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

Oncogene volume 18, pages 3725–3736 (1999)Cite this article

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 STAT5α 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.

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Abbreviations

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:

γ-interferon Activated Sequence

SRE:

STAT Responsive Element

IRE:

IRF-1 Recognition Element

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Acknowledgements

We thank M Grashoff and M Höxter for excellent technical support. Dr T Beckers for the gift of NIH3T3 cells expressing HER1 or HER2. Dr H Rahmsdorf for an expression construct coding for rasAsn17. Dr M Göttlicher for the collagenase promoter constructs. Dr B Groner for the gift of the expression construct for STAT5αΔ750 and the STAT sensitive reporter construct. Dr L van der Eb for the DNAs coding for E1a/b. Drs PH Krammer and ME Peter for critical reading of the manuscript and helpful discussions. This work has been supported by BMBF grant no. 0310697.

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  1. Sabine Kirchhoff

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

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

    Sabine Kirchhoff & Hansjörg Hauser

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Kirchhoff, S., Hauser, H. Cooperative activity between HER oncogenes and the tumor suppressor IRF-1 results in apoptosis. Oncogene 18, 3725–3736 (1999). https://doi.org/10.1038/sj.onc.1202704

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