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 cel l 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 cau se resistance to TNF-mediated apoptosis, Here we show that normal human dip loid fibroblasts that express the human papillomavirus type 16 E7 oncoprote in have a decreased propensity to undergo apoptosis in response to TNF trea tment. The ability of E7 to undermine TNF-mediated apoptosis correlates wit h cellular transformation. While E7 does not generally subvert signaling by tumor necrosis factor receptor I, pro-caspase 8 activation is decreased in E7-expressing cells, E7 also provides some protection from apoptosis cause d by stimulation of the TNF receptor 1-related cytokine receptor Fas, where induction of apoptosis occurs much slower in this cell type. Hence, E7-exp ressing normal human fibroblasts exhibit specific defect that obstructs cyt okine-mediated activation of pro-caspase 8 and apoptosis.