Negative regulation of the MHC class I enhancer in adenovirus type 12-transformed cells

The expression of major histocompatibility class I genes is repressed by the adenovirus 12 (Ad12) E1A gene product in Ad12-transformed cells. In contrast, the E1A gene product of adenovirus 5 (Ad5), does not repress class I expression. The ability of these viruses to reduce the levels of class I expression correlates with their ability to form tumors in syngeneic immunocompetent animals, Ad12 being highly oncogenic and Ad5 being non-oncogenic. The reduction of class I expression, previously attributed to decreased rates of transcription, is at least in part the result of an altered enhancer activity, as determined by transient transfection assays. Enhancer activity is reduced in Ad12, compared to Ad5 transformed cells, suggesting that Ad12 E1A may inactivate the enhancer. We show here that Ad12-transformed cells contain increased levels of a DNA binding activity to the R2 element of the enhancer. The increased binding is due to a 55-60 kDa protein whose binding specificity resembles that of the members of the nuclear hormone receptor superfamily, especially of the thyroid hormone/retinoic acid receptors. Constructs where R2 and a positive enhancer element R1 are cloned upstream of the class I H-2K$\sp{\rm b}$ promoter, show that R2 can repress transcription in Ad12-transformed cells, by interfering with the ability of R1 to activate transcription. In contrast, R2 does not repress R1 activity in Ad5-transformed cells. Repression of R1 activity is released in Ad12-transformed cells by treatment with retinoic acid (RA), while the R2 element in Ad5-transformed cells does not respond to RA. These results are consistent with a model where a member of the retinoic acid receptor family binds to the R2 enhancer element and, in the absence of RA, represses class enhancer activity in Ad12-transformed cells. This retinoic acid receptor is not active in Ad5-transformed cells, since the R2 element in these cells cannot repress R1 activity, nor respond to retinoic acid