Interferon (IFN)-γ increases the sensitivity of tumor cell lines, many of which are p53 mutants, to tumor necrosis factor-α-mediated and anti-Fas antibody-mediated cell death. To better understand the mechanism of IFN-γ action in modulating the cell death response independently of p53 function, we analyzed the death of the human colon adenocarcinoma cell line, HT-29, following treatment with IFN-γ and various cytotoxic agents. Here we show that IFN-γ modulates cell death by sensitizing the cells to killing by numerous pro-apoptotic stimuli but not pro-necrotic stimuli. Furthermore, we show that select genes from several important apoptosis-related gene families are induced by IFN-γ, including the apoptosis-signaling receptors CD95 (Fas/APO-1) and TNFR 1 and interleukin-1β-converting enzyme (Ice) family members Ice, CPP32 (Yama, apopain), ICE(rel)II (TX, Ich-2), Mch-3 (ICE-LAP3, CMH-1), Mch-4, and Mch-5 (MACH, FLICE). Of the bcl-2 family members, IFN-γ directly induced bax but notably not bax, which is activated by p53. The IFN- responsive transcriptional activator interferon regulatory factor-1 was also strongly induced and translocated into the nucleus following IFN-γ treatment. We propose that IFN-γ modulates a p53-independent apoptotic pathway by both directly and indirectly inducing select apoptosis-related genes.
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