A HLA CLASS-I CIS-REGULATORY ELEMENT WHOSE ACTIVITY CAN BE MODULATED BY HORMONES

To elucidate the basis of the down-regulation in major histocompatibil ity 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 c lass I HLA genes in human breast carcinoma cells. A 9 base pair (bp) n egative cis-regulatory element (NRE) has been identified using bandshi ft assays employing DNA sequences derived from the 5'-flanking region of HLA class I genes. This 9-bp element, GTCATGGCG, located within exo n 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 suppressiv e function in either the sense or anti-sense orientation. More interes tingly, NRE can suppress dexamethasone-mediated gene activation in the context of the reported glucocorticoid-responsive element (GRE) in MC F-7 cells but has no influence on the estrogen-mediated transcriptiona l activation of MCF-7 cells in the context of the reported estrogen-re sponsive element (ERE). Furthermore, the presence of such a regulatory element within the HLA class I gene whose activity can be modulated b y hormones correlates well with our observation that the level of HLA class I gene expression can be down-regulated by hormones in human bre ast carcinoma cells. Such interactions between negative regulatory ele ments and specific hormone trans-activators are novel and suggest a ve rsatile form of transcriptional control. (C) 1994 Wiley-Liss, Inc.