IRF-1 reverts the transformed phenotype of oncogenically transformed cells in vitro and in vivo.
The expression of the transcriptional activator and tumor suppressor IRF-1 induces multiple effects that counteract the growth of tumor cells in vitro and in vivo. These include the inhibition of cell proliferation, the secretion of interferon-beta (IFN-beta), the induction of apoptosis specifically in certain cell types and the induction of a strong T-cell response. Here, we show that apart from its immune-activating properties, IRF-1 expression leads to a reversion of the tumorigenic phenotype of NIH3T3 cells transformed by different oncogenes. This was analysed in detail in a cell line in which the expression of c-Ha-ras and c-myc is under the control of a doxycycline-regulated promoter allowing to switch between the normal and oncogenic cell status. In the same cells, a beta-estradiol activatable IRF-1 fusion protein is expressed. After IRF-1 activation the oncogene-mediated acceleration of the cell cycle is reverted. Further, a complete IRF-1-mediated reversion of the oncogenic phenotype is observed in soft-agar growth assays. IRF-1 activation induces IFN-beta secretion; however, the observed effects are not mediated by IFN-beta. Inhibition of tumor growth is observed in nude mice as long as IRF-1 is active, indicating that neither B- nor T-cells must become activated for tumor growth suppression.
Kröger
Andrea
A
Department of Gene Regulation and Differentiation, GBF - German Research Center for Biotechnology, Mascheroder Weg 1, D 38124 Braunschweig, Germany.
Dallügge
Andreas
A
Kirchhoff
Sabine
S
Hauser
Hansjörg
H
D016475:3T3 Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000637:transplantation; D000818:Animals; D002453:Cell Cycle; D002455:Cell Division; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004318:Doxycycline / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D018773:Genes, erbB-1 / Q000187:drug effects; D018734:Genes, erbB-2 / Q000187:drug effects; D016259:Genes, myc / Q000187:drug effects; D011905:Genes, ras / Q000187:drug effects; D006801:Humans; D050856:Interferon Regulatory Factor-1; D016899:Interferon-beta / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000628:therapy*; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D017434:Protein Structure, Tertiary; D011960:Receptors, Estrogen / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000502:physiology; D014162:Transfection; D014410:Tumor Stem Cell Assay
D004268:DNA-Binding Proteins; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; C494258:Irf1 protein, mouse; D010750:Phosphoproteins; D011960:Receptors, Estrogen; D011993:Recombinant Fusion Proteins; D004958:Estradiol; D016899:Interferon-beta; D004318:Doxycycline