Role of p300-family proteins in E1A oncogene induction of cytolytic susceptibility and tumor cell rejection.

The mechanism by which the adenoviral (Ad) E1A oncogene induces cellular susceptibility to lysis by killer lymphocytes involves interactions between its first exon and different second-exon accessory regions. Mutational analysis showed that two first-exon regions--one in the N terminus and one in the conserved region 1 (CR1) domain--are necessary for this activity. E1A complex formation with cellular p300 protein through these first-exon-encoded regions correlated with induction of the cytolytic susceptible phenotype but was only effective in the context of E1A second-exon expression. An E1A first-exon deletion that prevented p300 binding eliminated both oncoprotein-induced cytolytic susceptibility and rejection of transfected sarcoma cells by immunocompetent animals. These results suggest that the E1A oncogene induces cytolytic susceptibility and tumor rejection by interactions with cellular proteins of the p300 family that affect transcription of genes involved in the cellular response to injury inflicted by host killer cells.

E1A second exon requirements for induction of target cell susceptibility to lysis by natural killer cells: implications for the mechanism of action.

The E1A oncogene of adenovirus type 5 induces susceptibility of mammalian cells to lysis by natural killer lymphocytes (NK cells). It is unknown whether sensitization to NK killing is mediated directly by targeting effects of interactions between E1A peptides and cell surface MHC molecules or indirectly by an E1A activity that requires structural integrity of the oncoprotein. To discriminate between these hypotheses, rat and hamster cells expressing wild type E1A were contrasted with those expressing truncated products resulting from E1A termination or deletion mutations. Transfected rat cells, expressing truncated proteins from the E1A first exon that encodes MHC-binding peptides, remained resistant to lysis by NK cells, whereas cells expressing full-length E1A protein were highly susceptible to lysis. Studies of infected hamster cells showed that addition of either of two, nonoverlapping, second exon regions reconstituted cytolytic susceptibility induction by E1A. The results do not support the E1A-peptide-MHC hypothesis, since no single E1A peptide coding region was sufficient to convey cytolytic susceptibility to expresser cells. The data indicate that coordinate functions of the E1A first exon and redundant accessory regions in the second exon are required for E1A-induced susceptibility to NK killing.