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Molecular and Cellular Biology, July 2004, p. 6194-6204, Vol. 24, No. 14
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.14.6194-6204.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

A GATA Factor Mediates Cell Type-Restricted Induction of HLA-E Gene Transcription by Gamma Interferon

David M. Barrett,^1,2 Karen S. Gustafson,³ Jing Wang,¹ Shou Zhen Wang,¹ and Gordon D. Ginder^1,3,4*

Massey Cancer CenterDepartments of,¹ Internal Medicine,⁴ Human Genetics, Virginia Commonwealth University, Richmond, Virginia 23298,² Department of Pathology, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104³

Received 9 January 2004/ Returned for modification 16 February 2004/ Accepted 26 April 2004

The human major histocompatibility complex (MHC) class Ib gene, HLA-E, codes for the major ligand of the inhibitory receptor NK-G-2A, which is present on most natural killer (NK) cells and some CD8⁺ cytotoxic T lymphocytes. We have previously shown that gamma interferon (IFN-) induction of HLA-E gene transcription is mediated through a distinct IFN--responsive element, the IFN response region (IRR), in all cell types studied. We have now identified and characterized a cell type-restricted enhancer of IFN--mediated induction of HLA-E gene transcription, designated the upstream interferon response region (UIRR), which is located immediately upstream of the IRR. The UIRR mediates a three- to eightfold enhancement of IFN- induction of HLA-E transcription in some cell lines but not in others, and it functions only in the presence of an adjacent IRR. The UIRR contains a variant GATA binding site (AGATAC) that is critical to both IFN- responsiveness and to the formation of a specific binding complex containing GATA-1 in K562 cell nuclear extracts. The binding of GATA-1 to this site in response to IFN- was confirmed in vivo in a chromatin immunoprecipitation assay. Forced expression of GATA-1 in nonexpressing U937 cells resulted in a four- to fivefold enhancement of the IFN- response from HLA-E promoter constructs containing a wild-type but not a GATA-1 mutant UIRR sequence and increased the IFN- response of the endogenous HLA-E gene. Knockdown of GATA-1 expression in K562 cells resulted in a 4-fold decrease in the IFN- response of the endogenous HLA-E gene, consistent with loss of the increase in IFN- response of HLA-E promoter-driven constructs containing the UIRR in wild-type K562 cells. Coexpression of wild-type and mutant adenovirus E1a proteins that sequester p300/CBP eliminated IFN--mediated enhancement through the UIRR, but only partially reduced induction through the IRR, implicating p300/CBP binding to Stat-1 at the IRR in the recruitment of GATA-1 to mediate the cooperation between the UIRR and IRR. We propose that the GATA-1 transcription factor represents a cell type-restricted mediator of IFN- induction of the HLA-E gene.

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* Corresponding author. Mailing address: Departments of Internal Medicine, Human Genetics, and Microbiology and Immunology, Massey Cancer Center, Virginia Commonwealth University, 401 College St., P.O. Box 980037, Richmond, VA 23298-0037. Phone: (804) 628-1897. Fax: (804) 828-5083. E-mail: gdginder{at}hsc.vcu.edu.

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Molecular and Cellular Biology, July 2004, p. 6194-6204, Vol. 24, No. 14
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.14.6194-6204.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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