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* Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109; and
Department of Microbiology and Immunology, Indiana University School of Medicine, and
Walther Oncology Center, Indianapolis, IN 46202
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Although much of the sequence of the procathepsin E (proCatE) promoter is known, regulation of CatE transcription is not well understood. ProCatE promoter constructs can only be transcribed in cells that express endogenous CatE; thus, the expression probably depends upon cell type-specific transcription factors (6). The hemopoietic transcription factors PU.1, GATA1, and AP1 have been shown to enhance CatE expression, whereas the ubiquitous factor YY1 represses it (6). It has been proposed that YY1 may block transcription by competing with cell type-specific factors for binding to the promoter (6).
Class II transactivator (CIITA), a non-DNA-binding transcription factor, activates and is required for the expression of MHC II and other genes related to Ag presentation (9, 10, 11). CIITA can also modulate immune responses by repressing the transcription of other genes, including IL-4, collagen 
2, and Fas ligand (12, 13, 14, 15, 16, 17). Three different isoforms of CIITA have been identified, each transcribed from a separate, independently regulated promoter (18). Alternative splicing of these transcripts produces isoform-specific mRNAs. Two isoforms, types I and III, are expressed primarily in immature dendritic cells (DC) and B cells, respectively. Type I CIITA protein includes a caspase recruitment domain (CARD) at the N terminus (19). The CARD confers potent transactivation activity to the type I isoform, so that type I CIITA activates MHC II transcription more strongly than type III CIITA. However, other differences between the isoforms and their importance in cell-specific function remain to be determined.
In this study we report that CatE expression is negatively regulated by CIITA. CIITA–/– cells exhibited increased CatE, whereas cells overexpressing CIITA showed decreased CatE mRNA, protein, and proteolytic activity. In addition, CIITA repressed transcription at the CatE promoter, and interestingly, type III, but not type I, CIITA showed suppressive activity. We also report for the first time that PU.1- and p300-induced CatE promoter activity is inhibited by CIITA.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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CIITA–/– mice were previously described (20). A
–/– and C57BL/6 mice were purchased from Taconic Farms (Germantown, NY) and The Jackson Laboratory (Bar Harbor, ME), respectively. All mice were maintained under specific pathogen-free conditions at University of Michigan Medical School and Indiana University School of Medicine animal facilities.
Mouse splenic B cells were enriched by positive selection with anti-B220 magnetic microbeads (Miltenyi Biotech, Auburn, CA). RJ2.2.5 (CIITA-deficient EBV-transformed human B cell line) cells were provided by Dr. L. Denzin (Sloan-Kettering Cancer Institute, New York, NY). TA3 (mouse B cell line) cells were provided by Dr. P. Allen (Washington University, St. Louis, MO). DO11.10.109 (OVA-specific T cell hybridoma) cells were provided by Dr. S. Kovats (City of Hope National Medical Center, Duarte, CA), and HT-2 (IL-2-dependent mouse T cell line) cells were provided by Dr. P. Marrack (National Jewish Medical and Research Center, Denver, CO). AGS (human gastric adenocarcinoma, CRL-1739) and Raji (EBV-transformed human B cell, CCL-86) cell lines were purchased from American Type Culture Collection (Manassas, VA). AGS cells were maintained in Kaighn’s modification of Ham’s F-12-K medium. Raji, RJ2.2.5, TA3, DO11.10.109, and HT-2 cells were maintained in RPMI 1640 medium with 1 x 10–5 M 2-ME. All media were supplemented with 10% FBS, 2 mM L-glutamine, 1.5 g/l sodium bicarbonate, and 100 µg/ml penicillin and streptomycin.
Flow cytometry
Abs specific for HLA-DR (L243) were obtained from BD Biosciences (Mountain View, CA). Flow cytometry was performed using a FACScan or FACSCalibur, and data were analyzed using CellQuest software (BD Biosciences).
DNA microarray analysis
Total RNA was prepared using TRIzol (Invitrogen, Carlsbad, CA) and was concentrated using an RNeasy miniprep kit (Qiagen, Valencia, CA). Labeled cRNA probes were prepared from the total RNA samples and hybridized to murine genome arrays (U74Av2) from Affymetrix (Santa Clara, CA). Hybridization and data analysis were performed with assistance from the Michigan National Institute of Diabetes and Digestive and Kidney Diseases Biotechnology Center.
RT-PCR and quantitative real-time PCR
Total RNA was prepared using TRIzol (Invitrogen). The cDNA was prepared as previously described (21). Quantitative real-time PCR (qRT-PCR) of mouse and human CatE was performed using SYBR Green by the comparative threshold cycle (
CT) method, and data were normalized to mouse GAPDH or human -actin as previously described (7, 17). Mouse CatE primer sequences and concentrations were: forward: 5'-TGACTACATCCTGCCGGACCT-3' (300 nM); reverse, 5'-AAGCCACTGCCGCAGAACT-3' (900 nM; product size, 93 bp). Human CatE primer sequences and concentrations were: forward, 5'-TTTCCCAGTCCAGCACATACA-3' (300 nM); and reverse, 5'-TCTGCATCCACAAAGGTCTG-3' (300 nM; product size, 174 bp).
DNA and transfections
The following DNA constructs were previously described: FLAG-tagged type I and type III CIITA, L27Q mutant of type I CIITA, and the expression vector pcDNA3 (19); wild-type p300 (22); CIITA domain mutants encoding residues 1–331, 408–857, and 990-1130 (13); luciferase reporter constructs containing the MHC II E promoter (1991 bp) (12) or the proCatE promoter (M1 and M4) (6); and CMV promoter-driven -galactosidase (-gal) (12). Wild-type and antisense PU.1 expression vectors were generated by cloning cDNA encoding sense or antisense mouse PU.1 into the pCB6 vector (23, 24).
To generate AGS cells that stably express CIITA, AGS cells were transfected with the construct encoding cDNA for type III CIITA. Cells were then selected in 2 mg/ml G418 (Genetecin; Invitrogen), and HLA-DR-positive cells from two independently transfected pools of cells (T1 and T2) were sorted using a FACSVantage (BD Biosciences). Sorted cells were further maintained under the same selection. The populations of HLA-DR-positive cells used to make protein lysates underwent two rounds of expansion and positive selection using anti-HLA-DR magnetic microbeads (Miltenyi Biotech). A control line of AGS transfected with vector only (V) was transfected with pcDNA3, selected, and maintained in 2 mg/ml G418.
For functional studies of promoter activity, 1 x 105 AGS cells were transiently transfected with Fugene 6 (Roche, Indianapolis, IN) using 0.25 µg promoter/reporter construct, 0.25 µg -gal reporter, and 0.75 µg CIITA, CIITA mutant, or vector. For PU.1 and p300 studies, 0.125 µg of promoter/reporter construct, 0.125 µg of -gal reporter, 0.25 µg of CIITA or vector, and 0.25 µg of PU.1 (or p300) or vector were used. For dose-response curves, 1 x 105 AGS cells were transfected with 0.125 µg promoter/reporter construct, 0.125 µg of -gal reporter, and variable amounts of CIITA as indicated, and control vector was added to bring the total DNA per transfection to 1.5 µg. Cell lysates were prepared and used for luciferase and -gal assays as previously described (12). Relative luciferase activity was calculated using the luciferase activity of cells transfected with the reporter DNA alone. Each transfection was performed in triplicate, and values represent the average of at least three transfections.
Western blot
Western blots were performed using whole cell lysate as previously described (25). The primary Abs used were 7-H (anti-CIITA) (26), anti-CatD (sc-10725; Santa Cruz Biotechnology, Santa Cruz, CA), and rabbit polyclonal anti-CatE (provided by Dr. M. Taylor, Parke Davis, Ann Arbor, MI). For CatE Western blot, protein lysates were run using nonreducing loading buffer to detect both dimeric and monomeric CatE. All other blots were performed with denatured, boiled protein samples.
Quantification of Western blot samples was performed by densitometry analysis with a FluorChem 8900 Imaging System and AlphaEase FC software (Alpha Innotech, San Leandro, CA). Background-subtracted integrated density values were adjusted to -actin intensity, then normalized to expression from the control sample (set at 1).
In vitro digestion and Ag presentation assays
To assess Ag processing by AGS cells with and without CIITA, OVA was digested with lysates from AGS or a CIITA-transfected AGS stable line (T1) following the protocol described by Nishioku et al. (4). AGS and T1 cells were homogenized with a syringe, and cell lysates were clarified by centrifugation at 16,000 x g for 20 min at 4°C. In a 100-µl volume of citrate buffer, 85 µg of total cell protein from each clarified cell lysate was incubated with an equal volume of OVA (10 mg/ml in 100 mM citrate buffer, pH 5.5) at 37°C for 4 h. AGS or T1 OVA digests were boiled and clarified by centrifugation, then 100 µl of each digest was incubated for 16 h with TA3 cells (previously fixed in 0.5% paraformaldehyde). After washing, 4 x 104 TA3 cells were cocultured with 2 x 104 OVA-specific T cells (DO11.10.109 hybridoma) for 24 h. T cell IL-2 production was quantitated using the IL-2-dependent T cell line HT-2. HT-2 cells were incubated with cell culture supernatants from T cell hybridomas for 16 h. [3H]thymidine (1 µCi/well) was then added for 8 h, and the cells were harvested onto filters. Levels of [3H]thymidine incorporation were determined by liquid scintillation counting on a Wallac Microbeta unit (PerkinElmer, Wellesley, MA). All assays were performed in triplicate.
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Results |
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We initially observed differences in CatE expression in a DNA microarray analysis of gene expression in CIITA knockout (CIITA–/–) mice. CIITA–/– B cells expressed a higher level of CatE transcripts than the control cells (C57BL/6). However, the expression of all other cathepsins tested (B, C, D, F, G, H, L, S, and Z) was not significantly different from the control (data not shown). To confirm the differences observed by DNA microarray, we used qRT-PCR to compare CatE expression in splenic B cells from control and CIITA–/– mice. CIITA–/– B cells expressed 
3- to 4-fold more CatE mRNA than the controls (Fig. 1A). Because CIITA is required for transcription of MHC II genes, CIITA–/– mice also lack MHC II expression. To determine whether the increased CatE expression arose from the absence of CIITA or was secondary to the lack of MHC II, we also analyzed CatE expression in B cells from A–/– mice, which express CIITA but are deficient in MHC II. A–/– B cells expressed CatE at levels comparable to the controls (Fig. 1A), suggesting that the increased CatE expression is associated with the absence of CIITA.
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45-kDa monomer and an 85-kDa disulfide-linked dimer (reviewed in Ref. 1). To detect both dimeric and monomeric forms, we performed Western blot under nonreducing conditions for CatE. As shown in Fig. 1B, CIITA–/– splenocytes expressed greater CatE protein than the controls. This increase was observed for both dimeric and monomeric CatE. To quantify the difference by densitometry, signal from both forms was combined, adjusted to intensity of -actin, and normalized to control. CatE protein was 3-fold greater in CIITA–/– than controls, consistent with the degree of difference in mRNA expression.
After observing greater CatE mRNA and protein levels in CIITA–/– mice, we next tested whether CIITA also regulates CatE expression in human B cells. To do so, we evaluated CatE expression by qRT-PCR in Raji and RJ2.2.5 cells, a wild-type and a CIITA-deficient B cell line, respectively. The CIITA-deficient RJ2.2.5 cells expressed 2- to 3-fold more CatE mRNA than Raji cells (Fig. 1C). Thus, the lack of CIITA produces increased CatE expression in both mouse and human B cells. We then wished to determine whether CatE protein was also higher in RJ2.2.5. However, we were not able to detect CatE protein in the Raji or RJ2.2.5 cell lines by Western blot (data not shown). This finding is consistent with a previous study that reported very low levels of CatE in unstimulated human B cells (2).
Introduction of CIITA down-regulates CatE expression and decreases OVA Ag processing
Having found that cells lacking CIITA express greater CatE, we next asked whether introducing CIITA could down-regulate the expression of endogenous CatE. Because human B cells do not express a significant amount of CatE, we chose another human cell line that expresses a high basal level of CatE, the gastric adenocarcinoma line AGS. We stably transfected type III CIITA into AGS cells. To avoid clonal variability, we used pools of cells from two independent transfections, T1 and T2. AGS cells transfected with empty pcDNA3 vector only (V) were used as a control. As CIITA expression should activate endogenous MHC class II genes, we tested for MHC II (HLA-DR) as a marker for functional expression of transfected CIITA (21). As expected, both T1 and T2 lines expressed cell surface HLA-DR, whereas the control vector-only transfectants (V) did not (Fig. 2A).
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1.5- to 5-fold less protein (Fig. 2B, first and second panels). Nonlinearity of signal in Western blots with higher protein concentrations led to an underestimate of the fold decrease in CatE expression in the CIITA-transfected cells. To confirm that this change was specific to CatE, we also tested protein levels of another cathepsin family member, CatD. For both processed and unprocessed forms of CatD, protein levels were comparable across all four samples regardless of the presence or the absence of CIITA (Fig. 2B, third panel). Although both T1 and T2 expressed comparable levels of cell surface HLA-DR, T2 expressed more CIITA protein than T1 and showed a slightly greater repression of CatE expression (compare Fig. 2A and fourth panel of Fig. 2B). To determine whether the differences in CatE protein correlated with changes in CatE gene transcription in the CIITA-expressing cells, we also performed qRT-PCR with AGS, T1, T2, and V samples. Consistent with the Western blot data, CatE mRNA in T1 and T2 was 3- to 4-fold lower than that in AGS and V (Fig. 2C). Having established that CatE levels were lower in AGS lines expressing CIITA, we then asked whether the lower levels of CatE might correlate with a decrease in Ag processing. Previous studies of CatE protease activity have used OVA as a substrate, then quantified cleavage by presenting the processed OVA to a T cell hybridoma specific for cleaved OVA (3, 4). We used the same method to quantify processing of OVA by AGS cells or the CIITA-expressing T1 stable line. We digested OVA with total protein from AGS or T1 cell lysates, then incubated the digests with fixed TA3 mouse B cells as APC. OVA-loaded TA3 cells were used to activate a T cell hybridoma specific for OVA323–339 (DO11.10.109), and IL-2 production by activated T cells was measured using proliferation of HT-2 cells. As shown in Fig. 2D, the T cell response to OVA processed by lysates from CIITA-expressing T1 cells was greatly reduced compared with that of the parent AGS cells. The 4-fold difference observed between AGS and T1 for OVA processing was consistent with the 4-fold difference in CatE mRNA and protein expression between the same cell lines.
CIITA produces isoform-dependent repression at the proCatE promoter
We wanted to find out whether the difference observed in CatE expression is due to the regulation of proCatE promoter activity by CIITA. To study this activity, we used a luciferase reporter driven by 563 bp of the proCatE promoter (Fig. 3A) that was shown to be sufficient for expression in AGS cells (6). When AGS cells were transfected with M4 and type III CIITA, luciferase activity at the M4 reporter was decreased (Fig. 3B). To determine the minimum promoter elements required for CIITA-mediated repression, we tested a shorter proCatE promoter construct, M1, which contains 123 bp of the proCatE promoter (Fig. 3A). Transfection of CIITA resulted in a similar decrease in luciferase activity as with M4 (Fig. 3B), suggesting that M1 contains sufficient promoter elements necessary for repression by CIITA. Transcriptional activity at the MHC class II promoter-driven luciferase was enhanced by CIITA cotransfection (Fig. 3B), consistent with previous findings in other cell types (12).
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The N-terminal 331 aa of CIITA are sufficient to inhibit CatE
To investigate the mechanism by which CIITA decreases transcription at the proCatE promoter, we sought to identify which domains of CIITA are required for inhibition. Using the AGS transient transfection system, we tested CatE repression by CIITA mutants (Fig. 5A) containing the acidic and proline-serine-threonine-rich domain (acidic-P/S/T, aa 1–331), the GTP binding domain (GBD; aa 408–857), and leucine-rich repeats (aa 980-1130). The mutant comprised of the acidic-P/S/T domain (aa 1–331) repressed better than full-length CIITA, whereas the GBD-containing mutant (aa 408–857) repressed less well (Fig. 5B). In contrast, the leucine-rich repeat alone (aa 980-1130) showed very little effect (Fig. 5B). All three mutants also exhibited the same pattern at the shorter proCatE promoter M1 (data not shown). These data demonstrate that the acidic-P/S/T domain is sufficient to inhibit transcription at the CatE promoter, and that GBD alone can also exert some repression.
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Several transcription factors, including PU.1, are known to activate the CatE promoter (6). We therefore tested whether CIITA-mediated repression occurs through PU.1. Consistent with previous reports (6), transfection with PU.1 enhanced CatE promoter activity (Fig. 5C, lanes 1 and 3). However, in the presence of CIITA, PU.1 could not activate CatE (Fig. 5C, lanes 3 and 4). Antisense PU.1, used as a control, had no effect on CatE activity or on inhibition by CIITA (Fig. 5C, lanes 5 and 6).
We observed that the acidic-P/S/T domain is sufficient to repress CatE (Fig. 5B); the same domain has also been shown to repress IL-4 and collagen 2 expression by competing to bind CREB binding protein/p300, a critical coactivator (13, 14). To ask whether a similar suppressive mechanism might operate in CIITA regulation of CatE, we tested the effects of p300 and CIITA at the CatE promoter. As shown in Fig. 5D, p300 alone augmented CatE promoter activity (lanes 1 and 3), and cotransfection with CIITA inhibited p300-inducible CatE expression (lanes 3 and 4). This demonstrates a new role for p300 as an activator of CatE and that CIITA regulation of CatE can occur through its effects on p300.
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Discussion |
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2 promoters, repression by CIITA has been shown to occur through binding with CREB binding protein/p300, and the acidic-P/S/T domain capable of repressing transcription of CatE is also sufficient to repress IL-4 and collagen 2 (13, 14). Thus, CIITA may repress CatE through a similar mechanism. Repression by CIITA appears to be isoform specific, because type III, but not type I, CIITA was able to repress CatE expression. Less efficient repression by type I CIITA could be attributed to a smaller amount of type I CIITA protein, because we have previously observed that protein levels of type I CIITA were lower than those of type III for equal amounts of transfected DNA (19). However, even with a 30-fold excess of transfected DNA, type I CIITA did not repress CatE expression (Fig. 4). The reported difference in protein expression was much less; thus, it could only account for part of the difference in CatE repression (19). Despite the difference in repression, the type I and type III isoforms share identical domain structure, except for the N-terminal CARD found in type I. Our data suggest that the presence, but not the integrity, of the CARD are critical for repression of CatE, because the L27Q CARD mutant behaved similarly to type I CIITA. Thus, the steric hindrance of an N-terminal domain may be responsible for the lack of repressive activity observed with the type I isoform. Given that the acidic-P/S/T domain is present in both isoforms of CIITA, but only the type III form produces repression, the steric hindrance of an additional N-terminal domain may be what prevents the acidic-P/S/T domain from repressing CatE.
Regulation of cathepsin expression by CIITA appears to be complex and very specific to CatE. Although the highly homologous CatD has also been reported to cleave OVA (4), we found that only CatE was specifically regulated by CIITA. Others have shown that human tonsilar B cells express little CatE in the resting state, but increase CatE expression upon activation with heat-killed Staphylococcus aureus (2). In contrast, we observed that mouse B cells stimulated with IL-4 and LPS instead down-regulate CatE (data not shown). It is not yet clear whether the dissimilarity in regulation arises from differences in species, the source of the B cells, or the type of stimulation. Nevertheless, CIITA-mediated regulation of CatE occurs in B cells of both species.
We found that the expression of CIITA in AGS cells suppresses CatE expression and, consequently, OVA digestion. Thus, CIITA negatively regulates CatE proteolysis. We speculate that repression of CatE may help regulate Ag processing. However, because the cellular targets of CatE remain unknown, CIITA regulation of CatE protease function could either promote or oppose Ag processing and presentation. In the case of the former, production of antigenic epitopes by CatE could be down-regulated as part of an activation-induced shift from Ag processing to Ag presentation. This would be consistent with our findings that mouse B cells down-regulate CatE upon activation (data not shown). However, the possibility also exists that CatE could instead cleave productive Ags, Ag-MHC complexes, or chaperones. CatE has been reported to cleave human 2-macroglobulin, a capture protein that promotes internalization and degradation of target proteins (27). Thus, dissecting the role of CatE proteolysis in Ag presentation may depend upon identifying multiple targets of its protease activity.
Like other members of the cathepsin family, CatE is highly expressed in some primary tumors and tumor cell lines and may serve as a diagnostic marker for tumor progression (8, 28, 29). Increased expression of proteases, including CatE, may allow tumor cells to degrade the surrounding extracellular matrix, promote metastasis and angiogenesis, or more rapidly degrade Ags or chemokines that might otherwise trigger host antitumor responses (30, 31). Many tumor cells do not express CIITA, which leads to down-regulation of MHC class I and II expression and decreased presentation of tumor Ags (32). Indeed, AGS cells cannot up-regulate MHC class I and II in response to IFN, probably due to the absence of STAT1 (data not shown) (33). Loss of CIITA expression by a tumor could confer multiple selective advantages: not just reduced Ag presentation via MHC class I and II, but increased expression and activity of CatE. We have observed that CIITA-transfected stable lines gradually lose expression of CIITA and MHC class II (data not shown). The absence of CIITA and increased CatE expression may impart a growth advantage to the CIITA-deficient cells.
Inhibition of CatE by CIITA provides the first link between immune-specific regulation and CatE Ag processing. Modulation of CatE by CIITA, a key regulator of APC function, suggests many possible roles for CatE in Ag presentation and demonstrates the need for a better understanding of CatE expression. The observations offered in this study may also shed light upon the distinct functions of CIITA isoforms and their mechanisms of gene repression.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Cheong-Hee Chang, Department of Microbiology and Immunology, Walther Oncology Center, R2-302, 950 West Walnut Street, Indiana University School of Medicine, Indianapolis, IN 46202-5188. E-mail address: chechang{at}iupui.edu
3 Abbreviations used in this paper: CatE, cathepsin E; acidic-P/S/T, acidic and proline-serine-threonine-rich domain; CARD, caspase recruitment domain; CatD, cathepsin D; CIITA, class II transactivator; DC, dendritic cell; -gal, -galactosidase; GBD, GTP binding domain; proCatE, procathepsin E; qRT-PCR, quantitative real-time PCR; CT, comparative threshold cycle.
Received for publication October 21, 2003. Accepted for publication February 18, 2004.
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References |
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interferon-mediated suppression of collagen 2(I) and other promoters. Mol. Cell. Biol. 21:7078.2-macroglobulin by cathepsin E. Eur. J. Biochem. 270:1189.[Medline]
, macrophage inflammatory protein-1, and SLC that are expressed in human breast cancer. Am. J. Pathol. 162:1183.This article has been cited by other articles:
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  K. Harnesk, M. Swanberg, J. Ockinger, M. Diez, O. Lidman, E. Wallstrom, A. Lobell, T. Olsson, and F. Piehl Vra4 Congenic Rats with Allelic Differences in the Class II Transactivator Gene Display Altered Susceptibility to Experimental Autoimmune Encephalomyelitis J. Immunol., March 1, 2008; 180(5): 3289 - 3296. [Abstract] [Full Text] [PDF]
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 Y. Xu, J. A. Harton, and B. D. Smith CIITA Mediates Interferon-{gamma} Repression of Collagen Transcription through Phosphorylation-dependent Interactions with Co-repressor Molecules J. Biol. Chem., January 18, 2008; 283(3): 1243 - 1256. [Abstract] [Full Text] [PDF]
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H. Kakehashi, T. Nishioku, T. Tsukuba, T. Kadowaki, S. Nakamura, and K. Yamamoto Differential Regulation of the Nature and Functions of Dendritic Cells and Macrophages by Cathepsin E J. Immunol., November 1, 2007; 179(9): 5728 - 5737. [Abstract] [Full Text] [PDF]
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 M. Krawczyk, E. Leimgruber, Q. Seguin-Estevez, I. Dunand-Sauthier, E. Barras, and W. Reith Expression of RAB4B, a protein governing endocytic recycling, is co-regulated with MHC class II genes Nucleic Acids Res., January 28, 2007; 35(2): 595 - 605. [Abstract] [Full Text] [PDF]
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 G. Tosi, E. Pilotti, L. Mortara, A. D. L. Barbaro, C. Casoli, and R. S. Accolla Inhibition of human T cell leukemia virus type 2 replication by the suppressive action of class II transactivator and nuclear factor Y PNAS, August 22, 2006; 103(34): 12861 - 12866. [Abstract] [Full Text] [PDF]
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 S.-i. Sawa, D. Kamimura, G.-H. Jin, H. Morikawa, H. Kamon, M. Nishihara, K. Ishihara, M. Murakami, and T. Hirano Autoimmune arthritis associated with mutated interleukin (IL)-6 receptor gp130 is driven by STAT3/IL-7-dependent homeostatic proliferation of CD4+ T cells J. Exp. Med., June 12, 2006; 203(6): 1459 - 1470. [Abstract] [Full Text] [PDF]
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 G. Buttice, J. Miller, L. Wang, and B. D. Smith Interferon-{gamma} Induces Major Histocompatibility Class II Transactivator (CIITA), Which Mediates Collagen Repression and Major Histocompatibility Class II Activation by Human Aortic Smooth Muscle Cells Circ. Res., March 3, 2006; 98(4): 472 - 479. [Abstract] [Full Text] [PDF]
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Y. Wang, R. M. Baron, G. Zhu, M. Joo, J. W. Christman, E. S. Silverman, M. A. Perrella, R. J. Riese, and M. Cernadas PU.1 Regulates Cathepsin S Expression in Professional APCs J. Immunol., January 1, 2006; 176(1): 275 - 283. [Abstract] [Full Text] [PDF]
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P. Sengupta, Y. Xu, L. Wang, R. Widom, and B. D. Smith Collagen {alpha}1(I) Gene (COL1A1) Is Repressed by RFX Family J. Biol. Chem., June 3, 2005; 280(22): 21004 - 21014. [Abstract] [Full Text] [PDF]
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C. S. K. Yee, Y. Yao, Q. Xu, B. McCarthy, D. Sun-Lin, M. Tone, H. Waldmann, and C.-H. Chang Enhanced Production of IL-10 by Dendritic Cells Deficient in CIITA J. Immunol., February 1, 2005; 174(3): 1222 - 1229. [Abstract] [Full Text] [PDF]
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Y. Xu, L. Wang, G. Buttice, P. K. Sengupta, and B. D. Smith Major Histocompatibility Class II Transactivator (CIITA) Mediates Repression of Collagen (COL1A2) Transcription by Interferon {gamma} (IFN-{gamma}) J. Biol. Chem., October 1, 2004; 279(40): 41319 - 41332. [Abstract] [Full Text] [PDF]
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S. Nozell, Z. Ma, C. Wilson, R. Shah, and E. N. Benveniste Class II Major Histocompatibility Complex Transactivator (CIITA) Inhibits Matrix Metalloproteinase-9 Gene Expression J. Biol. Chem., September 10, 2004; 279(37): 38577 - 38589. [Abstract] [Full Text] [PDF]
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