Interferon-γ Modulates a p53-independent Apoptotic Pathway and Apoptosis-related Gene Expression

• Published in: The Journal of biological chemistry 1997-06, Vol.272 (26), p.16351
• Main Authors: Natalya K. Ossina, Angela Cannas, Virginia C. Powers, Paul A. Fitzpatrick, John D. Knight, James R. Gilbert, Eugene M. Shekhtman, L. David Tomei, Samuil R. Umansky, Michael C. Kiefer
• Format: Article
• Language: English
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.272.26.16351

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 bak 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.