Adenovirus E1A oncogene expression in tumor cells enhances killing by TNF-related apoptosis-inducing ligand (TRAIL).
Expression of the adenovirus serotype 5 (Ad5) E1A oncogene sensitizes cells to apoptosis by TNF-alpha and Fas-ligand. Because TNF-related apoptosis-inducing ligand (TRAIL) kills cells in a similar manner as TNF-alpha and Fas ligand, we asked whether E1A expression might sensitize cells to lysis by TRAIL. To test this hypothesis, we examined TRAIL-induced killing of human melanoma (A2058) or fibrosarcoma (H4) cells that expressed E1A following either infection with Ad5 or stable transfection with Ad5-E1A. E1A-transfected A2058 (A2058-E1A) or H4 (H4-E1A) cells were highly sensitive to TRAIL-induced killing, but Ad5-infected cells expressing equally high levels of E1A protein remained resistant to TRAIL. Infection of A2058-E1A cells with Ad5 reduced their sensitivity to TRAIL-dependent killing. Therefore, viral gene products expressed following infection with Ad5 inhibited the sensitivity to TRAIL-induced killing conferred by transfection with E1A. E1B and E3 gene products have been shown to inhibit TNF-alpha- and Fas-dependent killing. The effect of these gene products on TRAIL-dependent killing was examined by using Ad5-mutants that did not express either the E3 (H5dl327) or E1B-19K (H5dl250) coding regions. A2058 cells infected with H5dl327 were susceptible to TRAIL-dependent killing. Furthermore, TRAIL-dependent killing of A2058-E1A cells was not inhibited by infection with H5dl327. Infection with H5dl250 sensitized A2058 cells to TRAIL-induced killing, but considerably less than H5dl327-infection. In summary, expression of Ad5-E1A gene products sensitizes cells to TRAIL-dependent killing, whereas E3 gene products, and to a lesser extent E1B-19K, inhibit this effect.
Routes
J M
JM
Department of Medicine and Immunology, National Jewish Center for Immunology and Respiratory Medicine, Denver, CO 80206, USA. routesj@njc.org
Ryan
S
S
Clase
A
A
Miura
T
T
Kuhl
A
A
Potter
T A
TA
Cook
J L
JL
D017500:Adenovirus E1A Proteins / Q000096:biosynthesis* / Q000235:genetics*; D017501:Adenovirus E1B Proteins / Q000235:genetics / Q000502:physiology; D017503:Adenovirus E3 Proteins / Q000235:genetics / Q000502:physiology; D000260:Adenoviruses, Human / Q000235:genetics / Q000276:immunology; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins; D003602:Cytotoxicity, Immunologic / Q000235:genetics*; D005354:Fibrosarcoma / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000821:virology; D015967:Gene Expression Regulation, Viral / Q000276:immunology*; D006801:Humans; D008024:Ligands; D008545:Melanoma / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000821:virology; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000633:toxicity*; D009857:Oncogenes / Q000276:immunology*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000276:immunology / Q000473:pathology / Q000821:virology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000633:toxicity*
D017500:Adenovirus E1A Proteins; D017501:Adenovirus E1B Proteins; D017503:Adenovirus E3 Proteins; D051017:Apoptosis Regulatory Proteins; D008024:Ligands; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha