title: Promoter region architecture and transcriptional regulation of the genes for the MHC class I-related chain A and B ligands of NKG2D.
abstract: 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.
authors.affiliation: Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109, USA.
authors.forename: Gopalakrishnan M
authors.initials: GM
authors.lastname: Venkataraman
authors.forename: Dominic
authors.initials: D
authors.lastname: Suciu
authors.forename: Veronika
authors.initials: V
authors.lastname: Groh
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Boss
authors.forename: Thomas
authors.initials: T
authors.lastname: Spies
mesh_terms: D024506:5' Flanking Region; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation / Q000235:genetics*; D017930:Genes, Reporter / Q000235:genetics; D018869:Heat-Shock Response; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D008024:Ligands; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D055607:Receptors, Natural Killer Cell; D014158:Transcription, Genetic / Q000235:genetics*; D015533:Transcriptional Activation
chemical_list: D015395:Histocompatibility Antigens Class I; C527085:KLRK1 protein, human; D008024:Ligands; C099187:MHC class I-related chain A; C098080:MICB antigen; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell