNF-R2-induces depletion of TRAF2 and IAP proteins and accelerates TNF-R1-dependent activation of caspase-8 J. Cell Sci., January 7, 2002; 115(13): 2757 - 2770. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Kreuz, D. Siegmund, P. Scheurich, and H. Wajant NF-{kappa}B Inducers Upregulate cFLIP, a Cycloheximide-Sensitive Inhibitor of Death Receptor Signaling Mol. Cell. Biol., June 15, 2001; 21(12): 3964 - 3973. [Abstract] [Full Text]
|
|
|
|
|
|
H.-S. Teh, A. Seebaran, and S.-J. Teh TNF Receptor 2-Deficient CD8 T Cells Are Resistant to Fas/Fas Ligand-Induced Cell Death J. Immunol., November 1, 2000; 165(9): 4814 - 4821. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. ATEN, A. ROOS, N. CLAESSEN, E. J. M. SCHILDER-TOL, I. J. M. TEN BERGE, and J. J. WEENING Strong and Selective Glomerular Localization of CD134 Ligand and TNF Receptor-1 in Proliferative Lupus Nephritis J. Am. Soc. Nephrol., August 1, 2000; 11(8): 1426 - 1438. [Abstract] [Full Text]
|
|
|
|
 |
|
 G. Herbein and W. A. O'brien Tumor Necrosis Factor (TNF)-{alpha} and TNF Receptors in Viral Pathogenesis Experimental Biology and Medicine, March 1, 2000; 223(3): 241 - 257. [Abstract] [Full Text]
|
|
|
|
|
|
A. Laouar, D. Glesne, and E. Huberman Involvement of Protein Kinase C-beta and Ceramide in Tumor Necrosis Factor-alpha -induced but Not Fas-induced Apoptosis of Human Myeloid Leukemia Cells J. Biol. Chem., August 13, 1999; 274(33): 23526 - 23534. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Chiarle, A. Podda, G. Prolla, E. R. Podack, G. J. Thorbecke, and G. Inghirami CD30 Overexpression Enhances Negative Selection in the Thymus and Mediates Programmed Cell Death Via a Bcl-2-Sensitive Pathway J. Immunol., July 1, 1999; 163(1): 194 - 205. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Haas, M. Grell, H. Wajant, and P. Scheurich Continuous Autotropic Signaling by Membrane-expressed Tumor Necrosis Factor J. Biol. Chem., June 18, 1999; 274(25): 18107 - 18112. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Bachmann, H.-P. Eugster, K. Frei, A. Fontana, and H. Lassmann Impairment of TNF-Receptor-1 Signaling but not Fas Signaling Diminishes T-Cell Apoptosis in Myelin Oligodendrocyte Glycoprotein Peptide-Induced Chronic Demyelinating Autoimmune Encephalomyelitis in Mice Am. J. Pathol., May 1, 1999; 154(5): 1417 - 1422. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Feng, M. L. Gaeta, L. A. Madge, J.-H. Yang, J. R. Bradley, and J. S. Pober Caveolin-1 Associates with TRAF2 to Form a Complex That Is Recruited to Tumor Necrosis Factor Receptors J. Biol. Chem., March 9, 2001; 276(11): 8341 - 8349. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
