Cooperative activity between HER oncogenes and the tumor suppressor IRF-1 results in apoptosis

The tumor suppressor transcription factor IRE-I inhibits cell growth. In this report we show that IRF-1 also induces apoptosis of highly transformed and tumorigenic cell lines. This activity of IRF-1 is demonstrated with cell lines expressing HER oncogenes and an activatable IRE-I fusion protein. Growth of cell lines expressing inactive HER1 is inhibited on IRE-I activation. In contrast, the same cells are killed by apoptosis when HER1 and IRE-I are activated simultaneously. We identified promoters stimulated synergistically by IRF-1 and by activated HER1. To determine the signals causing transcriptional synergism and/or apoptosis we tried to modulate these effects by various dominant negative acting proteins. Dominant negative STAT5 alpha: abolished both induction of apoptosis and transcriptional synergy of IRF-1 and HER. Thus, these results provide new insights into the mechanism of oncogene-dependent apoptosis induced by the activation of a tumor suppressor.