The HPV E7 oncoprotein inhibits tumor necrosis factor alpha-mediated apoptosis in normal human fibroblasts.
Tumor necrosis factor-alpha (TNF) is a cytokine that induces programmed cell death, apoptosis, in a number of cell types and is employed by cytotoxic T cells to eliminate virus infected cells. Consequently, many viruses have acquired mechanisms to undermine these host cell defense mechanisms and cause resistance to TNF-mediated apoptosis. Here we show that normal human diploid fibroblasts that express the human papillomavirus type 16 E7 oncoprotein have a decreased propensity to undergo apoptosis in response to TNF treatment. The ability of E7 to undermine TNF-mediated apoptosis correlates with cellular transformation. While E7 does not generally subvert signaling by tumor necrosis factor receptor 1, pro-caspase 8 activation is decreased in E7-expressing cells. E7 also provides some protection from apoptosis caused by stimulation of the TNF receptor 1-related cytokine receptor Fas, where induction of apoptosis occurs much slower in this cell type. Hence, E7-expressing normal human fibroblasts exhibit a specific defect that obstructs cytokine-mediated activation of pro-caspase 8 and apoptosis.
Thompson
D A
DA
Department of Pathology and Harvard Center for Cancer Biology, Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts, MA 02115, USA.
Zacny
V
V
Belinsky
G S
GS
Classon
M
M
Jones
D L
DL
Schlegel
R
R
Münger
K
K
D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD / Q000378:metabolism / Q000502:physiology; D017209:Apoptosis; D002352:Carrier Proteins / Q000378:metabolism; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism; D053200:Fas-Associated Death Domain Protein; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D015870:Gene Expression; D006801:Humans; D051550:I-kappa B Kinase; D016328:NF-kappa B / Q000378:metabolism; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism*; D027383:Papillomaviridae / Q000378:metabolism*; D050725:Papillomavirus E7 Proteins; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism / Q000502:physiology; D047888:Receptors, Tumor Necrosis Factor, Type I; D047990:TNF Receptor-Associated Factor 1; D047992:TNF Receptor-Associated Factor 2; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology
D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D002352:Carrier Proteins; D061945:Caspase Inhibitors; D004792:Enzyme Precursors; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D016328:NF-kappa B; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D011506:Proteins; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047990:TNF Receptor-Associated Factor 1; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha; C059731:oncogene protein E7, Human papillomavirus type 16; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases