Induction of programmed cell death by parvovirus H-1 in U937 cells: connection with the tumor necrosis factor alpha signalling pathway.
The human promonocytic cell line U937 undergoes apoptosis upon treatment with tumor necrosis factor alpha (TNF-alpha). This cell line has previously been shown to be very sensitive to the lytic effect of the autonomous parvovirus H-1. Parvovirus infection leads to the activation of the CPP32 ICE-like cysteine protease which cleaves the enzyme poly(ADP-ribose)polymerase and induces morphologic changes that are characteristic of apoptosis in a way that is similar to TNF-alpha treatment. This effect is also observed when the U937 cells are infected with a recombinant H-1 virus which expresses the nonstructural (NS) proteins but in which the capsid genes are replaced by a reporter gene, indicating that the induction of apoptosis can be assigned to the cytotoxic nonstructural proteins in this cell system. The c-Myc protein, which is overexpressed in U937 cells, is rapidly downregulated during infection, in keeping with a possible role of this product in mediating the apoptotic cell death induced by H-1 virus infection. Interestingly, four clones (designated RU) derived from the U937 cell line and selected for their resistance to H-1 virus (J. A. Lopez-Guerrero et al., Blood 89:1642-1653, 1997) failed to decrease c-Myc expression upon treatment with differentiation agents and also resisted the induction of cell death after TNF-alpha treatment. Our data suggest that the RU clones have developed defense strategies against apoptosis, either by their failure to downregulate c-Myc and/or by activating antiapoptotic factors.
Angewandte Tumorvirologie, Abteilung F0100, Deutsches Krebsforschungszentrum, and Virologie Appliquée à l'Oncologie (Unité INSERM 375), D-69009 Heidelberg, Germany.
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B
Rayet
J A
JA
Lopez-Guerrero
J
J
Rommelaere
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C
Dinsart
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D020169:Caspases / Q000378:metabolism; D015536:Down-Regulation; D004789:Enzyme Activation; D016259:Genes, myc; D006801:Humans; D017992:Parvovirus / Q000235:genetics / Q000472:pathogenicity*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011995:Recombination, Genetic; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000502:physiology*; D020298:U937 Cells
D014409:Tumor Necrosis Factor-alpha; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases