E1A oncogene enhancement of caspase-2-mediated mitochondrial injury sensitizes cells to macrophage nitric oxide-induced apoptosis.
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 alpha and NO. E1A sensitizes cells to TNF by repressing its activation of NF-kappaB-dependent, antiapoptotic defenses. This suggested the hypothesis that E1A blockade of the NF-kappaB 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-kappaB-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-kappaB-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.
Section of Infectious Diseases, Immunology, and International Medicine, Department of Medicine and Microbiology-Immunology and the Cancer Center, University of Illinois, Chicago, IL 60612, USA.
Jay R
JR
Radke
Zeba K
ZK
Siddiqui
Tanya A
TA
Miura
John M
JM
Routes
James L
JL
Cook
D017500:Adenovirus E1A Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000235:genetics* / Q000276:immunology; D053143:Caspase 2 / Q000502:physiology*; D045744:Cell Line, Tumor; D006801:Humans; D007425:Intracellular Membranes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000201:enzymology* / Q000276:immunology / Q000473:pathology* / Q000821:virology; D008564:Membrane Potentials / Q000235:genetics / Q000276:immunology; D051379:Mice; D008928:Mitochondria / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D016328:NF-kappa B / Q000502:physiology; D041681:NIH 3T3 Cells; D009569:Nitric Oxide / Q000502:physiology*; D009857:Oncogenes
D017500:Adenovirus E1A Proteins; D016328:NF-kappa B; D009569:Nitric Oxide; D053143:Caspase 2