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From the
The enterotoxin from Clostridium difficile (ToxA) is
one of the causative agents of the antibiotic-associated
pseudomembranous colitis. In cultured monolayer cells ToxA exhibits
cytotoxic activity to induce disassembly of the actin cytoskeleton,
which is accompanied by morphological changes. ToxA-induced
depolymerization of actin filaments is correlated with a decrease in
the ADP-ribosylation of the low molecular mass GTP-binding Rho proteins
(Just, I., Selzer, J., von Eichel-Streiber, C., and Aktories, K.(1995)
J. Clin. Invest. 95, 1026-1031). Here we report on the
identification of the ToxA-induced modification of Rho. Applying
electrospray mass spectrometry, the mass of the modification was
determined as 162 Da, which is consistent with the incorporation of a
hexose into Rho. From several hexoses tested UDP-glucose selectively
served as cosubstrate for ToxA-catalyzed modification. The acceptor
amino acid of glucosylation was identified from a Lys-C-generated
peptide by tandem mass spectrometry as Thr-37. Mutation of Thr-37 to
Ala completely abolished glucosylation. The members of the Rho family
(RhoA, Rac1, and Cdc42Hs) were substrates for ToxA, whereas H-Ras,
Rab5, and Arf1 were not glucosylated. ToxA-catalyzed glucosylation of
lysates from ToxA-pretreated rat basophilic leukemia (RBL) cells
resulted in a decreased incorporation of
[
The enterotoxin (ToxA)
C. difficile ToxA
(15) and C. botulinum C3 exoenzyme
(16) were purified as described.
As Thr
We gratefully acknowledge the excellent technical
assistance of Monika Lerner and Gabriele Kiefer. We would like to thank
Dr. M. Zerial (EMBL, Heidelberg, Germany) for the kind gift of Rab5,
Dr. M. Aepfelbacher (Munich, Germany) for Cdc42Hs, Dr. M. Schmidt
(Essen, Germany) for Arf1, and Dr. A. Hall (London, UK) for plasmids.
Volume 270,
Number 23,
Issue of June 9, pp. 13932-13936, 1995
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
ABSTRACT
INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION FOOTNOTES
ACKNOWLEDGEMENTS
REFERENCES
C]glucose, indicating previous glucosylation in
the intact cell. Glucosylation of the Rho subtype proteins appears to
be the molecular mechanism by which C. difficile ToxA mediates
its cytotoxic effects on cells.
()
and the cytotoxin
(ToxB) secreted by pathogenic Clostridium difficile strains
are the virulence factors causing antibiotic-associated diarrhea and
the potentially fatal form, pseudomembranous
colitis
(1, 2, 3) . Genetic analysis demonstrated
an overall 63% homology of the amino acids of both toxins
(4) .
Nevertheless the activities of both toxins differ. In the hamster model
ToxA induces the typical clinical picture resembling pseudomembranous
colitis, whereas ToxB does not cause any kind of disease
(5) .
However, in cultured cell lines both toxins exhibit potent cytotoxic
activities, which are characterized by a disaggregation of the actin
cytoskeleton followed by rounding of the cells
(1, 6) .
Recently, we showed that ToxA (7) as well as ToxB
(8, 9) act on the low molecular mass GTPase Rho to inhibit the
C3-catalyzed ADP-ribosylation. Rho proteins, which are involved in the
formation of focal adhesions and stress fibers
(10) , are the
substrates of Clostridium botulinum C3
ADP-ribosyltransferase
(11, 12) . C3-catalyzed
ADP-ribosylation of Rho at Asn-41 renders the small GTPase inactive,
resulting in depolymerization of the actin
filaments
(13, 14) . Because C. difficile toxins
induced a decrease in Rho-ADP-ribosylation, which correlated with the
toxin-caused depolymerization of actin filaments, it was suggested that
ToxA and ToxB act on the regulatory Rho proteins. Several findings
indicate a covalent modification of Rho (7, 8). Toxin-induced
modification of recombinant Rho depends on the presence of a consumable
cytosolic factor, which is heat stable, nonproteinacious, and exhibits
a molecular mass between 500 and 3000 Da
(7) . Here we report on
the identification of the ToxA-induced modification by applying
electrospray mass spectrometry.
C-Labeled UDP-galactose, UDP-N-acetylglucosamine,
UDP-glucose, and [P]NAD were purchased from
DuPont NEN, Dreieich, Germany.
Recombinant Proteins
Recombinant proteins (RhoA, Rac1,
Cdc42Hs, and the mutant RhoA) were purified from
Escherichia coli transformed with a plasmid expressing
GST-RhoA (RhoA
, Rac1, and Cdc42Hs) fusion protein. RhoA,
RhoA
, and Rac1 plasmids were kindly donated by Dr. A.
Hall (MRC Laboratory for Molecular Cell Biology, London) and Cdc42Hs by
Dr. M. Aepfelbacher (Institut für Prophylaxe und Epidemiologie der
Kreislaufkrankheiten, Munich, Germany). The glutathione fusion proteins
were isolated by affinity purification with glutathione-Sepharose beads
(Pharmacia, Germany) followed by proteolytic cleavage with thrombin
(100 µg/ml for 30 min at 22 °C). Thrombin was removed by
precipitation with benzamidine-Sepharose beads (Pharmacia, Germany).
Rab5 was kindly donated by Dr. M. Zerial (EMBL, Heidelberg, Germany)
and Arf1 by Dr. M. Schmidt (Institut für Pharmakologie, Essen,
Germany).
Cell Culture
Rat basophilic leukemia (RBL) cells
were cultured as described
(7) . For intoxication the cells were
incubated with ToxA (500 ng/ml) for 4 h followed by lysis as described
below.
Preparation of the Cytosolic Fractions
RBL cells
were rinsed with ice-cold phosphate-buffered saline and were then
mechanically removed from the dishes in the presence of lysis buffer (2
mM MgCl
, 1 mM EGTA, 1 mM
dithiothreitol, 0.3 mM phenylmethylsulfonyl fluoride, 30
µg/ml leupeptin, 50 mM triethanolamine HCl, pH 7.5),
sonicated 5 times on ice, and centrifuged (10 min at 2,000
g). The supernatant was centrifuged for 60 min at 100,000
g to give the cytosolic fraction. For preparation of
the cytosolic subfraction, the cytosol was first incubated for 15 min
at 95 min and then centrifuged (15 min at 30,000
g).
Thereafter, the supernatant was passed through a filter membrane
(ultrafiltration membranes YM3, 3,000-Da cutoff, Amicon Corp.).
ADP-ribosylation Reaction
Recombinant RhoA (50
µg/ml) was incubated with ToxA (10 µg/ml) in the presence of
either cytosol from RBL cells, a cytosolic fraction, or various
UDP-hexoses (as indicated) (50 µM) for 45 min at 37
°C. Thereafter, the samples were incubated for 15 min at 37 °C
in a buffer (3 mM MgCl, 1 mM
dithiothreitol, 50 mM triethanolamine HCl, pH 7.5) containing
10 µM [P]NAD (0.5 µCi) and C3
exoenzyme (0.5 µg/ml) in a total volume of 50 µl. The reaction
was terminated by addition of Laemmli sample buffer.
Glucosylation Reaction
The glucosylation reaction
was performed in a medium containing 30 µM
UDP-[C]glucose (50 nCi), 3 mM
MgCl, 0.3 mM GDP, 150 mM KCl, 50
mM triethanolamine HCl, pH 7.5, 10 µg/ml ToxA, and the
indicated recombinant GTPases (50 µg/ml) or cell lysate (2 mg/ml
protein) in a total volume of 25 µl. The incubation was performed
at 37 °C for 45 min or as indicated. For the differential
glucosylation 30 µM UDP-[C]glucose
(500 nCi) was used. After the incubation, Laemmli sample buffer was
added and the proteins were separated on 12.5% SDS-PAGE.
Gel Electrophoresis
Proteins were separated by
12.5% SDS gel electrophoresis according to Ref. 17. The gels were
analyzed by the PhosphorImager SF from Molecular Dynamics.
Proteolytic Peptide Map
RhoA (100 µg) was
treated without or with ToxA (10 µg/ml) in the presence of the
cytosolic subfraction (<3,000 Da) for 90 min at 37 °C and was
then separated by HPLC chromatography on a Sephasil RP-C18 column
(Pharmacia). The proteins were eluted with a linear gradient from 0.1%
trifluoroacetic acid in water to 70% acetonitrile and 0.1%
trifluoroacetic acid. After freeze drying, RhoA was dissolved in 200
µl of a medium containing 1 M urea, 1 mM EDTA,
and 25 mM triethanolamine HCl, pH 8.5 and incubated with Lys-C
(10 µg/ml, Boehringer Mannheim, Germany) for 16 h at 30 °C. The
digestion was stopped by addition of 0.1% trifluoroacetic acid, and the
peptides were separated on the Sephasil RP-C18 column with the same
gradient as described above.
Mass Spectrometry
For mass spectrometric analyses
RhoA in its unmodified and modified form was purified with HPLC as
described above. The masses of control and modified RhoA protein were
measured on a electrospray triple quadrupole instrument (API III from
Sciex-Perkin Elmer, Ontario, Canada) equipped with a modified
electrospray source (18). One peptide from Lys-C digestion showed an
altered retention time for the modified RhoA in HPLC separation. For
identification it was subjected to tandem mass spectrometry in its
modified and unmodified form. To localize the acceptor amino acid, the
peptide was subdigested with pepsin. The resulting petide mixture was
analyzed with mass spectrometry. A modified peptide in the digest of
the original modified RhoA petide was selected for fragmentation. Its
smallest fragment, which still contained the modification, identified
the acceptor amino acid.
Glycohydrolase Activity
ToxA (250 µg/ml) was
incubated in buffer (10 µl) containing 50 mM
triethanolamine HCl, pH 7.0, 150 mM KCl, and 25
µM UDP-[C]glucose (80 nCi) for the
indicated times at 37 °C. Samples were spotted on polyethyleneimine
cellulose and run with 0.25 M LiCl. Evaluation of the TLC was
performed with the PhosphorImager SF (Molecular Dynamics). For testing
other hexoses, C-labeled UDP-galactose and
UDP-N-acetylglucosamine were used.
Identification of the Modification
Recombinant
RhoA, which had been treated with ToxA in the presence of the cytosolic
subfraction (<3,000 Da), was separated by HPLC and, subsequently,
subjected to electrospray mass spectrometry. The mass of the complete
protein was 162 ± 0.8 Da higher than the unmodified protein (not
shown). These data are consistent with a monoglycosylation of RhoA
(180-Da hexose minus 18 Da of released HO). To identify the
type of sugar incorporated into Rho several hexoses were tested.
Because the molecular weight of the cosubstrate is higher than
500
(7) , simple monohexoses (M
180) were
ruled out and activated forms of hexoses (UDP- and GDP-hexoses,
M 566) were tested (Fig. 1). Only in the
presence of UDP-glucose, ToxA was able to inhibit the C3-catalyzed
ADP-ribosylation of RhoA. Applying
UDP-[C]glucose, ToxA catalyzed the incorporation
of [C]glucose into RhoA
(Fig. 2A). Hydrolysis of UDP-glucose to glucose
1-phosphate by treatment with phosphodiesterase or oxidation to
UDP-glucuronic acid by dehydrogenase completely abolished incorporation
of glucose, indicating that UDP-glucose is the actual cosubstrate
(Fig. 2A). Monoglucosylation of RhoA depended on the
native structure of both the substrate RhoA and the transferase ToxA
because denaturation of either completely inhibited incorporation of
glucose (not shown). Glucosylation of Rho is significantly enhanced in
the presence of 150 mM KCl whereas 150 mM NaCl did
not increase incorporation (not shown). The time course of
glucosylation showed that incorporation of glucose did not exceed
incorporation of 1 mol of glucose/mol of Rho (Fig. 2C),
consistent with the findings of the mass spectrometry.
Figure 1:
Influence of various hexoses on the
C. difficile ToxA-induced decrease in C3-catalyzed
ADP-ribosylation of Rho. Recombinant RhoA (50 µg/ml) was incubated
with ToxA (10 µg/ml) in the presence of UDP-hexoses (50
µM) for 45 min at 37 °C. Thereafter, the samples were
subjected to ADP-ribosylation with C3 in the presence of
[P]NAD (10 µM, 0.5 µCi).
PhosphorImager data from SDS-PAGE are shown. UDPGlc,
UDP-glucose; UDPGal, UDP-galactose; UDPMan,
UDP-mannose; UDPGlcA, UDP-glucuronic acid; UDPGlcNAc,
UDP-N-acetylglucosamine; GDPMan, GDP-mannose;
ADPGlc, ADP-glucose; Glc,
glucose.
Figure 2:
ToxA-catalyzed incorporation of glucose
into Rho proteins. A, prior to the glucosylation reaction, 30
µM UDP-[C]glucose (50 nCi) was
treated with either 50 µg/ml phosphodiesterase from Crotalus
durissus (lane2) or with 500 µg/ml
UDP-glucose dehydrogenase and 100 µM NAD (lane3) for 30 min at 30 °C followed by incubation for 15
min at 95 °C to inactivate the UDP-glucose-degrading enzymes.
Lane1, control. Thereafter, the glucosylation
reaction (25 µl) was started by the addition of RhoA and ToxA.
B, substrate specificity of ToxA. The indicated recombinant
low molecular mass GTPases (50 µg/ml, dissolved in 3 mM
MgCl, 0.3 mM GDP, 150 mM KCl, 50
mM triethanolamine HCl, pH 7.5) or lysate from RBL cells were
incubated with 10 µg/ml ToxA and 30 µM
UDP-[C]glucose (50 nCi) in a total volume of 25
µl for 45 min at 37 °C. C, time course of
ToxA-catalyzed incorporation of glucose in the Rho subtype proteins.
The glucosylation reaction of RhoA (
), Rac1 (
), and
Cdc42Hs () (each 50 µg/ml) was performed as described in
B. After the indicated times, samples were separated by
SDS-PAGE (12.5%). From the PhosphorImager data incorporation of glucose
was calculated (mol of glucose/mol of G-protein). D,
glucosylation of RhoA
.
RhoA (50 µg/ml, dissolved in 3
mM MgCl, 0.3 mM GDP, 150 mM KCl,
50 mM triethanolamine HCl, pH 7.5) was either incubated with
C3 (0.5 µg/ml) and [P]NAD (10
µM) (lane1) or with ToxA (10 µg/ml)
and UDP-[
C]glucose (30 µM)
(lane2) for 45 min at 37 °C. PhosphorImager data
from SDS-PAGE are shown.
In cell-free
systems, ToxA exhibits its enzymatic effects on Rho only at
50-100 times higher concentration than usually applied to intact
cells. This finding indicates that ToxA is most likely activated
intracellularly but not in the cell-free assay. Because ToxA is taken
up via receptor-mediated endocytosis
(1, 6, 19) ,
it is most likely that ToxA is activated in the postendosomes
comparable with the reported mechanisms of diphtheria, pertussis, and
cholera toxins
(20) to elicit its transferase activity in the
cytosol.
Glycohydrolase Activity
Bacterial
ADP-ribosyltransferases catalyze incorporation of ADP-ribose into
eukaryotic target proteins by glycosidic bonds, but in the absence of
target proteins, they exhibit NAD glycohydrolase activity and cleave
NAD to ADP-ribose and nicotinamide. We tested whether ToxA exhibits a
comparable activity to cleave UDP-glucose into glucose and UDP. As
shown in Fig. 3, ToxA cleaved UDP-glucose in a time-dependent
manner. Other UDP-hexoses (UDP-galactose,
UDP-N-acetylglucosamine) were not hydrolyzed. These data
indicate that ToxA exhibits both transferase and glycohydrolase
activity.
Figure 3:
UDP-glucose hydrolase activity of ToxA.
250 µg/ml ToxA was incubated with 25 µM
UDP-[C]glucose (80 nCi) in a buffer (10 µl)
containing 150 mM KCl and triethanolamine HCl, pH 7.0, for the
indicated times. Samples were analyzed by TLC as described under
``Experimental Procedures.'' The amount of UDP-glucose
hydrolyzed (mol/mol of ToxA) was evaluated from TLC by the
PhosphorImager.
Acceptor Amino Acid
To identify the acceptor amino
acid of glucosylation, modified and unmodified RhoA was digested with
endopeptidase Lys-C. The peptides of both digests were separated by
HPLC on a Sephasil RP-C18 column. In the separation of the peptides
from modified RhoA one additional peak appeared. Mass spectrometry of
this HPLC fraction showed a mass of 2935.5 Da, which was 162 Da higher
than that of a peptide fragment corresponding to D28-K51 (2774.0 Da).
The assignment to peptide D28-K51 was confirmed by sequencing of the
unmodified (Fig. 4A) and the modified peptide
(Fig. 4B) with electrospray tandem mass spectrometry (ES
MS/MS) using a NanoES source
(18) . Both MS/MS spectra revealed
the same peptide sequence of the residues Asp to
Lys
of the RhoA protein. The modification was localized
within the N-terminal 16 residues (Fig. 4B). For final
determination of the site of modification the modified peptide
(Asp
-Lys
) was subdigested with pepsin, and
the digest was analyzed directly by ES MS/MS (Fig. 4C).
The peptide Asp
-Glu
in its modified form was
identified in the digest by its mass (1730.9 Da) and by its sequence.
ES MS/MS shows that the Thr
residue carries the
modification (Fig. 4C).
Figure 4:
Localization of the modification by ES
MS/MS. Sequencing was performed on a Sciex API III triple quadrupole
mass spectrometer. A, measurement of the unmodified peptide.
The measured mass (2773.6 Da, average mass) is consistent with peptide
D28-K51 (expected monoisotopic molecular mass, 2777.0 Da). Sequencing
by ES MS/MS confirmed the sequence by a series of B and Y" ions
(fragments with charge retention on the N- and C-terminal part of the
molecule, respectively) (25). In the figure, the Y" ion series covering
C-terminal amino acids of the peptide sequence are marked. B,
measurement of the modified peptide. The measured mass (2935.5Da) is
consistent with a modification of 162 Da. The same sequence-specific
fragment ions as in panelA were found. This
observation shows that the bond between the conjugate and the peptide
backbone is less stable than the backbone bond. Nevertheless,
comparison of the fragment spectra of the modified and the unmodified
peptide shows an additional fragment in the spectrum of the modified
peptide 162 Da larger in mass than the Y" ion. This
localizes the modification to the C-terminal 16 amino acids in the
peptide sequence. C, MS/MS analysis of a peptide from a pepsin
subdigest of the modified peptide Asp
-Lys
. A
peptide of mass 1730.9 Da was sequenced and identified as peptide
Asp
-Glu
in the modified form. A series of
fragment ions with accompanying +162 Da peaks was observed.
B
is the lowest fragment ion for which the modification is
observed localizing the modification to
Thr
.
As can be deduced from the
crystal structure of H-Ras, Thr (Thr
in Rho)
is located in the GTP-binding and hydrolyzing domain (G-2) and
participates in the coordination of Mg
, which is the
ligand for
- and -phosphates of GTP
(21) . In the
GDP-bound state, loop L2 moves and Thr
(Thr
in Rho) is now accessible
(22) . Consistent with this model
is our finding that GTP-bound Rho is a poor substrate compared with the
GDP-bound form (data not shown). To assess the specificity of the
acceptor amino acid Thr
, we tested whether the exchange of
Thr in position 37 to Ala abolishes glucosylation
(Fig. 2D). RhoA
was still
ADP-ribosylated by C3 exoenzyme indicating no gross alteration of the
protein structure in this mutant form. However, glucosylation of
RhoA by ToxA was completely blocked. There
are no alternative acceptor amino acid residues that are modified when
the acceptor Thr is eliminated by mutation. These findings
prove that ToxA selectively catalyzes attachment of glucose to
Thr
in Rho.
is located in the
putative effector domain of Rho (23), the hydrophilic glucose group in
this domain might interfere with the interaction of activated Rho
protein with the effector protein. This notion is in agreement with the
observed disassembly of actin filaments, resulting from a blockade of
the signal transduction due to Rho modification.
Substrate Specificity
Incubation of RBL cell
lysates with ToxA in the presence of
UDP-[C]glucose resulted in labeling of cellular
proteins with a molecular mass in the range of 20-24 kDa. No
additional proteins were labeled. These findings were observed with
several cell lines (NIH3T3 fibroblasts and PtK2 kidney epithelial
cells). To identify the target proteins of glucosylation, several
recombinant low molecular mass GTP-binding proteins were tested. As
shown in Fig. 2B, members of the Rho subfamily (RhoA,
Rac1, and Cdc42Hs) were glucosylated, whereas the other Ras-related
GTPases (H-Ras, Rab5, and Arf1) were not substrates for ToxA. Because
all the members of the Ras superfamily share a threonine in domain G-2
at the same position
(24) , it seems that structural requirements
only present in Rho subtype proteins are essential for modification by
ToxA. As shown for RhoA, incorporation of glucose did not exceed 1
mol/mol of Rac1 and Cdc42Hs, respectively, consistent with
monoglucosylation of these proteins (Fig. 2C). The Rho
subtype proteins seem to be the exclusive target proteins of ToxA.
In Vivo Glucosylation
To test whether Rho proteins
were glucosylated in intact cells during the intoxication process, the
method of differential glucosylation was applied. Assuming that in
intact cells ToxA catalyzes glucosylation of Rho subtype proteins,
subsequent C glucosylation of the lysates should result in
a decreased incorporation of [C]glucose into the
GTPases. As shown in Fig. 5pretreatment of cells with ToxA
decreased glucosylation of two substrate proteins (doubleband). The upperband of the doublet
was identified as RhoA and the lower one as Cdc42Hs by immunoblot of
two-dimensional separated cell lysates C-glucosylated by
ToxA (data not shown). As expected, C3-catalyzed
[P]ADP-ribosylation of Rho was also inhibited
(Fig. 5). These findings indicate that ToxA most likely catalyzes
glucosylation of the Rho subtype proteins not only in cell lysates but
also in intact cells.
Figure 5:
In vivo glucosylation. RBL cells were
treated with ToxA (500 ng/ml) until all cells were rounded. Lysates
from control and ToxA-treated cells were either glucosylated or
ADP-ribosylated. The lysates were incubated with 10 µg/ml ToxA and
30 µM UDP-[C]glucose (500 nCi) in
50 mM triethanolamine HCl (pH 7.5) for 45 min at 37 °C (25
µl, total volume). ADP-ribosylation of the lysates was performed
with 0.5 µg/ml C3 and 10 µM
[P]NAD (0.5 µCi) in triethanolamine HCl (50
mM, pH 7.5) for 45 min at 37 °C (25 µl, total volume).
After incubation the proteins were separated by 12.5% SDS-PAGE.
PhosphorImager data from SDS-PAGE are shown.
In summary, we demonstrate that C.
difficile ToxA catalyzes the O-glucosylation of Rho
subtype proteins in Thr. Substrate specificity of ToxA is
restricted to the Rho family (Rho, Rac, and Cdc42Hs) whereas other
subtypes of the Ras superfamily are not substrates. Because
ToxA-catalyzed glucosylation of Rho proteins occurs in intact cells we
suggest that monoglucosylation is the molecular mechanism by which ToxA
mediates its cytotoxicity and probably its in vivo enterotoxicity. The identified modification of GTP-binding
proteins is a novel mode of action by which bacterial toxins directly
attack intracellular regulatory proteins of eukaryotic cells.
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
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T. Jank, D. J. Reinert, T. Giesemann, G. E. Schulz, and K. Aktories Change of the Donor Substrate Specificity of Clostridium difficile Toxin B by Site-directed Mutagenesis J. Biol. Chem., November 11, 2005; 280(45): 37833 - 37838. [Abstract] [Full Text] [PDF]
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O. Rey, S. H. Young, J. Yuan, L. Slice, and E. Rozengurt Amino Acid-stimulated Ca2+ Oscillations Produced by the Ca2+-sensing Receptor Are Mediated by a Phospholipase C/Inositol 1,4,5-Trisphosphate-independent Pathway That Requires G12, Rho, Filamin-A, and the Actin Cytoskeleton J. Biol. Chem., June 17, 2005; 280(24): 22875 - 22882. [Abstract] [Full Text] [PDF]
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H. Kim, S. H. Rhee, E. Kokkotou, X. Na, T. Savidge, M. P. Moyer, C. Pothoulakis, and J. T. LaMont Clostridium difficile Toxin A Regulates Inducible Cyclooxygenase-2 and Prostaglandin E2 Synthesis in Colonocytes via Reactive Oxygen Species and Activation of p38 MAPK J. Biol. Chem., June 3, 2005; 280(22): 21237 - 21245. [Abstract] [Full Text] [PDF]
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 D. E. Voth and J. D. Ballard Clostridium difficile Toxins: Mechanism of Action and Role in Disease Clin. Microbiol. Rev., April 1, 2005; 18(2): 247 - 263. [Abstract] [Full Text] [PDF]
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K. Solomon, J. Webb, N. Ali, R. A. Robins, and Y. R. Mahida Monocytes Are Highly Sensitive to Clostridium difficile Toxin A-Induced Apoptotic and Nonapoptotic Cell Death Infect. Immun., March 1, 2005; 73(3): 1625 - 1634. [Abstract] [Full Text] [PDF]
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 F. Barbut, D. Decre, V. Lalande, B. Burghoffer, L. Noussair, A. Gigandon, F. Espinasse, L. Raskine, J. Robert, A. Mangeol, et al. Clinical features of Clostridium difficile-associated diarrhoea due to binary toxin (actin-specific ADP-ribosyltransferase)-producing strains J. Med. Microbiol., February 1, 2005; 54(2): 181 - 185. [Abstract] [Full Text] [PDF]
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 T. Nubel, W. Dippold, B. Kaina, and G. Fritz Ionizing radiation-induced E-selectin gene expression and tumor cell adhesion is inhibited by lovastatin and all-trans retinoic acid Carcinogenesis, August 1, 2004; 25(8): 1335 - 1344. [Abstract] [Full Text] [PDF]
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 C. Goncalves, D. Decre, F. Barbut, B. Burghoffer, and J.-C. Petit Prevalence and Characterization of a Binary Toxin (Actin-Specific ADP-Ribosyltransferase) from Clostridium difficile J. Clin. Microbiol., May 1, 2004; 42(5): 1933 - 1939. [Abstract] [Full Text] [PDF]
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 H. Hayashi, K. Szaszi, N. Coady-Osberg, W. Furuya, A. P. Bretscher, J. Orlowski, and S. Grinstein Inhibition and Redistribution of NHE3, the Apical Na+/H+ Exchanger, by Clostridium difficile Toxin B J. Gen. Physiol., April 26, 2004; 123(5): 491 - 504. [Abstract] [Full Text] [PDF]
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G. Pfeifer, J. Schirmer, J. Leemhuis, C. Busch, D. K. Meyer, K. Aktories, and H. Barth Cellular Uptake of Clostridium difficile Toxin B: TRANSLOCATION OF THE N-TERMINAL CATALYTIC DOMAIN INTO THE CYTOSOL OF EUKARYOTIC CELLS J. Biol. Chem., November 7, 2003; 278(45): 44535 - 44541. [Abstract] [Full Text] [PDF]
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A. Kumar, A. J. Knox, and A. M. Boriek CCAAT/Enhancer-binding Protein and Activator Protein-1 Transcription Factors Regulate the Expression of Interleukin-8 through the Mitogen-activated Protein Kinase Pathways in Response to Mechanical Stretch of Human Airway Smooth Muscle Cells J. Biol. Chem., May 23, 2003; 278(21): 18868 - 18876. [Abstract] [Full Text] [PDF]
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S. Karlsson, B. Dupuy, K. Mukherjee, E. Norin, L. G. Burman, and T. Akerlund Expression of Clostridium difficile Toxins A and B and Their Sigma Factor TcdD Is Controlled by Temperature Infect. Immun., April 1, 2003; 71(4): 1784 - 1793. [Abstract] [Full Text]
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 T. S. Liu, M. W. Musch, K. Sugi, M. M. Walsh-Reitz, M. J. Ropeleski, B. A. Hendrickson, C. Pothoulakis, J. T. Lamont, and E. B. Chang Protective role of HSP72 against Clostridium difficile toxin A-induced intestinal epithelial cell dysfunction Am J Physiol Cell Physiol, April 1, 2003; 284(4): C1073 - C1082. [Abstract] [Full Text] [PDF]
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E. Chaves-Olarte, E. Freer, A. Parra, C. Guzman-Verri, E. Moreno, and M. Thelestam R-Ras Glucosylation and Transient RhoA Activation Determine the Cytopathic Effect Produced by Toxin B Variants from Toxin A-negative Strains of Clostridium difficile J. Biol. Chem., February 28, 2003; 278(10): 7956 - 7963. [Abstract] [Full Text] [PDF]
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J. Yuan, L. W. Slice, J. Gu, and E. Rozengurt Cooperation of Gq, Gi, and G12/13 in Protein Kinase D Activation and Phosphorylation Induced by Lysophosphatidic Acid J. Biol. Chem., February 7, 2003; 278(7): 4882 - 4891. [Abstract] [Full Text] [PDF]
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N. Mani, D. Lyras, L. Barroso, P. Howarth, T. Wilkins, J. I. Rood, A. L. Sonenshein, and B. Dupuy Environmental Response and Autoregulation of Clostridium difficile TxeR, a Sigma Factor for Toxin Gene Expression J. Bacteriol., November 1, 2002; 184(21): 5971 - 5978. [Abstract] [Full Text] [PDF]
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G. Bug, T. Rossmanith, R. Henschler, L.A. Kunz-Schughart, B. Schroder, M. Kampfmann, M. Kreutz, D. Hoelzer, and O. G. Ottmann Rho family small GTPases control migration of hematopoietic progenitor cells into multicellular spheroids of bone marrow stroma cells J. Leukoc. Biol., October 1, 2002; 72(4): 837 - 845. [Abstract] [Full Text] [PDF]
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P. Spigaglia and P. Mastrantonio Molecular Analysis of the Pathogenicity Locus and Polymorphism in the Putative Negative Regulator of Toxin Production (TcdC) among Clostridium difficile Clinical Isolates J. Clin. Microbiol., September 1, 2002; 40(9): 3470 - 3475. [Abstract] [Full Text] [PDF]
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R. G. Spiro Protein glycosylation: nature, distribution, enzymatic formation, and disease implications of glycopeptide bonds Glycobiology, April 1, 2002; 12(4): 43R - 56R. [Abstract] [Full Text] [PDF]
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T. MAEGAWA, T. KARASAWA, T. OHTA, X. WANG, H. KATO, H. HAYASHI, and S. NAKAMURA Linkage between toxin production and purine biosynthesis in Clostridium difficile J. Med. Microbiol., January 1, 2002; 51(1): 34 - 41. [Abstract] [Full Text] [PDF]
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K. J. Fullner, W. I. Lencer, and J. J. Mekalanos Vibrio cholerae-Induced Cellular Responses of Polarized T84 Intestinal Epithelial Cells Are Dependent on Production of Cholera Toxin and the RTX Toxin Infect. Immun., October 1, 2001; 69(10): 6310 - 6317. [Abstract] [Full Text] [PDF]
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N. Mani and B. Dupuy Regulation of toxin synthesis in Clostridium difficile by an alternative RNA polymerase sigma factor PNAS, April 18, 2001; (2001) 101126598. [Abstract] [Full Text]
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A. Qamar, S. Aboudola, M. Warny, P. Michetti, C. Pothoulakis, J. T. LaMont, and C. P. Kelly Saccharomyces boulardii Stimulates Intestinal Immunoglobulin A Immune Response to Clostridium difficile Toxin A in Mice Infect. Immun., April 1, 2001; 69(4): 2762 - 2765. [Abstract] [Full Text] [PDF]
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 I. Castagliuolo, K. Karalis, L. Valenick, A. Pasha, S. Nikulasson, M. Wlk, and C. Pothoulakis Endogenous corticosteroids modulate Clostridium difficile toxin A-induced enteritis in rats Am J Physiol Gastrointest Liver Physiol, April 1, 2001; 280(4): G539 - G545. [Abstract] [Full Text] [PDF]
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A. Nusrat, C. von Eichel-Streiber, J. R. Turner, P. Verkade, J. L. Madara, and C. A. Parkos Clostridium difficile Toxins Disrupt Epithelial Barrier Function by Altering Membrane Microdomain Localization of Tight Junction Proteins Infect. Immun., March 1, 2001; 69(3): 1329 - 1336. [Abstract] [Full Text] [PDF]
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 E. Mylonakis, E. T. Ryan, and S. B. Calderwood Clostridium difficile-Associated Diarrhea: A Review Arch Intern Med, February 26, 2001; 161(4): 525 - 533. [Abstract] [Full Text] [PDF]
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C. Busch, K. Schomig, F. Hofmann, and K. Aktories Characterization of the Catalytic Domain of Clostridium novyi Alpha-Toxin Infect. Immun., November 1, 2000; 68(11): 6378 - 6383. [Abstract] [Full Text] [PDF]
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A. Verma, G. E. Davis, and G. M. Ihler Infection of Human Endothelial Cells with Bartonella bacilliformis Is Dependent on Rho and Results in Activation of Rho Infect. Immun., October 1, 2000; 68(10): 5960 - 5969. [Abstract] [Full Text] [PDF]
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C. Busch, F. Hofmann, R. Gerhard, and K. Aktories Involvement of a Conserved Tryptophan Residue in the UDP-Glucose Binding of Large Clostridial Cytotoxin Glycosyltransferases J. Biol. Chem., April 28, 2000; 275(18): 13228 - 13234. [Abstract] [Full Text] [PDF]
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D. Pavliakova, J. S. Moncrief, D. M. Lyerly, G. Schiffman, D. A. Bryla, J. B. Robbins, and R. Schneerson Clostridium difficile Recombinant Toxin A Repeating Units as a Carrier Protein for Conjugate Vaccines: Studies of Pneumococcal Type 14, Escherichia coli K1, and Shigella flexneri Type 2a Polysaccharides in Mice Infect. Immun., April 1, 2000; 68(4): 2161 - 2166. [Abstract] [Full Text] [PDF]
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H. Genth, J. Selzer, C. Busch, J. Dumbach, F. Hofmann, K. Aktories, and I. Just New Method To Generate Enzymatically Deficient Clostridium difficile Toxin B as an Antigen for Immunization Infect. Immun., March 1, 2000; 68(3): 1094 - 1101. [Abstract] [Full Text] [PDF]
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M. Eckhardt, H. Barth, D. Blocker, and K. Aktories Binding of Clostridium botulinum C2 Toxin to Asparagine-linked Complex and Hybrid Carbohydrates J. Biol. Chem., January 28, 2000; 275(4): 2328 - 2334. [Abstract] [Full Text] [PDF]
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U.-M. Goehring, G. Schmidt, K. J. Pederson, K. Aktories, and J. T. Barbieri The N-terminal Domain of Pseudomonas aeruginosa Exoenzyme S Is a GTPase-activating Protein for Rho GTPases J. Biol. Chem., December 17, 1999; 274(51): 36369 - 36372. [Abstract] [Full Text] [PDF]
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 K. K. Jefferson, M. F. Smith Jr., and D. A. Bobak Roles of Intracellular Calcium and NF-{kappa}B in the Clostridium difficile Toxin A-Induced Up-Regulation and Secretion of IL-8 from Human Monocytes J. Immunol., November 15, 1999; 163(10): 5183 - 5191. [Abstract] [Full Text] [PDF]
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G. Schmidt, U.-M. Goehring, J. Schirmer, M. Lerm, and K. Aktories Identification of the C-terminal Part of Bordetella Dermonecrotic Toxin as a Transglutaminase for Rho GTPases J. Biol. Chem., November 5, 1999; 274(45): 31875 - 31881. [Abstract] [Full Text] [PDF]
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 B. A. Feltis, A. S. Kim, K. M. Kinneberg, D. L. Lyerly, T. D. Wilkins, S. L. Erlandsen, and C. L. Wells Clostridium difficile Toxins May Augment Bacterial Penetration of Intestinal Epithelium Arch Surg, November 1, 1999; 134(11): 1235 - 1242. [Abstract] [Full Text] [PDF]
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M. Lerm, G. Schmidt, U.-M. Goehring, J. Schirmer, and K. Aktories Identification of the Region of Rho Involved in Substrate Recognition by Escherichia coli Cytotoxic Necrotizing Factor 1 (CNF1) J. Biol. Chem., October 8, 1999; 274(41): 28999 - 29004. [Abstract] [Full Text] [PDF]
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H. Genth, K. Aktories, and I. Just Monoglucosylation of RhoA at Threonine 37 Blocks Cytosol-Membrane Cycling J. Biol. Chem., October 8, 1999; 274(41): 29050 - 29056. [Abstract] [Full Text] [PDF]
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R. Zumbihl, M. Aepfelbacher, A. Andor, C. A. Jacobi, K. Ruckdeschel, B. Rouot, and J. Heesemann The Cytotoxin YopT of Yersinia enterocolitica Induces Modification and Cellular Redistribution of the Small GTP-binding Protein RhoA J. Biol. Chem., October 8, 1999; 274(41): 29289 - 29293. [Abstract] [Full Text] [PDF]
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H. Barth, C. Olenik, P. Sehr, G. Schmidt, K. Aktories, and D. K. Meyer Neosynthesis and Activation of Rho by Escherichia coli Cytotoxic Necrotizing Factor (CNF1) Reverse Cytopathic Effects of ADP-ribosylated Rho J. Biol. Chem., September 24, 1999; 274(39): 27407 - 27414. [Abstract] [Full Text] [PDF]
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A. K. Ganesan, T. S. Vincent, J. C. Olson, and J. T. Barbieri Pseudomonas aeruginosa Exoenzyme S Disrupts Ras-mediated Signal Transduction by Inhibiting Guanine Nucleotide Exchange Factor-catalyzed Nucleotide Exchange J. Biol. Chem., July 30, 1999; 274(31): 21823 - 21829. [Abstract] [Full Text] [PDF]
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 T. Arnould, L. Sellin, T. Benzing, L. Tsiokas, H. T. Cohen, E. Kim, and G. Walz Cellular Activation Triggered by the Autosomal Dominant Polycystic Kidney Disease Gene Product PKD2 Mol. Cell. Biol., May 1, 1999; 19(5): 3423 - 3434. [Abstract] [Full Text] [PDF]
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 W. W. Navarre and O. Schneewind Surface Proteins of Gram-Positive Bacteria and Mechanisms of Their Targeting to the Cell Wall Envelope Microbiol. Mol. Biol. Rev., March 1, 1999; 63(1): 174 - 229. [Abstract] [Full Text] [PDF]
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M. Lerm, J. Selzer, A. Hoffmeyer, U. R. Rapp, K. Aktories, and G. Schmidt Deamidation of Cdc42 and Rac by Escherichia coli Cytotoxic Necrotizing Factor 1: Activation of c-Jun N-Terminal Kinase in HeLa Cells Infect. Immun., February 1, 1999; 67(2): 496 - 503. [Abstract] [Full Text] [PDF]
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 M Warny, A Fatimi, E F Bostwick, D C Laine, F Lebel, J T LaMont, C Pothoulakis, and C P Kelly Bovine immunoglobulin concentrate-Clostridium difficile retains C difficile toxin neutralising activity after passage through the human stomach and small intestine Gut, February 1, 1999; 44(2): 212 - 217. [Abstract] [Full Text] [PDF]
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B. Qiu, C. Pothoulakis, I. Castagliuolo, S. Nikulasson, and J. T. LaMont Participation of reactive oxygen metabolites in Clostridium difficile toxin A-induced enteritis in rats Am J Physiol Gastrointest Liver Physiol, February 1, 1999; 276(2): G485 - G490. [Abstract] [Full Text] [PDF]
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C. Busch, F. Hofmann, J. Selzer, S. Munro, D. Jeckel, and K. Aktories A Common Motif of Eukaryotic Glycosyltransferases Is Essential for the Enzyme Activity of Large Clostridial Cytotoxins J. Biol. Chem., July 31, 1998; 273(31): 19566 - 19572. [Abstract] [Full Text] [PDF]
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W. P. Ciesla Jr. and D. A. Bobak Clostridium difficile Toxins A and B Are Cation-dependent UDP-glucose Hydrolases with Differing Catalytic Activities J. Biol. Chem., June 26, 1998; 273(26): 16021 - 16026. [Abstract] [Full Text] [PDF]
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C. Herrmann, M. R. Ahmadian, F. Hofmann, and I. Just Functional Consequences of Monoglucosylation of Ha-Ras at Effector Domain Amino Acid Threonine 35 J. Biol. Chem., June 26, 1998; 273(26): 16134 - 16139. [Abstract] [Full Text] [PDF]
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G. M. Calderon, J. Torres-Lopez, T.-J. Lin, B. Chavez, M. Hernandez, O. Munoz, A. D. Befus, and J. A. Enciso Effects of Toxin A from Clostridium difficile on Mast Cell Activation and Survival Infect. Immun., June 1, 1998; 66(6): 2755 - 2761. [Abstract] [Full Text] [PDF]
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J. A. Kink and J. A. Williams Antibodies to Recombinant Clostridium difficile Toxins A and B Are an Effective Treatment and Prevent Relapse of C. difficile-Associated Disease in a Hamster Model of Infection Infect. Immun., May 1, 1998; 66(5): 2018 - 2025. [Abstract] [Full Text] [PDF]
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F. Hofmann, C. Busch, and K. Aktories Chimeric Clostridial Cytotoxins: Identification of the N-Terminal Region Involved in Protein Substrate Recognition Infect. Immun., March 1, 1998; 66(3): 1076 - 1081. [Abstract] [Full Text] [PDF]
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J. K. Linevsky, C. Pothoulakis, S. Keates, M. Warny, A. C. Keates, J. T. Lamont, and C. P. Kelly IL-8 release and neutrophil activation by Clostridium difficile toxin-exposed human monocytes Am J Physiol Gastrointest Liver Physiol, December 1, 1997; 273(6): G1333 - G1340. [Abstract] [Full Text] [PDF]
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E Johansson, E Jennische, S Lange, and I Lonnroth Antisecretory factor suppresses intestinal inflammation and hypersecretion Gut, November 1, 1997; 41(5): 642 - 645. [Abstract] [Full Text] [PDF]
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J Salcedo, S Keates, C Pothoulakis, M Warny, I Castagliuolo, J T LaMont, and C P Kelly Intravenous immunoglobulin therapy for severe Clostridium difficile colitis Gut, September 1, 1997; 41(3): 366 - 370. [Abstract] [Full Text] [PDF]
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C. Fiorentini, A. Fabbri, G. Flatau, G. Donelli, P. Matarrese, E. Lemichez, L. Falzano, and P. Boquet Escherichia coli Cytotoxic Necrotizing Factor 1 (CNF1), a Toxin That Activates the Rho GTPase J. Biol. Chem., August 1, 1997; 272(31): 19532 - 19537. [Abstract] [Full Text] [PDF]
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S. Wesselborg, M. K. A. Bauer, M. Vogt, M. L. Schmitz, and K. Schulze-Osthoff Activation of Transcription Factor NF-kappa B and p38 Mitogen-activated Protein Kinase Is Mediated by Distinct and Separate Stress Effector Pathways J. Biol. Chem., May 9, 1997; 272(19): 12422 - 12429. [Abstract] [Full Text] [PDF]
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 B. B. Finlay and P. Cossart Exploitation of Mammalian Host Cell Functions by Bacterial Pathogens Science, May 2, 1997; 276(5313): 718 - 725. [Abstract] [Full Text]
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F. Hofmann, C. Busch, U. Prepens, I. Just, and K. Aktories Localization of the Glucosyltransferase Activity of Clostridium difficile Toxin B to the N-terminal Part of the Holotoxin J. Biol. Chem., April 25, 1997; 272(17): 11074 - 11078. [Abstract] [Full Text] [PDF]
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H. M. Lacerda, G. D. Pullinger, A. J. Lax, and E. Rozengurt Cytotoxic Necrotizing Factor 1from Escherichia coli and Dermonecrotic Toxin from Bordetella bronchiseptica Induce p21rho-dependent Tyrosine Phosphorylation of Focal Adhesion Kinase and Paxillin in Swiss 3T3 Cells J. Biol. Chem., April 4, 1997; 272(14): 9587 - 9596. [Abstract] [Full Text] [PDF]
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J. Selzer, F. Hofmann, G. Rex, M. Wilm, M. Mann, I. Just, and K. Aktories Clostridium novyi alpha -Toxin-catalyzed Incorporation of GlcNAc into Rho Subfamily Proteins J. Biol. Chem., October 11, 1996; 271(41): 25173 - 25177. [Abstract] [Full Text] [PDF]
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I. Just, Jör. Selzer, F. Hofmann, G. A. Green, and K. Aktories Inactivation of Ras by Clostridium sordellii Lethal Toxin-catalyzed Glucosylation J. Biol. Chem., April 26, 1996; 271(17): 10149 - 10153. [Abstract] [Full Text] [PDF]
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M. R. Popoff, E. Chaves-Olarte, E. Lemichez, C. von Eichel-Streiber, M. Thelestam, P. Chardin, D. Cussac, B. Antonny, P. Chavrier, G. Flatau, et al. Ras, Rap, and Rac Small GTP-binding Proteins Are Targets for Clostridium sordellii Lethal Toxin Glucosylation J. Biol. Chem., April 26, 1996; 271(17): 10217 - 10224. [Abstract] [Full Text] [PDF]
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U. Prepens, I. Just, C. von Eichel-Streiber, and K. Aktories Inhibition of Fc[IMAGE]RI-mediated Activation of Rat Basophilic Leukemia Cells by Clostridium difficile Toxin B (Monoglucosyltransferase) J. Biol. Chem., March 29, 1996; 271(13): 7324 - 7329. [Abstract] [Full Text] [PDF]
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E. Chaves-Olarte, I. Florin, P. Boquet, M. Popoff, C. von Eichel-Streiber, and M. Thelestam UDP-Glucose Deficiency in a Mutant Cell Line Protects against Glucosyltransferase Toxins from Clostridium difficile and Clostridium sordellii J. Biol. Chem., March 22, 1996; 271(12): 6925 - 6932. [Abstract] [Full Text] [PDF]
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H. Barth, G. Pfeifer, F. Hofmann, E. Maier, R. Benz, and K. Aktories Low pH-induced Formation of Ion Channels by Clostridium difficile Toxin B in Target Cells J. Biol. Chem., March 30, 2001; 276(14): 10670 - 10676. [Abstract] [Full Text] [PDF]
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D. Gineitis and R. Treisman Differential Usage of Signal Transduction Pathways Defines Two Types of Serum Response Factor Target Gene J. Biol. Chem., June 29, 2001; 276(27): 24531 - 24539. [Abstract] [Full Text] [PDF]
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C. Wilde, H. Genth, K. Aktories, and I. Just Recognition of RhoA by Clostridium botulinum C3 Exoenzyme J. Biol. Chem., May 26, 2000; 275(22): 16478 - 16483. [Abstract] [Full Text] [PDF]
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N. Mani and B. Dupuy Regulation of toxin synthesis in Clostridium difficile by an alternative RNA polymerase sigma factor PNAS, May 8, 2001; 98(10): 5844 - 5849. [Abstract] [Full Text] [PDF]
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