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J. Biol. Chem., Vol. 278, Issue 34, 31909-31917, August 22, 2003

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Identification of Upstream cis-Acting Regulatory Elements Controlling Lineage-specific Expression of the Mouse NK Cell Activation Receptor, NKR-P1C^*

Belma Ljutic  , James R. Carlyle ¶ || and Juan Carlos Zúñiga-Pflücker  **

From the Department of Immunology, University of Toronto, Sunnybrook and Women's Health Sciences Centre, Toronto, Ontario M4N 3M5, Canada and the ^¶Cancer Research Laboratory, Department of Molecular and Cell Biology, University of California, Berkeley, California 94720-3200

Mouse NKR-P1C (NK1.1) is a homodimeric type II transmembrane protein expressed on natural killer (NK) cells, NKT cells, and on CD117⁺ progenitor thymocytes capable of giving rise to cells of the T and NK lineages. Although its physiological ligands remain unknown, NKR-P1C engagement with a monoclonal antibody (mAb) leads to interferon- (IFN-) production and the directed release of cytotoxic granules from NK cells. We have cloned and sequenced a 10-kb genomic fragment corresponding to the 5'-flanking region of the C57Bl/6 mouse NKR-P1C gene. A transcriptional initiation site has been mapped in NK cells and an NK1.1⁺ T cell line by primer extension and rapid amplification of 5'-cDNA ends (5'-RACE) techniques. Although the 5'-flanking region of NKR-P1C is TATA-less, we have identified an initiator region and a downstream promoter element, which together constitute the principal minimal functional promoter. Computational analysis of the 10-kb 5'-flanking region revealed potential regulatory factor binding sites. DNaseI hypersensitivity assays identified a single hypersensitive site (HS) about a 9-kb upstream of the transcriptional initiation site. This site, termed HS1, was able to act as a transcriptional enhancer element in an NK cell line, while minimally affecting transcription in non-NK cell lines. Moreover, the HS1 element was shown to function as a promoter, with a transcript detected only in fetal NK1.1⁺ cells. An additional promoter and two non-coding exons were also characterized. These results identify the minimal upstream cis-acting elements, and point to a complex regulatory mechanism involved in the lineage-specific control of NKR-P1C expression in NK lymphocytes.

Received for publication, December 18, 2002 , and in revised form, June 10, 2003.

^* This work was supported by funds from the Canadian Institute for Health Research (CIHR). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by an Ontario Graduate Scholarship Award.

^|| Supported by a Long Term Fellowship from the Human Frontier Science Program.

^** Supported by an Investigator Award from the CIHR. To whom correspondence should be addressed: Dept. of Immunology, University of Toronto, Sunnybrook and Women's Health Sciences Centre, Room A-331, 2075 Bayview Ave., Toronto, Ontario M4N 3M5, Canada. Tel.: 416-480-6112; Fax: 416-480-4375; E-mail: jc.zuniga.pflucker{at}utoronto.ca.

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