Although many tumor cells are sensitive to tumor necrosis factor (TNF)-induced cell death, most normal cells are resistant. To determine whether the sensitive phenotype or the resistant phenotype is genetically dominant, we constructed somatic cell hybrids of TNF-resistant (TNP) C3H mouse 10T1/2 fibroblasts and Ha-ms-transformed TNF-sensitive (TNFs) 10T-EJ cells and then tested the sensitivity of those hybrids to TNF-induced cell death. All somatic cell hybrid cell lines tested were resistant to TNF-induced cell death. The TNFr 10T1/2 cells, however, exhibited sensitivity to TNF-induced cell death in the presence of cycloheximide (CHX), whereas TNFs 10T-EJ cells did not show any further increase in sensitivity to TNF-induced cell death in the presence of CHX. In addition, the killing of 1OT1/2 cells by TNF in the presence of CHX involved apoptosis. These results demonstrate that resistance to TNF-induced apoptosis is a genetically dominant phenotype and that certain protein(s) constitutively expressed or induced by TNF in resistant cells may confer protection against TNF-induced apoptosis.

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