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E1A Oncogene Enhancement of Caspase-2-Mediated Mitochondrial Injury Sensitizes Cells to Macrophage Nitric Oxide-Induced Apoptosis¹

Jay R. Radke^*, Zeba K. Siddiqui^*, Tanya A. Miura, John M. Routes and James L. Cook^2,*

^* Section of Infectious Diseases, Immunology, and International Medicine, Departments of Medicine and Microbiology-Immunology and the Cancer Center, University of Illinois, Chicago, IL 60612; Department of Microbiology, Molecular Biology and Immunology, University of Idaho, Moscow, ID 83884; and Section of Allergy and Clinical Immunology, Department of Pediatrics, Children’s Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee, WI 53226

The adenovirus E1A oncogene induces innate immune rejection of tumors by sensitizing tumor cells to apoptosis in response to injuries, such as those inflicted by macrophage-produced TNF and NO. E1A sensitizes cells to TNF by repressing its activation of NF-B-dependent, antiapoptotic defenses. This suggested the hypothesis that E1A blockade of the NF-B activation response might be the central mechanism of E1A induced cellular sensitivity to other proapoptotic injuries, such as macrophage-produced NO. However, creation of E1A-positive NIH-3T3 mouse cell variants with high-level, NF-B-dependent resistance to TNF did not coselect for resistance to apoptosis induced by either macrophage-NO or chemical-NO, as the hypothesis would predict. E1A expression did block cellular recovery from NO-induced mitochondrial injury and converted the reversible, NO-induced cytostasis response of cells to an apoptotic response. This viral oncogene-induced phenotypic conversion of the cellular injury response of mouse and human cells was mediated by an E1A-related increase in NO-induced activation of caspase-2, an apical initiator of intrinsic apoptosis. Blocking caspase-2 activation or expression eliminated the NO-induced apoptotic response of E1A-positive cells. These results define an NF-B-independent pathway through which the E1A gene of human adenovirus sensitizes mouse and human cells to apoptosis by enhancement of caspase-2-mediated mitochondrial injury.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the James A. and Marion C. Grant Fund and by Public Health Service Grants CA86727 (to J.L.C.) and CA76491 (to J.M.R.). J.R.R. is the James A. and Marion C. Grant Fellow in Immunology and Infectious Diseases.

² Address correspondence and reprint requests to Dr. James L. Cook, Section of Infectious Diseases, Immunology and International Medicine, M/C 735, University of Illinois 808 South Wood Street, Chicago, IL 60612. E-mail address: JLCook{at}uic.edu

³ Abbreviations used in this paper: E1A, early region 1A oncogene of adenovirus serotype 5; PI, propidium iodide; MMP, mitochondrial membrane potential; TMRE, tetramethylrhodamine ethyl ester perchlorate; shRNA, short hairpin RNA; TR, TNF-resistant, E1A-positive cell variants.