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 that is independent of cell surface recognition events. Since CLs can induce either apoptotic or necrotic cell death, we asked whether E1A sensitization to injury-induced apoptosis is sufficient to explain E1A-induced cytolytic susceptibility. Mouse, rat, hamster, and human cells that were rendered cytolytic susceptible by E1A were also sensitized to CL-induced and chemically induced apoptosis. In contrast, E1A-positive cells were no more susceptible to injury-induced necrosis than E1A-negative cells. Similar to induction of cytolytic susceptibility and in contrast to other E1A activities, cellular sensitization to chemically induced apoptosis depended on high-level E1A oncoprotein expression. Loss of both cytolytic susceptibility and sensitization to chemically induced apoptosis was coselected during in vivo selection of E1A-positive sarcoma cells for increased tumorigenicity. Furthermore, E1A mutant proteins that cannot bind the cellular transcriptional coactivator, p300, and that fail to induce cytolytic susceptibility also failed to 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.
Cook
J L
JL
College of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612, USA.
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Walker
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Colvin
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D016475:3T3 Cells; D017500:Adenovirus E1A Proteins / Q000096:biosynthesis* / Q000235:genetics; D000260:Adenoviruses, Human / Q000235:genetics; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D017209:Apoptosis; D016923:Cell Death; D002472:Cell Transformation, Viral; D006224:Cricetinae; D003602:Cytotoxicity, Immunologic; D047630:Depsipeptides; D050881:E1A-Associated p300 Protein; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D051379:Mice; D009154:Mutation; D009336:Necrosis; D009687:Nuclear Proteins / Q000378:metabolism; D010455:Peptides; D051381:Rats; D012513:Sarcoma, Experimental; D015534:Trans-Activators / Q000378:metabolism
D017500:Adenovirus E1A Proteins; D000900:Anti-Bacterial Agents; D047630:Depsipeptides; D009687:Nuclear Proteins; D010455:Peptides; D015534:Trans-Activators; C004456:beauvericin; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse; C494362:Ep300 protein, rat