E1A oncogene induction of cellular susceptibility to killing by cytolytic lymphocytes through target cell sensitization to apoptotic injury

E1A oncogene expression increases mammalian cell susceptibility to lysis by cytolytic lymphocytes (CLs) at a stage in this intercellular interaction t hat is independent of cell surface recognition events. Since CLs can induce either apoptotic or necrotic cell death, we asked whether E1A sensitizatio n to injury-induced apoptosis is sufficient to explain E1A-induced cytolyti c susceptibility. Mouse, rat, hamster, and human cells that were rendered c ytolytic susceptible by E1A were also sensitized to CL-induced and chemical ly induced apoptosis. In contrast, E1A-positive cells were no more suscepti ble to injury-induced necrosis than E1A-negative cells, Similar to inductio n of cytolytic susceptibility and in contrast to other E1A activities, cell ular sensitization to chemically induced apoptosis depended on high-level E 1A oncoprotein expression. Loss of both cytolytic susceptibility and sensit ization to chemically induced apoptosis was coselected during in vivo selec tion of E1A-positive sarcoma cells for increased tumorigenicity. Furthermor e, E1A mutant proteins that cannot bind the cellular transcriptional coacti vator, p300, and that fail to induce cytolytic susceptibility also failed t o sensitize cells to injury-induced apoptosis. These data indicate that E1A induces susceptibility to killer cell-induced lysis through sensitization of cells to injury-induced apoptosis. (C) 1999 Academic Press.