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B, and Stress-Activated Protein Kinase1
*
Departments of Microbiology and Molecular Genetics and Medicine, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA 02115; and
Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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B and induces many of the
phenotypic changes in B lymphocytes that accompany CD40 activation.
Since the phenotypic effects of LMP1 are similar to those of activated
CD40, we now compare signaling from the LMP1 CT with that from the CD40
CT fused to the LMP1 transmembrane domains. The LMPCD40 chimera was
similar to LMP1 in nuclear factor-B activation and in up-regulation
of epidermal growth factor receptor expression. CD40 ligation was known
to activate the stress-activated protein kinase, and both LMPCD40 and
LMP1 are now shown to induce stress-activated protein kinase activity
in the absence of ligand. Deletion of the first four transmembrane
domains of LMP1 abrogated LMP1 aggregation in the plasma membrane and
nearly abolished signaling from LMP1 or the LMPCD40 chimera. These
results highlight the role of LMP1 as a constitutively active receptor
similar to CD40 and provide a novel approach for the generation of
ligand-independent receptors. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B activation (5, 10, 11). Genetic and biochemical studies are compatible with the hypothesis that LMP1 mimics an activated TNF receptor (TNFR) similar to CD40 (12, 13, 14). The LMP1 N-terminal 24 amino acids are in the cytoplasm, and their function in growth transformation appears to be as an anchor for the first transmembrane domain (15). The six hydrophobic transmembrane domains of LMP1, separated by short reverse turns, are critical for lymphocyte growth transformation, and their activity is linked to their ability to confer aggregation in a patch in the plasma membrane (2). The LMP1 200-amino acid cytoplasmic carboxyl terminus (CT) is also essential for lymphocyte growth transformation (16). A membrane-proximal CT domain (amino acids 187–231) is sufficient for transformation in its natural linkage to the multiple transmembrane domains, although the outgrowth of the transformed cells is compromised compared with that of cells transformed by wild-type virus (16). In EBV-transformed LCLs this domain is constitutively associated with TNFR-associated factors (TRAFs) (12, 13, 14). Deletion of LMP1 codons 185 to 211, which encode the core LMP1 TRAF binding domain, results in EBV recombinants that are unable to transform primary B lymphocytes (17). This is consistent with the working hypothesis that TRAF interactions mediate most of LMP1’s transforming effects. TRAFs have been implicated in signal transduction from TNFRs, such as type I and II TNFRs, CD40, and CD30 (18, 19, 20, 21, 22). Unlike LMP1 association with TRAFs, which is constitutive, TNFRs associate with TRAFs only in response to ligand (23, 24, 25). Many of the LMP1-mediated phenotypic effects in B lymphocytes are similar to the effects of activated CD40 (7, 8).
In transient 293 cell transfection assays, the TRAF-interacting domain
of LMP1 contributes only approximately 25% of the total LMP1-mediated
NF-B activation (Fig. 1
) (10, 11, 12, 13, 14). A
second LMP1 domain (amino acids 333–386) at the carboxyl terminus of
the CT mediates approximately 75% of the NF-B activation (Fig. 1)
(10, 11). Surprisingly, only the TRAF-interacting domain can induce
EGFR expression in epithelial cells (26), consistent with the idea that
this domain mediates signaling processes other than NF-B activation
that are important for transformation and EGFR expression.
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). The LMP1 transmembrane domains should
enable the fusion protein to aggregate in the plasma membrane. The
locally high concentration of CD40 cytoplasmic domains should have
effects similar to those mediated by LMP1 or ligand-activated
CD40. |
Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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293 is a human embryonic kidney cell line, and C33 is a human cervical carcinoma cell line. The cells were grown in DMEM with 10% FBS (D10). 293 cells were transfected by electroporation. Briefly, 5 x 106 cells were trypsinized, washed twice in RPMI 1640 medium with 10% FBS (R10), and electroporated in 400 µl of R10 at 200 V and 960 µF in a 0.4-cm cuvette using a GenePulser electroporator (Bio-Rad Laboratories, Richmond, CA). The cells were then cultured in D10 at 37°C. C33 cells were transfected with calcium phosphate (27). Cells transfected with pCDNA3-based vectors (Invitrogen, San Diego, CA) were selected in D10 with 600 µg/ml G418 (Life Technologies, Grand Island, NY).
Plasmid construction
Constructs made from pSG5 (Stratagene, La Jolla, CA) use the
SV40 early promoter and are designated pS. Constructs made from pCDNA3
(Invitrogen) use the CMV immediate early promoter/enhancer and are
designated pC. PSLMP
194–386 lacks LMP1 codons 194
to 386; it was a gift from Dr. Martin Rowe (University of Cardiff,
Cardiff, U.K.) (10). The LMP1 transmembrane domain and CD40 cytoplasmic
domain fusion protein expression construct was made by PCR
amplification of codons 216 to 277 from a human CD40 cDNA (a gift from
Dr. Hitoshi Kikutani) with primers CD40N1
(5'-AAAAGGCCTTGAAAAAGGTGGCCAAGAAGCC-3') and CD40C1
(5'-AAAAGGCCTCACTGTCTCTCCTGCACTGAG-3'). The PCR product was digested
with StuI and cloned into the T4 DNA polymerase blunt-ended
NcoI site in pUCLMP1 (pUC with the LMP1 cDNA cloned
into the EcoRI site) to make pUCLMPCD40. The sequence of the
cloned CD40 cDNA fragment was identical with that of the wild type. The
chimeric cDNA was then subcloned into the EcoRI site of pSG5
to make pSLMPCD40. The pSD1LMPCD40 was made by subcloning the
XhoII fragment of pSLMPCD40 into the BamHI site
of pSG5. PSG5FLAGLMP1 has been previously described (17).
PSG5FLAGLMPCD40 was constructed by subcloning the XhoI
fragment of B220LMPCD40 into the XhoI site of pSG5FLAGLMP1.
B220LMPCD40 was constructed by subcloning the MamI to
Bpu1102 fragment of pSLMPCD40 into B220 (13). The pCLMP1 has
been previously described (9). PCLMPCD40 was made by cloning the
EcoRI insert from pUCLMPCD40 into the EcoRI site
of pCDNA3. PCD1LMPCD40 was made by cloning the XhoII
fragment from pSLMPCD40 into the BamHI site of pCDNA3.
PCLMP194–386 was made by subcloning the
EcoRI insert from pSLMP194–386 into the
EcoRI site of pCDNA3. The human CD40 expression vector
pEFBOSCD40 was a gift from Dr. Hitoshi Kikutani.
Luciferase reporter assays
Briefly, 293 cells in log phase growth at 50% confluence were
electroporated with the NF-B reporter construct 3x-B-L (11), an
expression plasmid, and a control phosphoglucokinase promoter-driven
ß-galactosidase expression plasmid (GKßgal) to normalize for
transfection efficiency. Twenty-four or forty-eight hours
posttransfection, the cells were harvested in PBS and lysed in
luciferase lysis buffer (Promega, Madison, WI). Luciferase and
ß-galactosidase activities were measured with an OPTOCOMP I (MGM,
Norwalk, CT) luminometer as previously described (13).
Antibodies
EGFR was detected with a rabbit polyclonal Ab (EGFR-1005, Santa Cruz Biotechnology, Santa Cruz, CA). LMP1 was detected with mAb S12. The LMPCD40 chimera was detected with a rabbit polyclonal Ab against amino acids 258 to 277 of the CD40 precursor (CD40C20, Santa Cruz Biotechnology). FLAG-tagged proteins were detected with the M5 mouse mAb (Eastman Kodak, Rochester, NY). c-Rel was detected with a rabbit polyclonal Ab (cREL(C), Santa Cruz Biotechnology).
Stress-activated protein kinase (SAPK) assay
To determine the effect of LMP1 or LMPCD40 chimeric constructs
on the activity of SAPK, 293 cells were electroporated with an
expression vector for one of these constructs and with an expression
vector (pEBG-SAPK-p54ß) (28) for a GST fusion of SAPK-p54ß
(GSTSAPK) (29). The cotransfected cells were grown for several hours in
D10. Following attachment of the cells to the tissue culture flask, the
culture media were changed to DMEM with 0.1% FBS. After incubation for
approximately 16 to 18 h, the cells were washed in PBS and lysed
in 25 mM Tris-HCl (pH 7.4), 150 mM NaCl, 5 mM EDTA, 1% Triton X-100,
10% glycerol, 10 mM ß-glycerophosphate, 1 mM DTT, 10 mM sodium
pyrophosphate, 1 mM sodium orthovanadate, 1 mM PMSF, and 18 µg/ml
aprotinin. A fraction of each cell lysate was analyzed by immunoblot to
determine the level of expression of GSTSAPK using a rabbit polyclonal
antiserum against GST. Two equal aliquots of each cell extract were
adsorbed to glutathione-Sepharose beads (Pharmacia, Piscataway, NJ) for
1 h at 4°C, and the beads were washed three times with 1 ml of
lysis buffer. One aliquot of SAPK bound to beads was analyzed by
immunoblot for GSTSAPK expression, while the second was washed twice
with 1x kinase buffer (20 mM Tris-HCl (pH 7.5) and 8 mM
MgCl2) and assayed for GSTJUN (a GST fusion of c-Jun
amino acids 1–79) phosphorylating activity in 20 µl of a reaction
mix containing 20 mM Tris-HCl (pH 7.5), 8 mM MgCl2, 0.1 mM
ATP, and 0.5 µCi of [
-32P]ATP at 30°C for 15
min.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). As a control, CD40 codons 216 to 277 were
fused in-frame to LMP1 codons 129 to 187. LMP1 codons 129 to 187 encode
the last two LMP1 transmembrane domains and constitute the
membrane-anchoring domain of D1LMP1, a protein that is expressed from
an internal promoter of the LMP1 gene in lytic EBV infection. D1LMP1
consists of LMP1 amino acids 129 to 386 (Fig. 1). Unlike LMP1, D1LMP1
accumulates diffusely in all cytoplasmic membranes and has no
transforming or activating effects when expressed in immortalized
rodent fibroblasts or human B lymphoblasts (30, 31). LMPCD40 and
D1LMPCD40 were tested for their ability to activate NF-B and
compared with wild-type LMP1 and LMP1194–386,
which lacks the LMP1 CT.
In 293 cells, LMP1 with an amino-terminal FLAG tag activated NF-B in
a standard reporter plasmid assay (Fig. 2A). Activation was
dependent on the LMP1 CT, since deletion of the CT resulted in minimal
or no activation (LMP194–386 in Fig. 2) as previously
reported (10, 11). Replacement of the LMP1 CT with the CD40 cytoplasmic
domain resulted in NF-B activation, similar to that obtained with
LMP1 (FLAGLMPCD40 in Fig. 2A). Western blot analysis
with an anti-FLAG Ab (M5 mouse monoclonal, Kodak) demonstrated that
FLAGLMPCD40 was expressed at levels similar to FLAGLMP1 (Fig. 2C). NF-B activation by LMPCD40 was also compared
with activation obtained by overexpression of CD40 alone in 293. When
CD40 was expressed at levels similar to or higher than those of
LMPCD40, it generated only 12% of the NF-B activation obtained with
LMPCD40 (mean values were calculated from three independent
experiments; data not shown). NF-B activation by LMPCD40 was largely
dependent on the LMP1 multiple hydrophobic transmembrane domains, since
D1LMPCD40 expression resulted in minimal NF-B activation (D1LMPCD40
in Fig. 2B). D1LMPCD40 expression levels in 293 cells
were similar to or higher than those of FLAGLMPCD40 as revealed by
immunoblot analysis with an Ab (CD40C20, Santa Cruz Biotechnology)
raised against part of the cytoplasmic tail of CD40 (Fig. 2D). Activation of the NF-B reporter construct by
LMPCD40 was also dependent on the integrity of the NF-B sites, since
a similar reporter construct with mutated NF-B sites (3x-mut-L)
(11) was only minimally activated by LMPCD40 (the activation of
3x-mut-L by LMPCD40 was <3% of the activation obtained with
wild-type 3x-B-L reporter; data not shown). Therefore, high level
NF-B activation by LMPCD40 is probably due to the ability of the
multiple hydrophobic transmembrane domains to enable signaling by
causing aggregation in the plasma membrane.
|
). Thus, high level NF-B activation
by LMPCD40, as opposed to low level NF-B activation by D1LMPCD40,
correlates with LMP1CD40 aggregation in the plasma membrane.
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).
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194–386 were transiently expressed in 293 cells
along with a GSTSAPK fusion protein (pEBG-SAPK-p54ß) (28). GSTSAPK
was then isolated from transfected cell lysates using
glutathione-coupled Sepharose beads, and SAPK activity was measured
using an Escherichia coli-expressed GSTJUN fusion protein as
a substrate. LMPCD40 and LMP1 activated SAPK severalfold over the
background of vector-transfected cells (Fig. 5A, compare lane 1
with lanes 2 and 3). The activation ranged
from two- to fivefold in three independent experiments. LMPCD40
consistently activated SAPK slightly more than LMP1. The activation of
SAPK by LMP1 and LMPCD40 is also evident in the slower mobility of the
GSTSAPK band (Fig. 5B, lanes 2 and
3), which has previously been associated with SAPK
phosphorylation and activation (34). This is the first demonstration of
SAPK activation by LMP1, and it implicates this protein kinase in the
LMP1 signaling process. Activation of SAPK by LMPCD40 and LMP1 was
dependent on the multiple hydrophobic transmembrane domains of LMP1 and
on the LMP1 or CD40 cytoplasmic domains, since neither the hydrophobic
transmembrane domains alone (pCLMP194–386) nor the last
two LMP1 transmembrane domains fused in-frame to the CD40 cytoplasmic
domain (pCD1LMPCD40) activated SAPK (Fig. 5). LMPCD40 and D1LMPCD40
were expressed at similar levels, as indicated by immunoblot analysis
with the CD40C20 Ab (data not shown). Therefore, the failure of
D1LMPCD40 to signal activation of SAPK is most likely due to the
inability of this protein to aggregate in the plasma membrane, a
property that requires all six LMP1 transmembrane domains of LMP1
(Fig. 3) (2, 30, 35).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B and SAPK, and
up-regulate EGFR expression. LMP1 transmembrane-domain mediated plasma membrane aggregation could be a general mechanism for constitutive, ligand-independent, receptor aggregation. For receptors such as TNFRs that exhibit sustained activation with continued ligand-induced aggregation, the LMP1 transmembrane domains could confer ligand-independent activation. Similar chimeric molecules expressed in specific tissues at specific stages of development may be of use in delineating the pure effects of cell type-restricted receptor activation in the absence of potential effects of ligand on surrounding cells or of countersignaling from the receptor to the ligand-expressing cell. Not all receptors exhibit sustained activation in response to ligand. Some, like surface Ig, that signal through nonreceptor tyrosine kinase pathways transmit transient activation and are desensitized to continuous signaling (36, 37). Interestingly, EBV encodes another multiple membrane-spanning integral membrane protein, LMP2, which also has an intrinsic ability to aggregate in the plasma membrane. LMP2 constitutively associates with Lyn and Syk protein tyrosine kinases and induces sustained desensitization to Lyn- and Syk-mediated signal transduction (38).
These experiments highlight the similarities between LMP1 and CD40
signal transduction. CD40 and the membrane proximal domain of the LMP1
CT have similar primary amino acid sequences through which they engage
TRAFs (13, 19). Both activate NF-B through TRAF2 (13, 20, 25). The
major NF-B-activating domain of LMP1 is located at the distal end of
the CT. Despite its lower NF-B-activating capability, only the
membrane-proximal LMP1 CT domain, and not the distal domain, can
directly engage TRAFs and up-regulate EGFR expression. Thus, EGFR
up-regulation requires a pathway distinct from general NF-B
activation and appears to correlate with direct TRAF engagement by the
LMP1 membrane-proximal CT or the CD40 cytoplasmic domain.
CD40 has been known to activate SAPK, and we now show that LMP1 is
similar to CD40 in SAPK activation. SAPK-mediated phosphorylation
potentiates the trans-activating properties of certain
transcription factors such as c-Jun and activating transcription
factor-2 (39, 40). These factors have been implicated in
trans-activation of growth regulatory genes, and they may be
used by CD40 or LMP1 to promote cell growth, transformation, or EGFR
induction (41). TRAF2 has recently been shown to mediate SAPK
activation by TNF through a NF-B-independent pathway (42, 43). Since
both the LMP1 CT and the cytoplasmic tail of CD40 engage TRAF2, TRAF2
probably mediates SAPK activation from both cytoplasmic domains.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. George Mosialos, Brigham and Women’s Hospital, 181 Longwood Ave., Boston, MA 02115. E-mail address:
3 Abbreviations used in this paper: LMP1, latent membrane protein-1; LCLs, lymphoblastoid cell lines; EGFR, epidermal growth factor receptor; NF-B, nuclear factor-B; TNFR, tumor necrosis factor receptor; CT, carboxyl terminus; TRAF, tumor necrosis factor receptor-associated factor; SAPK, stress-activated protein kinase; GST, glutathione-S-transferase.
Received for publication June 12, 1997. Accepted for publication October 14, 1997.
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B activation by latent infection membrane protein 1, the Epstein-Barr virus transforming protein. Proc. Natl. Acad. Sci. USA 93:11085.B by TNF receptor 2 and CD40. Science 269:1424.B activation and binding specificity. Proc. Natl. Acad. Sci. USA 93:9699.B. Proc. Natl. Acad. Sci. USA 94:2460.B activation. J. Virol. 71:586.[Abstract]
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B. Damania, J.-K. Choi, and J. U. Jung Signaling Activities of Gammaherpesvirus Membrane Proteins J. Virol., February 15, 2000; 74(4): 1593 - 1601. [Full Text]
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K. M. Izumi, E. C. McFarland, E. A. Riley, D. Rizzo, Y. Chen, and E. Kieff The Residues between the Two Transformation Effector Sites of Epstein-Barr Virus Latent Membrane Protein 1 Are Not Critical for B-Lymphocyte Growth Transformation J. Virol., December 1, 1999; 73(12): 9908 - 9916. [Abstract] [Full Text]
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K. M. Kaye, K. M. Izumi, H. Li, E. Johannsen, D. Davidson, R. Longnecker, and E. Kieff An Epstein-Barr Virus That Expresses Only the First 231 LMP1 Amino Acids Efficiently Initiates Primary B-Lymphocyte Growth Transformation J. Virol., December 1, 1999; 73(12): 10525 - 10530. [Abstract] [Full Text]
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M. Fenton and A. J. Sinclair Divergent Requirements for the MAPKERK Signal Transduction Pathway during Initial Virus Infection of Quiescent Primary B Cells and Disruption of Epstein-Barr Virus Latency by Phorbol Esters J. Virol., October 1, 1999; 73(10): 8913 - 8916. [Abstract] [Full Text] [PDF]
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K. M. Izumi, E. C. McFarland, A. T. Ting, E. A. Riley, B. Seed, and E. D. Kieff The Epstein-Barr Virus Oncoprotein Latent Membrane Protein 1 Engages the Tumor Necrosis Factor Receptor-Associated Proteins TRADD and Receptor-Interacting Protein (RIP) but Does Not Induce Apoptosis or Require RIP for NF-kappa B Activation Mol. Cell. Biol., August 1, 1999; 19(8): 5759 - 5767. [Abstract] [Full Text] [PDF]
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H. Takeshita, T. Yoshizaki, W. E. Miller, H. Sato, M. Furukawa, J. S. Pagano, and N. Raab-Traub Matrix Metalloproteinase 9 Expression Is Induced by Epstein-Barr Virus Latent Membrane Protein 1 C-Terminal Activation Regions 1 and 2 J. Virol., July 1, 1999; 73(7): 5548 - 5555. [Abstract] [Full Text]
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A. G. Eliopoulos, N. J. Gallagher, S. M. S. Blake, C. W. Dawson, and L. S. Young Activation of the p38 Mitogen-activated Protein Kinase Pathway by Epstein-Barr Virus-encoded Latent Membrane Protein 1 Coregulates Interleukin-6 and Interleukin-8 Production J. Biol. Chem., June 4, 1999; 274(23): 16085 - 16096. [Abstract] [Full Text] [PDF]
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M. P. Peppelenbosch, M. DeSmedt, T. ten Hove, S. J.H. van Deventer, and J. Grooten Lipopolysaccharide Regulates Macrophage Fluid Phase Pinocytosis Via CD14-Dependent and CD14-Independent Pathways Blood, June 1, 1999; 93(11): 4011 - 4018. [Abstract] [Full Text] [PDF]
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 L. K. Busch and G. A. Bishop The EBV Transforming Protein, Latent Membrane Protein 1, Mimics and Cooperates with CD40 Signaling in B Lymphocytes J. Immunol., March 1, 1999; 162(5): 2555 - 2561. [Abstract] [Full Text] [PDF]
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A. G. Eliopoulos, S. M. S. Blake, J. E. Floettmann, M. Rowe, and L. S. Young Epstein-Barr Virus-Encoded Latent Membrane Protein 1 Activates the JNK Pathway through Its Extreme C Terminus via a Mechanism Involving TRADD and TRAF2 J. Virol., February 1, 1999; 73(2): 1023 - 1035. [Abstract] [Full Text]
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P. G. Stevenson and P. C. Doherty Non-Antigen-Specific B-Cell Activation following Murine Gammaherpesvirus Infection Is CD4 Independent In Vitro but CD4 Dependent In Vivo J. Virol., February 1, 1999; 73(2): 1075 - 1079. [Abstract] [Full Text]
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O. Devergne, E. C. McFarland, G. Mosialos, K. M. Izumi, C. F. Ware, and E. Kieff Role of the TRAF Binding Site and NF-kappa B Activation in Epstein-Barr Virus Latent Membrane Protein 1-Induced Cell Gene Expression J. Virol., October 1, 1998; 72(10): 7900 - 7908. [Abstract] [Full Text] [PDF]
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W. Kulwichit, R. H. Edwards, E. M. Davenport, J. F. Baskar, V. Godfrey, and N. Raab-Traub Expression of the Epstein-Barr virus latent membrane protein 1 induces B cell lymphoma in transgenic mice PNAS, September 29, 1998; 95(20): 11963 - 11968. [Abstract] [Full Text] [PDF]
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B. S. Sylla, S. C. Hung, D. M. Davidson, E. Hatzivassiliou, N. L. Malinin, D. Wallach, T. D. Gilmore, E. Kieff, and G. Mosialos Epstein-Barr virus-transforming protein latent infection membrane protein 1 activates transcription factor NF-kappa B through a pathway that includes the NF-kappa B-inducing kinase and the Ikappa B kinases IKKalpha and IKKbeta PNAS, August 18, 1998; 95(17): 10106 - 10111. [Abstract] [Full Text] [PDF]
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A. C. Grammer, J. L. Swantek, R. D. McFarland, Y. Miura, T. Geppert, and P. E. Lipsky TNF Receptor-Associated Factor-3 Signaling Mediates Activation of p38 and Jun N-Terminal Kinase, Cytokine Secretion, and Ig Production Following Ligation of CD40 on Human B Cells J. Immunol., August 1, 1998; 161(3): 1183 - 1193. [Abstract] [Full Text] [PDF]
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W. E. Miller, J. L. Cheshire, and N. Raab-Traub Interaction of Tumor Necrosis Factor Receptor-Associated Factor Signaling Proteins with the Latent Membrane Protein 1 PXQXT Motif Is Essential for Induction of Epidermal Growth Factor Receptor Expression Mol. Cell. Biol., May 1, 1998; 18(5): 2835 - 2844. [Abstract] [Full Text]
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M. A. Luftig, E. Cahir-McFarland, G. Mosialos, and E. Kieff Effects of the NIK aly Mutation on NF-kappa B Activation by the Epstein-Barr Virus Latent Infection Membrane Protein, Lymphotoxin beta Receptor, and CD40 J. Biol. Chem., April 27, 2001; 276(18): 14602 - 14606. [Abstract] [Full Text] [PDF]
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E. D. Cahir-McFarland, D. M. Davidson, S. L. Schauer, J. Duong, and E. Kieff NF-kappa B inhibition causes spontaneous apoptosis in Epstein-Barr virus-transformed lymphoblastoid cells PNAS, May 23, 2000; 97(11): 6055 - 6060. [Abstract] [Full Text] [PDF]
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