Transcriptional regulation of class-I major histocompatibility complex genes transformed in murine cells is mediated by positive and negative regulatory elements

The expression of class-I major histocompatibility complex (MHC) antigens on the surface of cells transformed by adenovirus 12 (Ad 12) is generally very low or absent; a phenotype that correlates with the high tumorigenicity of these cell lines. In primary mouse embryonal fibroblasts (MEF) from class-I transgenic mice (PD1 transgenic mice), Adl2-mediated transformation results in down-regulation of both endogenous genes and the transgene. Functional analysis of class-I regulatory elements revealed that the suppression of a class-I promoter is mediated by two negative regulatory elements, one of which functions specifically in Adl2-transformed cells. In addition, Adl2-transformed cells produce only minute amounts of the nuclear factors that bind to the major class-I enhancer, RI (region I or H2TF1). A silencer element derived from the 5′ region of the miniature swine class-I gene (PD1) is capable of competing for the binding of nuclear factors to a second enhancer, RII (region II or CREII), that is located upstream from RI in the class-I regulatory element (CRE). Based on these results, we propose that down-regulation of class-I genes in Adl2-transformed cells is mediated mainly by negative regulators.