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Cooperative activity between HER oncogenes and the tumor suppressor IRF-1 results in apoptosis
1Department of Gene Regulation and Differentiation, GBF-National Research Center for Biotechnology, Braunschweig, Germany.
Abstract:
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 STAT5alpha 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.
Insights
The tumor suppressor IRF-1 induces apoptosis in cancer cells. Simultaneous activation of HER oncogenes and IRF-1 triggers synergistic effects, leading to cell death via STAT5alpha signaling.
Area of Science:
- Molecular Biology
- Oncology
- Cell Biology
Background:
- The transcription factor IRF-1 is known to inhibit cell growth.
- Oncogenes like HER can drive tumor development.
- Understanding the interplay between tumor suppressors and oncogenes is crucial for cancer therapy.
Purpose of the Study:
- To investigate the role of IRF-1 in inducing apoptosis in highly transformed and tumorigenic cell lines.
- To explore the synergistic effects of IRF-1 and HER oncogenes on cell growth and apoptosis.
- To identify signaling pathways involved in oncogene-dependent apoptosis.
Main Methods:
- Utilized cell lines expressing HER oncogenes and an activatable IRF-1 fusion protein.
- Assessed cell growth inhibition and apoptosis induction upon IRF-1 activation.
- Identified and analyzed promoters synergistically stimulated by IRF-1 and activated HER1.
- Employed dominant-negative STAT5alpha to modulate transcriptional synergy and apoptosis.
Main Results:
- IRF-1 induces apoptosis in highly transformed and tumorigenic cell lines, particularly those expressing HER oncogenes.
- Simultaneous activation of HER1 and IRF-1 leads to apoptosis, contrasting with IRF-1-induced growth inhibition alone.
- Discovered promoters synergistically activated by IRF-1 and HER1.
- Dominant-negative STAT5alpha abrogated both IRF-1/HER1-induced apoptosis and transcriptional synergy.
Conclusions:
- IRF-1 possesses potent apoptosis-inducing capabilities in cancer cells.
- The interplay between IRF-1 and HER oncogenes can dictate cell fate, promoting apoptosis under specific conditions.
- STAT5alpha signaling is a critical mediator of oncogene-dependent apoptosis induced by tumor suppressor activation.