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/DOß Heterodimer1
Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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subunit, DN, of the class II
processing factor DO as an additional CIITA-inducible gene. Northern
analysis confirmed that DN is induced by IFN-
in 2fTGH
fibrosarcoma cells, and CIITA is necessary for high-level expression in
B cells. The ß subunit, DOß, is not inducible in fibrosarcoma cells
by IFN- or exogenous CIITA expression. Moreover, in contrast to
other class II genes, DOß expression remains high in the absence of
CIITA in B cells. The promoters for DN and DOß contain the highly
conserved WXY motifs, and, like other class II genes, expression of
both DN and DOß requires RFX. These findings demonstrate that both
DN and DOß are regulated by RFX. However, DN is defined for the
first time as a CIITA-inducible gene, and DOß as a MHC class II gene
whose expression is independent of CIITA. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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/ß heterodimers on
the surfaces of B cells, activated T cells, dendritic cells, and many
somatic cells following induction by IFN-. Intracellularly, class II
molecules associate with the invariant chain
(Ii)3
(1). Ii inhibits binding of peptides to class II molecules
in the endoplasmic reticulum and directs class II molecules to the
endosomal MHC class II compartment (2), where Ii is
degraded and binding of antigenic peptides occurs (3, 4, 5).
Efficient peptide loading also requires the function of DM, a class
II-like heterodimer that resides in the MHC class II compartment
(6, 7, 8). DM acts as a chaperone for MHC class II molecules,
catalyzing the release of an Ii-derived peptide class II-associated Ii
peptide (CLIP) from class II molecules, stabilizing the empty
peptide-binding grooves and permitting loading of appropriate high
stability peptide ligands (for review, see Refs. 9, 10, 11).
Two additional genes within the MHC locus, DN (formerly DZ) and
DOß, also have homology to MHC proteins. The DN protein originally
was presumed to be independent from the DO heterodimer because in
fibroblasts DN, but not DOß, is induced by IFN-
(12). However, the association between the two subunits
was suggested in studies examining DO localization in human B lymphoma
cells. DO was shown to accumulate in lysosomes in a DM-dependent
fashion, and accumulation depended upon both DN and DOß
(13). Association between DN and DOß also has been
demonstrated directly by copurification of baculovirus-expressed
proteins (14) and by coimmunoprecipitation of endogenous
proteins in PGF B cell lysates (15). Virtually all DO
molecules are physically associated with DM (14, 16), and
DO originally was thought to function primarily as an inhibitor of DM
due to its ability to cause accumulation of DR-CLIP complexes when
overexpressed (16, 17). The biological role of this
inhibition was clarified when gene knockout mice were made for the
murine counterpart of DO, H2-O (18). Cells from
H2-O-deficient mice had normal levels of class II expression, normal
levels of CLIP, and a mixture of peptides like wild-type mice. However,
the absence of H2-O resulted in a loss of discrimination between
different forms of Ags, and inhibition by DO was shown to occur
selectively at high pH. These results suggest that DO functions by
decreasing presentation of Ags internalized by fluid-phase endocytosis
in favor of Ags internalized via membrane Ig receptors. Consistent with
this model, DO has been shown to promote presentation of stable
DR-peptide complexes when expressed at more physiological levels
(14). This is especially true for DR alleles that are DM
dependent and bind weakly to DM, such as DR4 (14). Thus,
whether DO acts as an enhancer or inhibitor of DM may be dependent upon
levels of DO expression, the quality of Ag, and the class II allele
(for review, see Refs. 19, 20, 21).
The majority of MHC class II-related genes are coregulated. W, X, and Y
boxes in their promoters are conserved in sequence and spacing, and
this triad motif is known to govern B cell-specific and
IFN--inducible gene expression of DR, DP, DQ, DM, and Ii. Four
complementation groups from bare lymphocyte syndrome (BLS) patients
have defined two master regulators that are essential for cell-specific
class II expression, RFX and class II transcriptional activator
(CIITA). RFX is a trimeric protein composed of RFX5 (complementation
group C) (22), RFXAP (group D) (23), and
RFXANK/RFX-B (group B) (24, 25). RFX is thought to direct
B cell-specific and IFN--inducible expression of MHC class II genes
through binding to the X box (26) and possibly the W box
(27). CIITA (group A) (28) is the only MHC
class II transcription factor known to be induced in response to
IFN-, and its expression alone is sufficient to activate expression
of the MHC class II genes (29, 30, 31). CIITA is a
nonclassical transactivator that requires intact W, X, and Y boxes, yet
functions without apparent DNA binding. CIITA has several functional
domains typically associated with transcriptional activation, including
an amino terminal acidic domain (32, 33, 34),
proline/serine/threonine-rich regions (28, 35), a nuclear
localization sequence (36), and several leucine-rich
repeats (37). However, its primary mode of action is
thought to involve the bridging of multiple transcription factors
together at the class II promoter. CIITA has been shown to interact
with several other transcriptional activators, including TAFII32,
Bob-1, RFX5, RFXANK, CREB, CREB binding protein, PTEFb, and NF-YB and C
(34, 38, 39, 40, 41, 42, 58, 59). CIITA
also is unique in that it is the only transcriptional activator known
to be regulated by GTP binding (43). Though the DN and
DOß gene promoters also contain W, X, and Y boxes, expression of
these genes is often incongruous with other MHC class II-associated
genes (12, 15, 44), and whether DN and DOß are
induced by RFX or CIITA remains an open question.
In the present study, we have performed representational difference
analysis (RDA) to identify uncharacterized CIITA-inducible genes. RDA
is a powerful methodology that combines subtractive hybridization and
PCR amplification to identify differentially expressed genes
(45, 46, 47, 48). Enrichment of differentially expressed genes is
2-fold: subtractive enrichment is obtained through hybridization with
an excess of driver cDNA, and kinetic enrichment is obtained through
higher rates of annealing and removal of the more abundant DNA species
(47). Subsequent PCR amplification allows recovery of
genes that are expressed even at very low level. Successive rounds of
hybridization/subtraction and PCR also can be done, resulting in the
exponential enrichment of differentially expressed genes. We have
performed RDA using cDNA from G3A fibrosarcoma cells stably transfected
with CIITA vs cells transfected with a vector control. All
CIITA-induced genes were found to be MHC class II related. DN was
identified for the first time as a CIITA-inducible gene. We show that
DN is induced by IFN- in 2fTGH cells and that its high-level
expression in B cells requires CIITA. In contrast, DOß is shown to be
refractive to induction by CIITA. Implications for the discoordinate
regulation of these two genes are discussed.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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2fTGH and G3A fibrosarcoma cells (49) were grown in
Dulbecco’s Modified Eagles Medium supplemented with 10% FCS (Life
Technologies). G3A is a mutant cell line derived from 2fTGH that is
deficient in IFN- induction of MHC class II. CIITA transcript is
absent in uninduced G3A cells, and is detectable in IFN--induced
cells at a very low level, which does not lead to MHC expression
(30). The preparation of G3A-p4 and G3A-CIITA cell lines
has been described (50). Briefly, pREP4 (Invitrogen, San
Diego, CA) and pREP4-CIITA (50) episomal expression
plasmids were transfected into G3A cells, and cells were selected for 2
wk in media containing 250 µg/ml hygromycin B (Boehringer Mannheim,
Mannheim, Germany). Media was changed every 3 days. Cells were cultured
subsequently in 250 µg/ml hygromycin B. Expression of CIITA in
G3A-CIITA cells was confirmed by Northern blotting for CIITA, and
induction of MHC class II expression was confirmed by Northern analysis
and FACS staining for DR. Where indicated, 2fTGH, G3A, or G3A-p4 cells
were induced for 24 h with 500 U/ml IFN- (Genzyme, Cambridge,
MA). Jurkat E6–1 T lymphocytes (TIB 152; American Type Culture
Collection, Manassas, VA), Raji B lymphocytes (CCL86; American Type
Culture Collection), RJ2.2.5 and BCH CIITA-mutant B cells
(28), BLS-1 RFXANK-deficient B cells (24),
and SJO RFX5-deficient B cells (22) were cultured in RPMI
1640, 10% FCS. Cells were incubated at 37°C in 5%
CO2.
Representational difference analysis
Cytoplasmic mRNA was purified from G3A-p4 and G3A-CIITA cells by
two passes over Oligotex particles (Qiagen, Chatsworth, CA), and mRNA
integrity was confirmed by Northern blotting with
32P labeled GAPDH and DR. CDNA was prepared
using the Superscript Choice System for cDNA Synthesis (Life
Technologies). Complete cDNA synthesis was confirmed by low-level
incorporation of [32P]dCTP, electrophoresis,
and autoradiography. RDA was performed essentially as described using
the Bgl-24 and Bgl-12 oligo series (47, 48). The steps
taken to isolate CIITA-induced genes are outlined in Fig. 1
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Representations of G3A-p4 and G3A-CIITA cDNA were prepared by digesting
2 µg of cDNA with DpnII, ligating paired adaptor/primer
oligonucleotides, and PCR amplifying. Three rounds of
hybridization/subtraction and PCR amplification were completed using
G3A-CIITA representation as tester and G3A-p4 representation as driver.
Adaptors were changed for each round. Tester:driver ratios of 1:100,
1:800, and 1:400,000 were used in successive rounds, yielding
difference products (DP) 1–3. For DP4 and 5, the MHC driver was
prepared by combining DN, CIITA, and known CIITA-induced genes,
including DR, DRß, DP, DPß, DQ, DQß, DM, DMß, and
Ii (American Type Culture Collection). Tester and driver were combined
at ratios of 1:1,000 and 1:200,000 for DP4 and DP5, respectively. Gene
fragments from DP3 and DP5 were cloned by digestion with
DpnII and ligation into BamHI-digested Bluescript
II vector (Stratagene, La Jolla, CA). Following transformation, known
CIITA-induced genes were further eliminated by colony hybridization
(51) using radiolabeled MHC driver. Southern hybridization
of plasmids from unlabeled colonies with 32P MHC
driver was performed as a final step to eliminate as many known genes
as possible. Cloned gene fragments were sequenced and identified
through blast searches. All manipulations of mRNA and cDNA were done
with aerosol tips to avoid cross contamination of samples.
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Northern analysis was performed using 
100 ng mRNA. The mRNA
was isolated using Oligotex direct purification (Qiagen),
electrophoresed on formaldehyde gels, and blotted onto nylon membranes.
Probes were prepared by random priming of isolated gene fragments
(Prime-it II; Stratagene) for DR, DOß, and GAPDH (American Type
Culture Collection) or by PCR probe synthesis of a cloned 453- to
781-bp fragment for DN. Northern analyses were run in parallel or
stripped and reprobed for each gene set. Southern analysis was
performed using 4 µl of cDNA from G3A-p4 representation, G3A-CIITA
representation, or difference products from successive rounds of RDA.
The probes were prepared as described above.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To identify uncharacterized CIITA-induced genes, stable cell lines
were prepared containing a CIITA expression plasmid (pREP4-CIITA) or a
vector control plasmid (pREP4) (50). G3A fibrosarcoma
cells were chosen as a background for expression because deficient MHC
class II induction in these cells correlates with suboptimal induction
of CIITA (30). To avoid any potential background from the
low-level endogenous CIITA induced by IFN-, transcripts in G3A-p4
and G3A-CIITA cells were compared in the absence of IFN-.
Cytoplasmic mRNA was isolated from G3A-p4 and G3A-CIITA cells and
reverse transcribed, and representations (cDNA fragments representing
the entire mRNA contents of cells) were amplified following digestion
with DpnII (Fig. 1
). To
identify genes exclusively expressed in G3A-CIITA cells, the G3A-p4
representation was used in excess as the driver, and the G3A-CIITA
representation as the tester. Three rounds of hybridization/subtraction
and PCR amplification were performed with increasing ratios of G3A-p4
driver to G3A-CIITA tester. The G3A-p4 driver, G3A-CIITA tester, and
difference products (DP) from successive rounds of subtraction/PCR
amplification were analyzed by electrophoresis and ethidium bromide
staining (Fig. 2A). As
expected, the G3A-p4 driver and G3A-CIITA tester each appeared as
continuous smears of bands (lanes p4 and
CII). DP1 to 3 were progressively subtracted to a ladder of
discrete bands (lanes DP1–3). This is consistent
with the effective selection of a subset of gene fragments from the
G3A-CIITA tester.
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gene as a model CIITA-inducible gene
(Fig. 2B). Results indicated that DR gene fragments were
enriched significantly in the first round of subtraction
(lane DP1). Levels of DR remained high in the
subsequent two rounds (Fig. 2B, lanes DP2 and
DP3), while the total DNA content was reduced (Fig. 2A, lanes DP2 and DP3). This is
consistent with the progressive enrichment of CIITA-induced genes.
Levels of the housekeeping gene GAPDH as assessed by dot blot
hybridization appeared to decrease during subtraction, indicating that
enrichment was specific for MHC class II genes (data not shown). Gene
fragments were subcloned into Bluescript II vector and analyzed by
sequencing. Fragments from DR, DRß, DQ, DQß, and Ii genes
were identified, further confirming the appropriate enrichment of
CIITA-induced genes (Table I).
Significantly, DN was also isolated as a potential CIITA-induced
gene. This was indicated by the recovery of a 453- to 781-bp fragment
of the DN-coding region, as well as a 3' untranslated fragment from
the 3.5-kb alternative DN transcript (52).
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,
DRß, DP, DPß, DQ, DQß, DM, DMß, Ii, CIITA, and DN
as driver (Fig. 1). As seen by ethidium bromide staining, the ladder of
fragments appeared to reduce in complexity even further during these
two additional rounds (Fig. 2A, lanes DP4 and
DP5). Moreover, Southern analysis for DR indicated
significant reduction of known MHC genes from the pool during this
process (Fig. 2B, lanes DP4 and DP5).
Gene fragments from DP5 were cloned, and known MHC genes were further
filtered out by colony hybridization with radiolabeled MHC genes.
Eighty colonies that hybridized poorly with radiolabeled MHC were
cultured, plasmids were isolated, and an additional round of negative
selection was performed to screen out known MHC genes by Southern
analysis with pooled MHC. Gene fragments that survived these four
additional screening steps then were sequenced. Despite extensive
negative screening, several known CIITA-induced genes remained in the
pool, including DR, DQß, and Ii, as well as the DN 3'
untranslated fragment (Table I). This likely is due to the selectively
high abundance of these genes in CIITA-induced cells. Several ribosomal
genes and a mitochondrial gene were also identified during the
analysis. We have observed these genes commonly in other RDA searches
and thus they are likely artifacts of the procedure. We also recovered
six nonhousekeeping genes that could not be confirmed to be
differentially expressed by Northern hybridization. Thus, the only
genes induced by CIITA that could be detected by this protocol are MHC
class II genes, and the recovery of fragments from DN strongly
suggest that it is an additional CIITA-inducible gene.
DN and DOß are discoordinately regulated by CIITA
Northern analysis was performed to confirm DN mRNA induction by
CIITA. Consistent with the RDA results, DN transcript was found in
G3A-CIITA cells, but not in G3A-p4 cells (Fig. 3). Expression was seen for both the
full-length 1.1-kb (53) and the alternatively spliced
3.5-kb transcript. To determine whether DN transcription is induced
by endogenous CIITA expression, mRNA was collected from wild-type 2fTGH
cells following IFN- induction. DN transcripts were detected in
IFN--treated 2fTGH cells, but not in untreated cells. DN levels
also were low in IFN--treated G3A-p4 cells, indicating that IFN-
induction of DN requires CIITA. To test whether DN expression
correlates with CIITA expression in B cells, mRNA was tested from
wild-type Raji B lymphoblasts vs its CIITA-defective counterpart,
RJ2.2.5 (28). An additional CIITA-deficient cell line,
BCH, also was tested. As expected, DN 3.5-kb and 1.1-kb transcripts
were expressed in Raji cells. Levels were reduced in RJ2.2.5 cells and
absent in BLS-2 cells. Reduction in RJ2.2.5 of the 1.1-kb transcript
was 3-fold, while the 3.5-kb transcript was 1.6-fold. However, this
disparity is of unknown significance because both transcripts yield the
same protein (52). These findings indicate that DN
expression is inducible by CIITA in fibrosarcoma cells and is partially
to fully dependent upon CIITA in B cells.
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exists intracellularly as a heterodimer with DOß (termed DO)
(15). To test whether DOß is similarly regulated by
CIITA in the same cell, Northern blots were probed with radiolabeled
DOß cDNA. Surprisingly, DOß was not induced either endogenously by
IFN- in 2fTGH, or by exogenous CIITA expression in G3A-CIITA cells
(Fig. 3, panel DOß). As previously observed (12), DOß
is expressed in Raji B lymphocytes, yet levels of expression remain
high even in the absence of CIITA in RJ2.2.5. DOß expression was also
high in CIITA-deficient BLS-2 cells. However, expression was absent in
Jurkat T cells, suggesting that, while not dependent upon CIITA, DOß
expression is B cell specific. These findings suggest that the DO
heterodimer subunits are regulated discoordinately.
RFX is essential for DN and DOß expression in B cells
The DOß promoter, similar to other known CIITA-inducible
promoters, is comprised of conserved W, X, and Y elements (Table II). In part, CIITA derives its activity
through interaction with the trimeric transcription factor RFX, which
is essential for transactivation from the X box and is thought to bind
the W box as well (27, 40). Voliva et al. have shown that
the X box of DOß can substitute functionally in the DR promoter
(54). However, in gel shift assays, the DOß X box is
unable to compete for X-binding complexes on the DR X box. Based on
these findings, the authors have hypothesized that a different protein
complex may bind to the X box of DOß (54). To directly
test whether RFX is involved in the expression of DN and DOß in B
cells, mRNA from the RFX mutant B cell lines BLS-1 and SJO was
examined. BLS-1 is deficient in the RFXANK subunit (24),
while SJO is deficient in the RFX5 subunit of the RFX heterotrimer
(22). Northern analysis indicates that both DN and
DOß expression are absent in these mutant cell lines (Fig. 4). These findings indicate that,
although expression of DOß is CIITA independent, RFX is required for
both DN and DOß expression in B cells.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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subunit of MHC processing factor DO
also was defined for the first time as a CIITA-inducible gene, whereas
the DOß gene is CIITA independent. While we cannot rule out the
possibility that there may be additional unknown CIITA-inducible genes,
DN was the only one found in this system. Several rounds of
screening were done to filter out known CIITA genes. Initially, two
additional rounds of subtraction were done using a pool of all known
CIITA-inducible genes. Next, colony hybridization was done using pooled
radiolabeled MHC cDNA to eliminate residual CIITA-induced genes.
Finally, gene fragments from unlabeled/lightly labeled colonies were
assayed by Southern blotting with pooled radiolabeled MHC cDNA. Despite
these efforts to eliminate known MHC genes from the final difference
product, the genes recovered were those previously known to be CIITA
induced, DN, or artifacts. Note, however, that this procedure
may not be exhaustive. It is possible that some CIITA-induced genes
were lost during the PCR amplification or subtraction steps. Because
CIITA was expressed exogenously in G3A cells in the absence of IFN-,
genes whose induction depends both on CIITA and additional
IFN--inducible components may be missed. Also, it is possible that
there are additional CIITA-inducible genes that are expressed in APCs
in vivo.
The identification of DN as a CIITA-induced gene is consistent with
the IFN- induction of DN in human fibroblasts (12)
and neuroblastoma cells (55). We also have confirmed the
requirement for CIITA for DN expression by Northern analysis: DN
is induced both by exogenous CIITA expression in G3A cells and by
endogenous CIITA in 2fTGH cells following IFN- treatment.
Furthermore, DN gene expression is reduced in complementation group
A cell lines. However, the CIITA-dependent expression of DN we
observe is seemingly in contrast to the expression of its murine
homologue, H2-O, in the spleen of CIITA knockout mice
(44). We have shown that DN is partially expressed in
CIITA-defective RJ2.2.5 cells. Thus, it is possible that in B cells
there is an alternate mechanism of regulation that can partially
activate DN. Alternatively, regulation may differ in mouse and
human B cells.
Whereas expression of DN is regulated by CIITA, we have shown that
its heterodimeric partner, DOß, is not CIITA inducible in G3A cells.
This is consistent with the lack of DOß observed in IFN--induced
fibroblasts (12). We also have shown that DOß expression
is independent of CIITA in B cells, consistent with the expression of
H2-Oß in CIITA knockout mice (44). The refractiveness of
the DOß gene to CIITA is of interest for several reasons. First, the
DN and DOß genes comprise a unique MHC-related heterodimer in that
they appear to be regulated independently. The biological role of
discoordinate expression is unclear. It is especially intriguing that
DN is expressed in the absence of DOß in IFN--induced cells
(Ref. 12 and Fig. 3). It is possible that DN has a
function that is independent of DOß. Alternately, it may pair with an
unknown ß subunit in IFN--induced cells. To address these
possibilities, it will be necessary to perform localization and
immunoprecipitation experiments using anti-DN Abs.
A second point of interest is that DOß is unusual in its ability to
be expressed independent of CIITA. This is a surprising finding because
the promoter of DOß, like all MHC class II genes, has conserved W, X,
and Y boxes. Additionally, we have shown that expression of DOß
requires the X-binding protein, RFX. CIITA is thought to act as a
transcriptional scaffold by recruiting transcription factors that bind
W, X, and Y boxes. It is possible that in B cells there is an unknown
transcriptional coactivator that can bridge proteins onto the DOß
promoter in the absence of CIITA. It is likely that sequences outside
of the proximal promoter region are involved because a 250-bp fragment
of the DOß promoter is not sufficient to confer activation of a
reporter gene in Raji cells (54). Nevertheless, the DOß
promoter provides an interesting model for studying mechanisms of MHC
gene regulation without the overwhelming effects of CIITA. This
promoter might be used to more precisely define functional interactions
between W, X, and Y factors on the MHC promoter that occur independent
of CIITA. Furthermore, the DOß promoter may serve as a model for
identifying new transcriptional activators, transcriptional repressors,
and/or chromatin remodeling factors involved in MHC class II gene
activation. The DO heterodimer is also expressed in some, but not all,
cultured dendritic cells (15, 20, 21), and it would be of
interest to determine the parameters that determine dendritic cell
expression. Lastly, it would be of interest to determine whether CIITA
is involved in the LAN-5 neuroblastoma model in which DOß is induced
by IFN- (55).
In summary, we have used RDA for the first time to identify
CIITA-inducible genes. We have shown that all genes induced in this
system are MHC class II genes or MHC class II-associated genes. We have
characterized DN for the first time as an additional CIITA-induced
gene, and have demonstrated an interesting disparity in DN and DOß
control by CIITA. Finally, we show that despite this disparity, both
DN and DOß are controlled by RFX. It will be of interest to
identify additional factors controlling the expression of DOß and to
elucidate the function of DN expression independent of DOß.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Jenny P.-Y. Ting, Department of Microbiology and Immunology, 209 Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599-7295.
3 Abbreviations used in this paper: Ii, invariant chain; CLIP, class II-associated Ii peptide; CIITA, class II transcriptional activator; RDA, representational difference analysis; DP, difference product; BLS, bare lymphocyte syndrome.
Received for publication February 18, 2000. Accepted for publication May 11, 2000.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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S. F. Greer, J. A. Harton, M. W. Linhoff, C. A. Janczak, J. P.-Y. Ting, and D. E. Cressman Serine Residues 286, 288, and 293 within the CIITA: A Mechanism for Down-Regulating CIITA Activity through Phosphorylation J. Immunol., July 1, 2004; 173(1): 376 - 383. [Abstract] [Full Text] [PDF]
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T. M. C. Hornell, G. W. Beresford, A. Bushey, J. M. Boss, and E. D. Mellins Regulation of the Class II MHC Pathway in Primary Human Monocytes by Granulocyte-Macrophage Colony-Stimulating Factor J. Immunol., September 1, 2003; 171(5): 2374 - 2383. [Abstract] [Full Text] [PDF]
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 D. J. Taxman, J. P. MacKeigan, C. Clements, D. T. Bergstralh, and J. P-Y. Ting Transcriptional Profiling of Targets for Combination Therapy of Lung Carcinoma with Paclitaxel and Mitogen-activated Protein/Extracellular Signal-regulated Kinase Kinase Inhibitor Cancer Res., August 15, 2003; 63(16): 5095 - 5104. [Abstract] [Full Text] [PDF]
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M. Bouillon, Y. El Fakhry, J. Girouard, H. Khalil, J. Thibodeau, and W. Mourad Lipid Raft-dependent and -independent Signaling through HLA-DR Molecules J. Biol. Chem., February 21, 2003; 278(9): 7099 - 7107. [Abstract] [Full Text] [PDF]
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U. M. Nagarajan, A. Bushey, and J. M. Boss Modulation of Gene Expression by the MHC Class II Transactivator J. Immunol., November 1, 2002; 169(9): 5078 - 5088. [Abstract] [Full Text] [PDF]
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 J. P. MacKeigan, D. J. Taxman, D. Hunter, H. S. Earp III, L. M. Graves, and J. P-Y. Ting Inactivation of the Antiapoptotic Phosphatidylinositol 3-Kinase-Akt Pathway by the Combined Treatment of Taxol and Mitogen-activated Protein Kinase Kinase Inhibition Clin. Cancer Res., July 1, 2002; 8(7): 2091 - 2099. [Abstract] [Full Text] [PDF]
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U. M. Nagarajan, J. Lochamy, X. Chen, G. W. Beresford, R. Nilsen, P. E. Jensen, and J. M. Boss Class II Transactivator Is Required for Maximal Expression of HLA-DOB in B Cells J. Immunol., February 15, 2002; 168(4): 1780 - 1786. [Abstract] [Full Text] [PDF]
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C. Roucard, C. Thomas, M.-A. Pasquier, J. Trowsdale, J.-J. Sotto, J. Neefjes, and M. van Ham In Vivo and In Vitro Modulation of HLA-DM and HLA-DO Is Induced by B Lymphocyte Activation J. Immunol., December 15, 2001; 167(12): 6849 - 6858. [Abstract] [Full Text] [PDF]
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D. E. Cressman, W. J. O'Connor, S. F. Greer, X.-S. Zhu, and J. P.-Y. Ting Mechanisms of Nuclear Import and Export That Control the Subcellular Localization of Class II Transactivator J. Immunol., October 1, 2001; 167(7): 3626 - 3634. [Abstract] [Full Text] [PDF]
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 K. S. Glazier, S. B. Hake, H. M. Tobin, A. Chadburn, E. J. Schattner, and L. K. Denzin Germinal Center B Cells Regulate Their Capability to Present Antigen by Modulation of HLA-DO J. Exp. Med., April 15, 2002; 195(8): 1063 - 1069. [Abstract] [Full Text] [PDF]
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