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J. Biol. Chem., Vol. 275, Issue 47, 37246-37250, November 24, 2000
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and 
Promote T-cell Survival by a
Rsk-dependent Phosphorylation and Inactivation of BAD*
§,,
, and**
From the INSERM U526, Activation des Cellules
Hématopoïétiques, Physiopathologie de la Survie et
de la Mort Cellulaires et Infections Virales, Équipe
Labelisée Ligue, 06107 Nice Cedex 2, France, ¶ INSERM U145,
Action des Récepteurs Tyrosine Kinase sur le Métabolisme,
la Croissance et la Différentiation Cellulaires, Aspects
Physiologiques et Physiopathologiques, 06107 Nice Cedex 2, France, and
Institute for Medical Biology and Human Genetics, University of
Innsbruck, A-6020 Innsbruck, Austria
Received for publication, August 24, 2000
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ABSTRACT |
|---|
 TOP
 ABSTRACT
 INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS AND DISCUSSION
REFERENCES
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Both MAPK and protein kinase C (PKC) signaling
pathways promote cell survival and protect against cell death. Here, we
show that 12-O-tetradecanoylphorbol-13-acetate (TPA)
prevents Fas-induced apoptosis in T lymphocytes. The effect of TPA was
specifically abolished by the PKC inhibitor GF109203X and by dominant
negative PKC In several cell lines, apoptosis is antagonized by growth factors
and hormones and, more generally, by stimuli that promote cell
survival. Interleukin 3 and insulin-like growth factor 1 exert their
antiapoptotic effect through activation of phosphatidylinositol 3-kinase, which, in turn, leads to activation of the serine/threonine protein kinase B (PKB/Akt), which promotes cell survival by
phosphorylating BAD at Ser136 (1-6). Interestingly,
interleukin 3, through activation of a mitochondrial membrane based
protein kinase A, also stimulates phosphorylation of BAD at
Ser112 (6, 7). When phosphorylated at Ser112 or
Ser136, BAD is complexed to the cytosolic 14.3.3 protein.
Association of BAD with 14.3.3 prevents its dimerization with the
antiapoptotic Bcl-XL protein, thus favoring cell survival
(6). Furthermore, brain-derived neurotrophic factor and agonists such
as the phorbol ester 12-O-tetradecanoylphorbol-13-acetate
(TPA)1 have been shown to
phosphorylate BAD at Ser112 (8, 9). Brain-derived
neurotrophic factor exerts its antiapoptotic effect in a
mitogen-activated protein kinase (MAPK)/extracellular signal-regulated
kinase pathway (8). The mechanism of action of TPA remains
unclear, although MAPK-dependent (10-13) and -independent pathways have been described (9). TPA is a tumor promoter that binds
and activates members of a family of serine/threonine protein kinases
termed protein kinase C (PKC). PKC comprised at least 12 isotypes that
have been classified into three groups according to their structure and
cofactor requirement: (a) conventional PKCs (PKC Reporter Plasmids, Transfections, and Luciferase
Assays--
Transfections of Jurkat T cells were done by
electroporation with simple electric shock (320 V, 960 microfarads)
using the gene pulser system (Bio-Rad). Cells were transfected with 5 µg of the c-fos SRE luciferase vector with or without 14 µg of the different PKC mutants or transfected with 5 µg of a SRE luciferase reporter plasmid with 14 µg of the constitutively active PKC isoforms (14) in presence or absence of 14 µg of Rsk2-KN (8). Cells were
exposed to the different effectors as indicated in the figure legends.
Two days after transfection, soluble extracts were harvested in lysis
buffer (Promega) and assayed for luciferase activity. Luciferase
activity was normalized by protein amount. Transfections of HEK 293 cells were performed with a calcium phosphate transfection method
(Stratagene). HEK 293 cells were transfected with 2.5 µg of
glutathione S-transferase-BAD (New England Biolabs) with or without 2.5 µg of empty vector or vector encoding the PKC mutant constructs in presence or absence of Rsk2-KN. Two days after
transfection, cells were exposed to different effectors for the
indicated time as described in figure legends and then lysed to perform
Western blotting experiments.
Western Blot Assays--
Jurkat T cells or HEK 293 cells were
incubated with different effectors for the times indicated in the
figure legends, and then the cells were lysed in buffer containing 50 mM Hepes (pH 7.4), 150 mM NaCl, 20 mM EDTA, 100 µM NaF, 10 mM
Na3VO4, 1 mM phenylmethylsulfonyl
fluoride, 1 mM leupeptin, 20 µg/ml aprotinin, and 1%
Nonidet P-40. Proteins were separated on 10% SDS-polyacrylamide gels,
transferred to PVDF membrane (Immobilon, Millipore), and then exposed
to the appropriate antibodies. BAD was detected with polyclonal
phospho-specific BAD Ser112 or Ser136
antibodies (New England Biolabs; dilution, 1:1000) or with an antibody
that recognizes BAD regardless of its phosphorylation state (New
England Biolabs; dilution, 1:1000) and with a secondary peroxidase-conjugated anti-rabbit antibody at a 1:10000 dilution. Caspase 3, PKC DNA Fragmentation--
Jurkat T cells exposed to the different
effectors were collected and lysed with 200 µl of lysis buffer
containing 10 mM Tris (pH 7.5), 1 mM EDTA, and
0.2% Triton X-100. Samples were treated with 100 µg/ml RNase for 30 min and then treated with 100 µg/ml proteinase K for 30 min at
37 °C. Cellular DNA was isopropanol-precipitated, dried, and
resuspended in Tris-EDTA buffer for 30 min at 55 °C. DNA was
analyzed by electrophoresis on 1.2% agarose gels containing ethidium bromide.
Apoptosis is characterized by cytoplasmic shrinkage, chromatin
condensation, and nuclear DNA fragmentation and culminates in cellular
death (22). In Jurkat T cells, induction of apoptosis by CH11, an
anti-Fas monoclonal antibody that mimics the proapoptotic effect of Fas
ligand, results in the disappearance of intact DNA and in
internucleosomal DNA fragmentation (Fig.
1A). In the presence of TPA no
DNA ladder, indicative of fragmentation, was observed, demonstrating
that this phorbol ester protects cell from apoptosis and may promote
cell survival (Fig. 1A) (12). The caspase family of proteins
consists of more than a dozen proteins, among which caspase 3 is
crucial for the final step of the apoptotic program. CH11-induced
activation of caspase 3, as followed by the disappearance of its 32-kDa
zymogen form in Western blotting, was also blocked by treatment with
TPA (Fig. 1B). The effect of TPA on both DNA fragmentation
and caspase 3 activation was completely abrogated by the PKC inhibitor
GF109203X (GFX) but was weakly sensitive to the MEK
inhibitor PD98059 (PD, Fig. 1, A and
B). These results indicate that the extracellular
signal-regulated kinase pathway plays only a minor role in the
protective effect of TPA. Execution of the apoptotic program is
achieved through cleavage by caspases of numerous cellular proteins
that are essential for cell proliferation and survival (23). Among
these substrates, we previously identified the serum response factor as
a target for caspase 3 during CH11-mediated apoptosis (24). In Jurkat T
cells, cleavage of serum response factor results in a drastic
inhibition of the activity of a c-fos SRE luciferase reporter plasmid
(Fig. 1C) (24). Interestingly, TPA was found to counteract
the inhibitory effect of CH11 on SRE activity and to concomitantly
abrogate serum response factor cleavage (Fig. 1C) (24).
Consistent with DNA fragmentation and caspase 3 immunoblotting
analysis, the protective effect of TPA on SRE activity was completely
abolished by GF109203X but only weakly affected by PD98059. These
results indicate that SRE luciferase activity can be used as a reporter
to monitor the apoptotic process. To define which PKC isoforms were
involved in the protective effect of TPA on cell death, we verified the
activity of several PKC mutant constructs on CH11-mediated apoptosis.
We first assessed the ability of PKC mutant constructs to
mediate SRE activation. Jurkat cells were transiently cotransfected
with the SRE luciferase vector and different PKC mutant constructs. As
observed in HEK 293 cells, constitutively active mutants of PKC
, PKC
, and PKC
, suggesting that novel and
conventional PKC isoforms mediate phorbol ester action. Moreover, TPA
stimulated phosphorylation of BAD at serine 112, an effect abrogated by
GF109203X but not by the MEK inhibitor PD98059. Expression of
constitutively active PKC increased the phosphorylation of BAD at
serine 112 but not at serine 136. Additionally, Fas-mediated cell death
was enhanced by overexpression of a catalytically inactive form of p90Rsk (Rsk2-KN). Finally, Rsk2-KN abolished the protective effect of
constitutively active PKC and totally blocked phosphorylation of BAD on
serine 112. Thus, novel PKC and PKC rescue T lymphocytes from
Fas-mediated apoptosis via a p90Rsk-dependent
phosphorylation and inactivation of BAD.
INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS AND DISCUSSION
REFERENCES
,
PKC
I, PKCII, and PKC
) are diacylglycerol- and
calcium-dependent, (b) novel PKCs (PKC
,
PKC, PKC
, PKC, and PKCµ) are
diacylglycerol-dependent but calcium-independent, and
(c) atypical PKCs (PKC
, PKC
, and PKC
) are not
activated by phorbol esters but can bind diacylglycerol (14, 15).
Overexpression of PKC, PKC, or PKC increases the resistance of
cells to apoptosis, and PKC inhibitors are known to sensitize cells to
apoptosis (16-20). Additionally, Fas ligation-induced apoptosis in
Jurkat T cells resulted in a blockade of cellular PKC activity,
suggesting a link between the two events (21). Although involvement of
PKC in the suppression of apoptosis has been demonstrated recently, the
mechanisms by which PKC promotes cell survival remain to be elucidated.
EXPERIMENTAL PROCEDURES
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS AND DISCUSSION
REFERENCES
, PKC, and PKC were detected with monoclonal antibodies (Transduction Laboratory) at 1:4000 and 1:1000 dilution, respectively, for PKC in saturation buffer and with a secondary anti-mouse antibody at a 1:5000 dilution. Proteins were visualized with
the Amersham ECL system.
RESULTS AND DISCUSSION
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS AND DISCUSSION
REFERENCES
,
PKC, and PKC stimulated SRE activity (with PKC 
PKC > PKC), whereas dominant negative mutants of these PKCs
were found to weakly inhibit the basal promoter activity (Fig.
2A) (25). Immunoblotting of
lysates from mock-transfected cells or cells transfected with either
PKC, PKC, or PKC revealed that the level of expression of the
corresponding proteins was comparable (Fig. 2A). We then
studied the effect of PKC constructs on CH11-induced apoptosis.
Introduction of the constitutively active form of PKC and PKC
totally prevented the CH11-induced inhibition of SRE activity, whereas
the effect of PKC was less pronounced (Fig. 2B). On the
other hand, constitutively active PKC failed to affect the induction
of apoptosis by CH11 (data not shown). The protective effect evoked by
constitutively active PKC, PKC, and, to a lesser extent, PKC
was abolished by GF109203X (Fig. 2B). Furthermore, dominant
negative mutants of PKC had no protective effect but rather increased
the inhibitory effect of CH11 on SRE activity, suggesting that they
behave as proapoptotic stimuli (Fig. 2B). Additionally,
dominant negative PKC, PKC, and PKC impaired the stimulatory
effect of TPA on SRE activity, indicating that each of these PKC
isoforms may mediate the effect of TPA, although PKC again appears
to be the most potent (Fig. 2C). These results strongly
suggest that TPA, through the activation of novel and probably
conventional PKC isoforms, protects cells from apoptosis. To better
understand how these PKC isoforms exert their antiapoptotic function,
we investigated the possible participation of an important regulator of
the cell death machinery, BAD. First, immunoblotting of protein lysates prepared from untreated, TPA-treated, or CH11-treated Jurkat T cells
with phospho-specific BAD antibodies revealed that TPA increased BAD
phosphorylation at Ser112, whereas CH11 dramatically
reduced the phosphorylation of BAD at the same site (Fig.
3, A and B). This
result indicates that CH11, which stimulates apoptosis through the
activation of death receptors, not only leads to caspase activation but
also plays a role in the regulation of the phosphorylation state of
BAD. Additionally, TPA promotes cell survival and BAD phosphorylation at Ser112 in Jurkat T cells. In HEK 293 cells,
TPA also stimulated phosphorylation of BAD at Ser112 but
not at Ser136, in agreement with the results of Tan
et al. (9) (Fig. 3C). In Jurkat T cells and in
HEK 293 cells, phosphorylation of BAD at Ser112 was
drastically inhibited by GF109203X, whereas PD98059 had no significant
ability to inhibit Ser112 phosphorylation (Fig. 3,
B and C). Thus, although PKC has been previously
shown to activate the MAPK pathway, MAPK activation is unlikely to be
the major signaling pathway by which TPA abrogates apoptosis (26-28).
Furthermore, we observed that Ly294002 had no effect on the TPA-induced
rise in BAD Ser112 phosphorylation, ruling out the
involvement of Akt in the protective effect of TPA (data not shown).
Interestingly, introduction of constitutively active PKC, PKC,
and PKC in HEK 293 cells also led to phosphorylation of BAD at
Ser112 (Fig. 4A)
but not at Ser136 (Fig. 4B). Moreover, in cells
overexpressing dominant negative PKC, phosphorylation of BAD at
Ser112 was significantly reduced (Fig. 4A),
indicating that under basal conditions, BAD is already phosphorylated
in a PKC-dependent fashion at Ser112. Finally,
dominant negative PKC and, more particularly, PKC blocked
TPA-induced stimulation of BAD at Ser112, demonstrating
that TPA-induced cell survival is mediated by these PKC isoforms (Fig.
4C). Until now, it has not been possible to show a direct
phosphorylation of BAD by PKC (9). On the other hand, it has recently
been demonstrated that the MAPK-activated p90 ribosomal S6 kinase
family (Rsk), a downstream target of extracellular signal-regulated
kinase, phosphorylates BAD at Ser112 both in
vitro and in vivo, and Rsk has been reported to protect cells from BAD-induced apoptosis (8, 9, 29, 30). Using the SRE
luciferase assay (24), we observed that introduction, in Jurkat T
cells, of a catalytically inactive form of Rsk 2, Rsk2-KN, not only
markedly decreased the protective effect of constitutively active
PKC, PKC, and PKC but also potentiated the inhibitory effect
of CH11 (Fig. 5A).
Immunoblotting of HEK 293 cell lysates with the phospho-specific BAD
Ser112 antibody revealed that expression of Rsk2-KN
abrogated constitutively active PKC-induced phosphorylation of BAD at
Ser112 (Fig. 5B). Taken together, these results
demonstrate that Rsk is involved in the protective effect of PKC.
View larger version (35K):
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Fig. 1.
TPA promotes cell survival in a
PKC-dependent pathway. A, Jurkat T cells
were left untreated or incubated with GF109203X (Calbiochem; 2 µM) or PD98059 (Calbiochem; 20 µM) for 30 min before treatment with TPA (Sigma Chemical Co.; 100 ng/ml) and CH11
(Euromedex; 80 ng/ml) for 4 h. The cells were then lysed and
analyzed for fragmented DNA. B, Jurkat T cells were exposed
to the different effectors as described in A. Immunoblotting
was done with a mouse monoclonal antibody that recognizes human caspase
3. C, Jurkat T cells were transiently transfected with a SRE
luciferase vector. Thirty-six h later, cells were exposed as described
in A and then assessed for their luciferase activity.
Results are expressed as a percentage of the luciferase activity from
unstimulated cells. Data are the means ± S.E. of three
independent experiments.
View larger version (18K):
[in a new window]
Fig. 2.
PKC ,
PKC, and PKC block
Fas-induced apoptosis. A, Jurkat T cells were
transfected with a c-fos SRE luciferase vector together with either an
empty vector or an expression vector encoding the constitutively active
(CA) or dominant negative (DN) PKC mutants. Two
days after transfection, cells were assayed for their luciferase
activity. Lysates from mock-transfected cells or cells transfected with
PKC constructs were immunoblotted with mouse monoclonal antibodies that
recognize either PKC, PKC, or PKC, and the results are
representative of several experiments. The fold stimulation over
the basal c-fos SRE luciferase evoked by PKC transfection is shown at
the top of the column. B, Jurkat T cells were
transfected as described in A. Two days after transfection,
cells were preincubated for 30 min with GF109203X (2 µM)
or PD98059 (20 µM) before exposure to CH11 (80 ng/ml) for
4 h. Cells were then assayed for their luciferase activity. The
fold stimulation over the basal c-fos SRE luciferase evoked by PKC
transfection when cells were treated with CH11 is shown at the
top of the column. C, Jurkat T cells were
transfected with DN-PKC mutants as described in A. Two days
after transfection, cells were exposed to TPA (100 ng/ml) for 4 h
and then assayed for their luciferase activity. Results of transfection
in A-C are expressed as a percentage of the luciferase
activity from unstimulated cells. Data are the means ± S.E. of
three independent experiments.
View larger version (30K):
[in a new window]
Fig. 3.
A and B, CH11 and TPA,
through a PKC-dependent but MAPK-independent pathway, exert
opposite effects on BAD Ser112 phosphorylation in Jurkat T
cells. C, HEK 293 cells transfected with a
glutathione S-transferase-BAD mammalian expression vector
were treated with different effectors as described in the Fig. 1
legend. Cell lysates (100 µg) were immunoblotted with polyclonal
phospho-specific BAD Ser112 and BAD Ser136
antibodies or with an antibody that recognizes BAD regardless of its
phosphorylation state.
View larger version (29K):
[in a new window]
Fig. 4.
PKC ,
PKC, and PKC promote
cell survival by phosphorylating BAD at Ser112.
A and B, HEK 293 cells were transfected as
described previously, together with either an empty vector or an
expression vector encoding various constitutively active
(CA) or dominant negative (DN) PKC constructs.
Immunoblotting was done with polyclonal phospho-specific BAD
Ser112 or Ser136 antibodies or with an antibody
that recognizes BAD regardless of its phosphorylation state.
C, HEK 293 cells were transfected as described in
A and B. Two days after transfection, cells were
incubated with TPA (100 ng/ml) for 4 h. The level of
phosphorylated BAD in cell lysates was analyzed by Western blot using
polyclonal phospho-specific BAD Ser112.
View larger version (17K):
[in a new window]
Fig. 5.
PKC-induced cell survival and BAD
phosphorylation at Ser112 through a
Rsk-dependent pathway. A, Jurkat T cells
were transfected with the SRE luciferase vector together with either an
empty vector or an expression vector encoding the constitutively active
(CA) PKC mutants in the presence or absence of a
catalytically inactive form of Rsk2 (Rsk2-KN). Two day later, cells
were left untreated or treated with CH11 (80 ng/ml) for 4 h before
they were assayed for luciferase activity. The total amount of
transfected DNA was kept constant by the addition of empty control
vector. Results are expressed as a percentage of the luciferase
activity from unstimulated cells. Data are the means ± S.E. of
three independent experiments. B, HEK 293 cells were
transfected as described in Fig. 3, C and D, in
the presence or absence of Rsk2-KN. Two days after transfection,
immunoblotting of cell lysates was done with polyclonal
phospho-specific BAD Ser112 antibody.
In this report, we showed that PKC, PKC, and, to a lesser extent,
PKC trigger BAD phosphorylation at Ser112, thus
preventing Fas-induced cell death and promoting cell survival. In
conclusion, we demonstrate that phorbol esters promote cell survival
essentially through a PKC-Rsk-dependent, MAPK-independent pathway that leads to phosphorylation and inactivation of BAD.
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ACKNOWLEDGEMENTS |
|---|
We thank Dr. M. Greenberg for providing the expression plasmid containing the catalytically inactive form of Rsk2 (Rsk2-KN). We are grateful to Dr. F. Mac Enzie for critical reading of the manuscript.
| |
FOOTNOTES |
|---|
* This work was supported by INSERM, The Ligue Nationale contre le Cancer.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.
§ Recipient of a fellowship from The Ligue Nationale contre le Cancer.
** To whom correspondence should be addressed: INSERM U526, Activation des Cellules Hématopoïétiques, Physiopathologie de la Survie et de la Mort Cellulaires et Infections Virales, Équipe Labelisée Ligue, IFR 50, 28 Avenue de Valombrose, 06107 Nice Cedex 2, France. Tel.: 33-4-93-37-76-76; Fax: 33-4-93-81-78-52; E-mail: auberger@unice.fr.
Published, JBC Papers in Press, September 6, 2000, DOI 10.1074/jbc.M007732200
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ABBREVIATIONS |
|---|
The abbreviations used are: TPA, 12-O-tetradecanoylphorbol-13-acetate; MAPK, mitogen-activated protein kinase; PKC, protein kinase C; MEK, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase; SRE, serum response element; HEK, human embryonic kidney.
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REFERENCES |
|---|
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TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS AND DISCUSSION
REFERENCES
|
|---|
| 1. | Datta, S. R., Dudek, H., Tao, X., Masters, S., Fu, H., Gotoh, Y., and Greenberg, M. E. (1997) Cell 91, 231-241 |
| 2. | Datta, S. R., and Greenberg, M. E. (1998) Horm. Signaling 1, 257-306 |
| 3. | Kinoshita, T., Yokota, T., Arai, K., and Miyajima, A. (1995) EMBO J. 14, 266-275 |
| 4. | del Peso, L., Gonzales-Garcia, M., Page, C., Herrera, R., and Nunez, G. (1997) Science 278, 687-689 |
| 5. | Yang, E., Zha, J., Jockel, J., Thompson, C. B., and Korsmeyer, S. J. (1995) Cell 80, 285-291 |
| 6. | Zha, J., Harada, H., Yang, E., Jockel, J., and Korsmeyer, S. J. (1996) Cell 87, 619-628 |
| 7. | Harada, H., Becknell, B., Wilm, M., Mann, M., Huang, L. J., Taylor, S. S., Scott, J. D., and Korsmeyer, S. J. (1999) Mol. Cell 3, 413-422 |
| 8. | Bonni, A., Brunet, A., West, A. E., Datta, S. R., Takasu, M. A., and Greenberg, M. E. (1999) Science 286, 1358-1362 |
| 9. | Tan, Y., Ruan, H., Demeter, M. R., and Comb, M. J. (1999) J. Biol. Chem. 274, 34859-34867 |
| 10. | Cuvillier, O., Pirianov, G., Kleuser, B., Vanek, P. G., Coso, O. A., Gutkind, J. S., and Spiegel, S. (1996) Nature 381, 800-803 |
| 11. | Gardner, A. M., and Johnson, G. L. (1996) J. Biol. Chem. 271, 14560-14566 |
| 12. | Holmström, T. H., Chow, S. C., Elo, I., Coffey, E. T., Orrenius, S., Sistonen, L., and Eriksson, J. E. (1998) J. Immunol. 160, 2626-2636 |
| 13. | Yeh, J. H., Hsu, S. C., Han, S. H., and Lai, M. Z. (1998) J. Exp. Med. 188, 1795-1802 |
| 14. | Baier-Bitterlich, G., Uberall, F., Bauer, B., Fresser, F., Wachter, H., Grunicke, H., Utermann, G., Altman, A., and Baier, G. (1996) Mol. Cell. Biol. 16, 1842-1850 |
| 15. | Newton, A. C. (1995) J. Biol. Chem. 270, 28495-28498 |
| 16. | Gray, M. O., Karliner, J. S., and Mochly-Rosen, D. (1997) J. Biol. Chem. 272, 30945-30951 |
| 17. | Jarvis, W. D., Turner, A. J., Povirk, L. F., Traylor, R. S., and Grant, S. (1994) Cancer Res. 54, 1707-1714 |
| 18. | Mayne, G. C., and Murray, A. W. (1998) J. Biol. Chem. 273, 24115-24121 |
| 19. | Savickiene, J., Gineitis, A., and Stigbrand, T. (1999) Cell Death Differ. 6, 698-709 |
| 20. | Whelan, R. D., and Parker, P. J. (1998) Oncogene 16, 1939-1944 |
| 21. | Chen, C. Y., and Faller, D. V. (1999) J. Biol. Chem. 274, 15320-15328 |
| 22. | Smith, C. A., Farrah, T., and Goodwin, R. G. (1994) Cell 76, 959-962 |
| 23. | Widmann, C., Gibson, S., and Johnson, G. L. (1998) J. Biol. Chem. 273, 7141-7147 |
| 24. | Bertolotto, C., Ricci, J. E., Luciano, F., Mari, B., Chambard, J. C., and Auberger, P. (2000) J. Biol. Chem 275, 12941-12947 |
| 25. | Soh, J. W., Lee, E. H., Prywes, R., and Weinstein, I. B. (1999) Mol. Cell. Biol. 19, 1313-1324 |
| 26. | Marquardt, B., Frith, D., and Stabel, S. (1994) Oncogene 9, 3213-3218 |
| 27. | Kolch, W., Heidecker, G., Kochs, G., Hummel, R., Vahidi, H., Mischak, G., Finkenzeller, D., Marme, D., and Rapp, U. R. (1993) Nature 364, 249-252 |
| 28. | Sozeri, O. K., Vollmer, M., Liyanage, D., Frith, D., Kour, G., Mark, G. E. D., and Stabel, S. (1992) Oncogene 7, 2259-2262 |
| 29. | Blenis, J. (1993) Proc. Natl. Acad. U. S. A. 90, 5889-5892 |
| 30. | Fisher, T. L., and Blenis, J. (1996) Mol. Cell. Biol. 16, 1212-1219 |
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 S.-L. Tan, J. Zhao, C. Bi, X. C. Chen, D. L. Hepburn, J. Wang, J. D. Sedgwick, S. R. Chintalacharuvu, and S. Na Resistance to Experimental Autoimmune Encephalomyelitis and Impaired IL-17 Production in Protein Kinase C{theta}-Deficient Mice. J. Immunol., March 1, 2006; 176(5): 2872 - 2879. [Abstract] [Full Text] [PDF]
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 M. DelCarlo and R. F. Loeser Chondrocyte cell death mediated by reactive oxygen species-dependent activation of PKC-betaI Am J Physiol Cell Physiol, March 1, 2006; 290(3): C802 - C811. [Abstract] [Full Text] [PDF]
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X.-J. Qi, G. M. Wildey, and P. H. Howe Evidence That Ser87 of BimEL Is Phosphorylated by Akt and Regulates BimEL Apoptotic Function J. Biol. Chem., January 13, 2006; 281(2): 813 - 823. [Abstract] [Full Text] [PDF]
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R. Barouch-Bentov, E. E. Lemmens, J. Hu, E. M. Janssen, N. M. Droin, J. Song, S. P. Schoenberger, and A. Altman Protein Kinase C-{theta} Is an Early Survival Factor Required for Differentiation of Effector CD8+ T Cells J. Immunol., October 15, 2005; 175(8): 5126 - 5134. [Abstract] [Full Text] [PDF]
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H. Okhrimenko, W. Lu, C. Xiang, N. Hamburger, G. Kazimirsky, and C. Brodie Protein Kinase C-{varepsilon} Regulates the Apoptosis and Survival of Glioma Cells Cancer Res., August 15, 2005; 65(16): 7301 - 7309. [Abstract] [Full Text] [PDF]
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A. Hashimoto, K. Hirose, and M. Iino BAD Detects Coincidence of G2/M Phase and Growth Factor Deprivation to Regulate Apoptosis J. Biol. Chem., July 15, 2005; 280(28): 26225 - 26232. [Abstract] [Full Text] [PDF]
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A. Hurbin, J.-L. Coll, L. Dubrez-Daloz, B. Mari, P. Auberger, C. Brambilla, and M.-C. Favrot Cooperation of Amphiregulin and Insulin-like Growth Factor-1 Inhibits Bax- and Bad-mediated Apoptosis via a Protein Kinase C-dependent Pathway in Non-small Cell Lung Cancer Cells J. Biol. Chem., May 20, 2005; 280(20): 19757 - 19767. [Abstract] [Full Text] [PDF]
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A. Duensing, N. E. Joseph, F. Medeiros, F. Smith, J. L. Hornick, M. C. Heinrich, C. L. Corless, G. D. Demetri, C. D. M. Fletcher, and J. A. Fletcher Protein Kinase C {theta} (PKC{theta}) Expression and Constitutive Activation in Gastrointestinal Stromal Tumors (GISTs) Cancer Res., August 1, 2004; 64(15): 5127 - 5131. [Abstract] [Full Text] [PDF]
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 K. M. Grebe, R. L. Clarke, and T. A. Potter Ligation of CD8 leads to apoptosis of thymocytes that have not undergone positive selection PNAS, July 13, 2004; 101(28): 10410 - 10415. [Abstract] [Full Text] [PDF]
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S. Trombino, A. Cesario, S. Margaritora, P. Granone, G. Motta, C. Falugi, and P. Russo {alpha}7-Nicotinic Acetylcholine Receptors Affect Growth Regulation of Human Mesothelioma Cells: Role of Mitogen-Activated Protein Kinase Pathway Cancer Res., January 1, 2004; 64(1): 135 - 145. [Abstract] [Full Text] [PDF]
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K. M. Eisenmann, M. W. VanBrocklin, N. A. Staffend, S. M. Kitchen, and H.-M. Koo Mitogen-Activated Protein Kinase Pathway-Dependent Tumor-Specific Survival Signaling in Melanoma Cells through Inactivation of the Proapoptotic Protein Bad Cancer Res., December 1, 2003; 63(23): 8330 - 8337. [Abstract] [Full Text] [PDF]
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B. Yan, M. Zemskova, S. Holder, V. Chin, A. Kraft, P. J. Koskinen, and M. Lilly The PIM-2 Kinase Phosphorylates BAD on Serine 112 and Reverses BAD-induced Cell Death J. Biol. Chem., November 14, 2003; 278(46): 45358 - 45367. [Abstract] [Full Text] [PDF]
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 C.-W. Chiang, C. Kanies, K. W. Kim, W. B. Fang, C. Parkhurst, M. Xie, T. Henry, and E. Yang Protein Phosphatase 2A Dephosphorylation of Phosphoserine 112 Plays the Gatekeeper Role for BAD-Mediated Apoptosis Mol. Cell. Biol., September 15, 2003; 23(18): 6350 - 6362. [Abstract] [Full Text] [PDF]
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D. M. Tillman, K. Izeradjene, K. S. Szucs, L. Douglas, and J. A. Houghton Rottlerin Sensitizes Colon Carcinoma Cells to Tumor Necrosis Factor-related Apoptosis-inducing Ligand-induced Apoptosis via Uncoupling of the Mitochondria Independent of Protein Kinase C Cancer Res., August 15, 2003; 63(16): 5118 - 5125. [Abstract] [Full Text] [PDF]
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 K. El-Haschimi, S. D. Dufresne, M. F. Hirshman, J. S. Flier, L. J. Goodyear, and C. Bjorbaek Insulin Resistance and Lipodystrophy in Mice Lacking Ribosomal S6 Kinase 2 Diabetes, June 1, 2003; 52(6): 1340 - 1346. [Abstract] [Full Text] [PDF]
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N. Engedal and H. K. Blomhoff Combined Action of ERK and NFkappa B Mediates the Protective Effect of Phorbol Ester on Fas-induced Apoptosis in Jurkat Cells J. Biol. Chem., March 21, 2003; 278(13): 10934 - 10941. [Abstract] [Full Text] [PDF]
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E. Astoul, A. D. Laurence, N. Totty, S. Beer, D. R. Alexander, and D. A. Cantrell Approaches to Define Antigen Receptor-induced Serine Kinase Signal Transduction Pathways J. Biol. Chem., March 7, 2003; 278(11): 9267 - 9275. [Abstract] [Full Text] [PDF]
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D. E. Muscarella and S. E. Bloom Cross-linking of Surface IgM in the Burkitt's Lymphoma Cell Line ST486 Provides Protection against Arsenite- and Stress-induced Apoptosis That Is Mediated by ERK and Phosphoinositide 3-Kinase Signaling Pathways J. Biol. Chem., January 31, 2003; 278(6): 4358 - 4367. [Abstract] [Full Text] [PDF]
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B. Cipriani, H. Knowles, L. Chen, L. Battistini, and C. F. Brosnan Involvement of Classical and Novel Protein Kinase C Isoforms in the Response of Human V{gamma}9V{delta}2 T Cells to Phosphate Antigens J. Immunol., November 15, 2002; 169(10): 5761 - 5770. [Abstract] [Full Text] [PDF]
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Y.-J. Chwae, M. J. Chang, S. M. Park, H. Yoon, H.-J. Park, S. J. Kim, and J. Kim Molecular Mechanism of the Activation-Induced Cell Death Inhibition Mediated by a p70 Inhibitory Killer Cell Ig-Like Receptor in Jurkat T Cells J. Immunol., October 1, 2002; 169(7): 3726 - 3735. [Abstract] [Full Text] [PDF]
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B. Yusta, J. Estall, and D. J. Drucker Glucagon-like Peptide-2 Receptor Activation Engages Bad and Glycogen Synthase Kinase-3 in a Protein Kinase A-dependent Mann |
