INHIBITION OF IFN-STIMULATED GENE-EXPRESSION AND IFN INDUCTION OF CYTOLYTIC RESISTANCE TO NATURAL-KILLER-CELL LYSIS CORRELATE WITH E1A-P300BINDING

Treatment of target cells with IFN induces resistance to NK cell lysis , This process is blocked by expression of E1A gene products in adenov irus (Ad)-infected and Ad-transformed cells, We compared the ability o f adenovirus serotype 5 (Ad5) E1A exon 1 mutants to inhibit the induct ion of cytolytic resistance by IFN and block IFN-stimulated gene expre ssion with their capacity to bind the cellular proteins p105 (retinobl astoma gene product), p107, and p300, E1A mutants that did not express conserved region 3 (CR3; residues 138-184) or contained deletions in the nonconserved regions between residues 26-35 or 86-120, bound p105, p107, and p300 and were not impaired in their capacity to block IFN-s timulated gene expression or IFN's induction of cytolytic resistance. E1A mutants with deletions in CR2 (residues 121-138) could not bind p1 05 or p107, but blocked IFN-stimulated gene expression and IFN's induc tion of cytolytic resistance. In contrast, mutants in CR1 or the N-ter minal nonconserved region (residues 2, 4-25, and 48-60), which define E1A's binding site for p300, were unable to block either IFN-stimulate d gene expression or IFN's induction of cytolytic resistance, We concl ude that E1A's capacity to block both IFN-stimulated gene expression a nd IFN's induction of cytolytic resistance appears to be transduced th rough a pathway that involves E1A-p300 binding, The capacity of E1A to block IFN's induction of cytolytic resistance is probably secondary t o E1A's more general ability to inhibit IFN-stimulated gene expression .