A HLA class I cis-regulatory element whose activity can be modulated by hormones.
To elucidate the basis of the down-regulation in major histocompatibility complex (MHC) class I gene expression and to identify possible DNA-binding regulatory elements that have the potential to interact with class I MHC genes, we have studied the transcriptional regulation of class I HLA genes in human breast carcinoma cells. A 9 base pair (bp) negative cis-regulatory element (NRE) has been identified using band-shift assays employing DNA sequences derived from the 5'-flanking region of HLA class I genes. This 9-bp element, GTCATGGCG, located within exon I of the HLA class I gene, can potently inhibit the expression of a heterologous thymidine kinase (TK) gene promoter and the HLA enhancer element. Furthermore, this regulatory element can exert its suppressive function in either the sense or anti-sense orientation. More interestingly, NRE can suppress dexamethasone-mediated gene activation in the context of the reported glucocorticoid-responsive element (GRE) in MCF-7 cells but has no influence on the estrogen-mediated transcriptional activation of MCF-7 cells in the context of the reported estrogen-responsive element (ERE). Furthermore, the presence of such a regulatory element within the HLA class I gene whose activity can be modulated by hormones correlates well with our observation that the level of HLA class I gene expression can be down-regulated by hormones in human breast carcinoma cells. Such interactions between negative regulatory elements and specific hormone trans-activators are novel and suggest a versatile form of transcriptional control.
Department of Immunology, Scripps Research Institute, La Jolla, CA.
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D001483:Base Sequence; D001667:Binding, Competitive; D015152:Blotting, Northern; D001943:Breast Neoplasms; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D004742:Enhancer Elements, Genetic; D004967:Estrogens / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D015236:HLA-C Antigens / Q000235:genetics; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D016296:Mutagenesis; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D013937:Thymidine Kinase / Q000235:genetics; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
D004967:Estrogens; D015236:HLA-C Antigens; C038653:HLA-C*03 antigen; D015395:Histocompatibility Antigens Class I; D012333:RNA, Messenger; D003907:Dexamethasone; D004247:DNA; D013937:Thymidine Kinase