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Identification of distinct regions of 5' flanking DNA that mediate constitutive, IFN-gamma, STAT1, and TGF-beta-regulated expression of the class II transactivator gene.
J Immunol. 1998 Jan 01; 160(1):233-40.JI

Abstract

Class II transactivator (CIITA) is a master regulator required for constitutive and IFN-gamma-inducible expression of class II MHC genes. Although the role of CIITA is greatly appreciated, the mechanisms underlying constitutive and IFN-gamma-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-gamma-induced, and TGF-beta-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-gamma requires sequences contained in an additional 4 kb of upstream DNA. This region mediates an IFN-gamma 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-gamma induction by expression of STAT1 in STAT1-defective U3A cells. TGF-beta significantly inhibits IFN-gamma-mediated induction of the CIITA promoter in 2fTGH fibroblasts, which indicates that the promoter is a target for TGF-beta. 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-gamma-induced, and TGF-beta-suppressed expression of CIITA.

Authors+Show Affiliations

University of North Carolina Lineberger Comprehensive Cancer Center, Department of Microbiology-Immunology, University of North Carolina at Chapel Hill, 27599, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

9551976

Citation

Piskurich, J F., et al. "Identification of Distinct Regions of 5' Flanking DNA That Mediate Constitutive, IFN-gamma, STAT1, and TGF-beta-regulated Expression of the Class II Transactivator Gene." Journal of Immunology (Baltimore, Md. : 1950), vol. 160, no. 1, 1998, pp. 233-40.
Piskurich JF, Wang Y, Linhoff MW, et al. Identification of distinct regions of 5' flanking DNA that mediate constitutive, IFN-gamma, STAT1, and TGF-beta-regulated expression of the class II transactivator gene. J Immunol. 1998;160(1):233-40.
Piskurich, J. F., Wang, Y., Linhoff, M. W., White, L. C., & Ting, J. P. (1998). Identification of distinct regions of 5' flanking DNA that mediate constitutive, IFN-gamma, STAT1, and TGF-beta-regulated expression of the class II transactivator gene. Journal of Immunology (Baltimore, Md. : 1950), 160(1), 233-40.
Piskurich JF, et al. Identification of Distinct Regions of 5' Flanking DNA That Mediate Constitutive, IFN-gamma, STAT1, and TGF-beta-regulated Expression of the Class II Transactivator Gene. J Immunol. 1998 Jan 1;160(1):233-40. PubMed PMID: 9551976.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Identification of distinct regions of 5' flanking DNA that mediate constitutive, IFN-gamma, STAT1, and TGF-beta-regulated expression of the class II transactivator gene. AU - Piskurich,J F, AU - Wang,Y, AU - Linhoff,M W, AU - White,L C, AU - Ting,J P, PY - 1998/4/29/pubmed PY - 1998/4/29/medline PY - 1998/4/29/entrez SP - 233 EP - 40 JF - Journal of immunology (Baltimore, Md. : 1950) JO - J Immunol VL - 160 IS - 1 N2 - Class II transactivator (CIITA) is a master regulator required for constitutive and IFN-gamma-inducible expression of class II MHC genes. Although the role of CIITA is greatly appreciated, the mechanisms underlying constitutive and IFN-gamma-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-gamma-induced, and TGF-beta-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-gamma requires sequences contained in an additional 4 kb of upstream DNA. This region mediates an IFN-gamma 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-gamma induction by expression of STAT1 in STAT1-defective U3A cells. TGF-beta significantly inhibits IFN-gamma-mediated induction of the CIITA promoter in 2fTGH fibroblasts, which indicates that the promoter is a target for TGF-beta. 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-gamma-induced, and TGF-beta-suppressed expression of CIITA. SN - 0022-1767 UR - https://www.unboundmedicine.com/medline/citation/9551976/Identification_of_distinct_regions_of_5'_flanking_DNA_that_mediate_constitutive_IFN_gamma_STAT1_and_TGF_beta_regulated_expression_of_the_class_II_transactivator_gene_ L2 - http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=9551976 DB - PRIME DP - Unbound Medicine ER -