Cooperative activity between HER oncogenes and the tumor suppressor IRF-1 results in apoptosis.
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.
Kirchhoff
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Department of Gene Regulation and Differentiation, GBF-National Research Center for Biotechnology, Braunschweig, Germany.
Hauser
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H
D016475:3T3 Cells / Q000473:pathology; D017500:Adenovirus E1A Proteins / Q000502:physiology; D017501:Adenovirus E1B Proteins / Q000502:physiology; D000818:Animals; D002461:Cell Line, Transformed / Q000473:pathology; D002472:Cell Transformation, Viral; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000235:genetics / Q000502:physiology*; D004958:Estradiol / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D050856:Interferon Regulatory Factor-1; D007372:Interferons / Q000378:metabolism; D051379:Mice; D008894:Milk Proteins; D008979:Moloney murine leukemia virus / Q000502:physiology; D009857:Oncogenes; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D011401:Promoter Regions, Genetic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D050799:STAT5 Transcription Factor; D012509:Sarcoma / Q000473:pathology; D015398:Signal Transduction; D015534:Trans-Activators / Q000502:physiology; D014158:Transcription, Genetic; D014162:Transfection; D018631:ras Proteins / Q000502:physiology
D017500:Adenovirus E1A Proteins; D017501:Adenovirus E1B Proteins; D004268:DNA-Binding Proteins; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D004958:Estradiol; D050856:Interferon Regulatory Factor-1; D007372:Interferons; D008894:Milk Proteins; D010750:Phosphoproteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D018631:ras Proteins; C494257:IRF1 protein, human; C494258:Irf1 protein, mouse