Department of Gene Regulation and Differentiation, GBF - National Research Center for Biotechnology, Mascheroder Weg 1, D-38124 Braunschweig, Germany

Correspondence to: Hansjörg Hauser, Department of Gene Regulation and Differentiation, GBF - National Research Center for Biotechnology, Mascheroder Weg 1, D-38124 Braunschweig, Germany

^aCurrent address: Tumor Immunology Program, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany

The tumor suppressor transcription factor IRF-1 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 IRF-1 fusion protein. Growth of cell lines expressing inactive HER1 is inhibited on IRF-1 activation. In contrast, the same cells are killed by apoptosis when HER1 and IRF-1 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 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.

interferon regulatory factor-1; HER; apoptosis; cell growth; STAT5; transcriptional activity

EGF, Epidermal Growth Factor; EGFR, EGF Receptor; HER, Human Epidermal Growth Factor Receptor; hER, hormone binding domain of the human Estrogen Receptor; PS, Phosphatidyl Serine; PI, Propidium Iodide; ISRE, Interferon Stimulated Regulatory Element; IRF-1, Interferon Regulatory Factor 1; STAT, Signal Transducers and Activators of Transcription; SH2, Src Homology domain 2; GAS, -interferon Activated Sequence; SRE, STAT Responsive Element; IRE, IRF-1 Recognition Element