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* Fred Hutchinson Cancer Research Center, Seattle, WA 98109; and
Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322
Ligands of the NKG2D receptor, which activates NK cells and costimulates effector T cells, are inducibly expressed under harmful conditions, such as malignancies and microbial infections. Moreover, aberrant expression in autoimmune disease lesions may contribute to disease progression. Among these ligands are the closely related human MHC class I-related chains (MIC) A and B, which appear to be regulated by cellular stress. Analyses of MIC gene 5'-end flanking regions in epithelial tumor cells defined minimal core promoters that directed near maximum heat shock- or oxidative stress-induced transcriptional activation. Considerably larger fully functional promoters were required for maximum proliferation-associated activation. These activities were dependent on core promoter sequences that included heat shock elements, which inducibly bound heat shock factor 1, TATA-like elements, and constitutively occupied Sp1 and inverted CCAAT box factor sites. By contrast, MIC gene activation by CMV infection was largely independent of these and upstream promoter sequences, and expression of viral immediate early gene (IE1 or IE2) products was sufficient for induction of transcription and surface protein expression. Altogether, these results reveal distinct modes of activation of the genes for the MIC ligands of NKG2D and provide a molecular framework for analyses of gene regulation under different cellular insult conditions.
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.
1 This work was supported by Grants GM47310 (to J.M.B.) and AI30581 and AI52319 (to T.S.) from the National Institutes of Health.
2 Address correspondence and reprint requests to Dr. Thomas Spies, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, D1-100, Seattle, WA 98109. E-mail address: tspies{at}fhcrc.org
3 Abbreviations used in this paper: MIC, MHC class I-related chain; CBF, CCAAT box factor; ChIP, chromatin immunoprecipitation; HSE, heat shock element; HSF1, heat shock factor 1; HSP, heat shock protein; ICE, inverted CCAAT box-like element; IE, immediate early; Inr, initiator.
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