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Molecular and Cellular Biology, January 1999, p. 431-440, Vol. 19, No. 1
Lineberger Comprehensive Cancer Center and
Department of Microbiology and Immunology, University of North
Carolina at Chapel Hill, Chapel Hill, North Carolina
Received 11 August 1998/Returned for modification 9 September
1998/Accepted 28 September 1998
The major histocompatibility complex (MHC) class II transactivator
(CIITA) is the master regulatory factor required for appropriate expression of class II MHC genes. Understanding the expression of CIITA
is key to understanding the regulation of class II MHC genes. This
report describes the independent regulation of two distinct CIITA
promoters by cytokines with opposing functions, gamma interferon
(IFN-
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Copyright © 1999, American Society for Microbiology. All rights reserved.
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
) and transforming growth factor
(TGF-
). A functional
analysis of deletion mutations of the upstream promoter (promoter III)
identified an IFN-
-responsive region located approximately 5 kb from
the transcriptional start site. An in vivo DNase I hypersensitivity analysis detected a hypersensitive site in this area which supports the
relevance of this region. When the downstream promoter (promoter IV)
was studied by in vivo genomic footprinting, IFN-
-induced changes at
putative binding sites for STAT1, interferon regulatory factor 1 (IRF-1), and E-box proteins were seen. Gel shift and supershift
analyses for IRF-1 confirmed the in vivo footprint results. The role of
the IFN-
-inducible transcription factor STAT1 was examined
functionally. Although both promoters were controlled by STAT1,
promoter-specific regulation was exhibited. The IFN-
response of
promoter III was completely dependent on STAT1 and not IRF-1, while
promoter IV was partially activated by IRF-1 in the total absence of
STAT1 expression. While both promoters were affected by TGF-
,
activation of promoter III by IFN-
was more severely diminished by
TGF-
treatment. The differential control of CIITA promoters by
TGF-
, IRF-1, and STAT1 may be important in refining regulation of
class II MHC genes in different cell types and under different
stimulatory conditions.
*
Corresponding author. Mailing address: Lineberger
Comprehensive Cancer Center, Department of Microbiology and Immunology, CB 7295, University of North Carolina at Chapel Hill, Chapel Hill, NC
27599. Phone: (919) 966-5538. Fax: (919) 966-3015. E-mail: panyun{at}med.unc.edu.
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