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, STAT1, and TGF-ß-Regulated Expression of the Class II Transactivator Gene1
University of North Carolina Lineberger Comprehensive Cancer Center, Department of Microbiology-Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
Class II transactivator (CIITA) is a master regulator required for
constitutive and IFN-
-inducible expression of class II MHC genes.
Although the role of CIITA is greatly appreciated, the mechanisms
underlying constitutive and IFN--induced expression of CIITA are not
understood. The study of CIITA induction is extremely important, but
has been fraught with difficulty. This study describes for the first
time a large (7-kb) fragment of 5' flanking sequences that mediates the
B cell-specific, IFN--induced, and TGF-ß-suppressed expression of
CIITA. This pattern of expression matches the authentic expression of
the endogenous gene. Within the 7-kb fragment, sequences that lie
between nucleotides -545 and -113 relative to the transcriptional
start site are critical for constitutive promoter expression in B
cells. In contrast, inducible activation of CIITA by IFN- requires
sequences contained in an additional 4 kb of upstream DNA. This region
mediates an IFN- response when linked to either the endogenous CIITA
promoter or a heterologous promoter. A role for STAT1 in regulation of
the CIITA promoter is shown by the rescue of IFN- induction by
expression of STAT1 in STAT1-defective U3A cells. TGF-ß significantly
inhibits IFN--mediated induction of the CIITA promoter in 2fTGH
fibroblasts, which indicates that the promoter is a target for TGF-ß.
This inhibition is achieved by suppression of the basal promoter. This
study provides a focal point for understanding the mechanism of B
cell-specific, IFN--induced, and TGF-ß-suppressed expression of
CIITA.
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N. Ghosh, J. F. Piskurich, G. Wright, K. Hassani, J. P.-Y. Ting, and K. L. Wright A Novel Element and a TEF-2-like Element Activate the Major Histocompatibility Complex Class II Transactivator in B-lymphocytes J. Biol. Chem., November 5, 1999; 274(45): 32342 - 32350. [Abstract] [Full Text] [PDF]
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Y. Itoh-Lindstrom, J. F. Piskurich, N. J. Felix, Y. Wang, W. J. Brickey, J. L. Platt, B. H. Koller, and J. P.-Y. Ting Reduced IL-4-, Lipopolysaccharide-, and IFN-{gamma}-Induced MHC Class II Expression in Mice Lacking Class II Transactivator Due to Targeted Deletion of the GTP-Binding Domain J. Immunol., September 1, 1999; 163(5): 2425 - 2431. [Abstract] [Full Text] [PDF]
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W. Wojciechowski, J. DeSanctis, E. Skamene, and D. Radzioch Attenuation of MHC Class II Expression in Macrophages Infected with Mycobacterium bovis Bacillus Calmette-Guerin Involves Class II Transactivator and Depends on the Nramp1 Gene J. Immunol., September 1, 1999; 163(5): 2688 - 2696. [Abstract] [Full Text] [PDF]
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L. H. Milocco, J. A. Haslam, J. Rosen, and H. M. Seidel Design of Conditionally Active STATs: Insights into STAT Activation and Gene Regulatory Function Mol. Cell. Biol., April 1, 1999; 19(4): 2913 - 2920. [Abstract] [Full Text] [PDF]
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C. Sudarshan, J. Galon, Y.-j. Zhou, and J. J. O'Shea TGF-{beta} Does Not Inhibit IL-12- and IL-2-Induced Activation of Janus Kinases and STATs J. Immunol., March 1, 1999; 162(5): 2974 - 2981. [Abstract] [Full Text] [PDF]
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C. Pardoux, X. Ma, S. Gobert, S. Pellegrini, P. Mayeux, F. Gay, G. Trinchieri, and S. Chouaib Downregulation of Interleukin-12 (IL-12) Responsiveness in Human T Cells by Transforming Growth Factor-beta : Relationship With IL-12 Signaling Blood, March 1, 1999; 93(5): 1448 - 1455. [Abstract] [Full Text] [PDF]
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Y. Zhang, Y.-y. Zhang, M. Ogata, P. Chen, A. Harada, S.-i. Hashimoto, and K. Matsushima Transforming Growth Factor-beta 1 Polarizes Murine Hematopoietic Progenitor Cells to Generate Langerhans Cell-Like Dendritic Cells Through a Monocyte/Macrophage Differentiation Pathway Blood, February 15, 1999; 93(4): 1208 - 1220. [Abstract] [Full Text] [PDF]
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W. Rohn, L. P. Tang, Y. Dong, and E. N. Benveniste IL-1{beta} Inhibits IFN-{gamma}-Induced Class II MHC Expression by Suppressing Transcription of the Class II Transactivator Gene J. Immunol., January 15, 1999; 162(2): 886 - 896. [Abstract] [Full Text] [PDF]
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J. F. Piskurich, M. W. Linhoff, Y. Wang, and J. P.-Y. Ting Two Distinct Gamma Interferon-Inducible Promoters of the Major Histocompatibility Complex Class II Transactivator Gene Are Differentially Regulated by STAT1, Interferon Regulatory Factor 1, and Transforming Growth Factor beta Mol. Cell. Biol., January 1, 1999; 19(1): 431 - 440. [Abstract] [Full Text] [PDF]
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J. M. Soos, J. Morrow, T. A. Ashley, B. E. Szente, E. K. Bikoff, and S. S. Zamvil Astrocytes Express Elements of the Class II Endocytic Pathway and Process Central Nervous System Autoantigen for Presentation to Encephalitogenic T Cells J. Immunol., December 1, 1998; 161(11): 5959 - 5966. [Abstract] [Full Text] [PDF]
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G. B. Ehret, P. Reichenbach, U. Schindler, C. M. Horvath, S. Fritz, M. Nabholz, and P. Bucher DNA Binding Specificity of Different STAT Proteins. COMPARISON OF IN VITRO SPECIFICITY WITH NATURAL TARGET SITES J. Biol. Chem., February 23, 2001; 276(9): 6675 - 6688. [Abstract] [Full Text] [PDF]
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N. Ghosh, I. Gyory, G. Wright, J. Wood, and K. L. Wright Positive Regulatory Domain I Binding Factor 1 Silences Class II Transactivator Expression in Multiple Myeloma Cells J. Biol. Chem., April 27, 2001; 276(18): 15264 - 15268. [Abstract] [Full Text] [PDF]
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A. M. Girvin, K. B. Gordon, C. J. Welsh, N. A. Clipstone, and S. D. Miller Differential abilities of central nervous system resident endothelial cells and astrocytes to serve as inducible antigen-presenting cells Blood, May 15, 2002; 99(10): 3692 - 3701. [Abstract] [Full Text] [PDF]
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