Impairment of Interferon-Induced IRF-7 Gene Expression due to Inhibition of ISGF3 Formation by Trichostatin A

Génin, Pierre; Morin, P; Civas, Ahmet

doi:10.1128/jvi.77.12.7113-7119.2003

Cited by 50 publications

(43 citation statements)

References 40 publications

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“…7b), since histone deacetylase inhibitors even counteract IFN-signaling by preventing the formation of the multimeric transcription factor complex ISGF3. 44 The same was true when cells were pretreated with a DNA demethylating agent, also revealing an absence of IFN-b mRNA in the RT-PCR reaction (Fig. 7a).…”

Section: Discussionmentioning

confidence: 62%

Genetic redundancy in human cervical carcinoma cells: Identification of cells with “normal” properties

Bachmann

Zawatzky

Rösl

2007

Intl Journal of Cancer

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Although it is generally assumed that cancer arises from a singular cell, a tumor must be considered as a dynamic and emergent biological structure, whose organizing principle is determined by genetic and epigenetic modifications, occurring variably in response to microenvironmental selection conditions. As previously shown, HPV-positive cervical carcinoma cells have lost their ability to induce IFN-b upon TNF-a treatment. However, regarding cancer as a non-linear system, which may, even in the absence of an apparent selection pressure, fluctuate between different ''metastable'' phenotypes, we demonstrate that TNF-a mediated IFN-b induction is not irreversibly disturbed in all cells. Using the IFN-b sensitive Encephalomyocarditis virus (EMCV) as a tool to monitor antiviral activity in long-term established malignant HeLa cells, rare IFN-b expressing clones were rescued from a population of non-responsive and EMCV-sensitive cells. Antiviral activity was mediated by the re-expression of IRF-1 and p48 (IRF-9), both key regulatory molecules normally found to be suppressed in cervical carcinoma cells. Upon inoculating of selected clones into immunocompromised animals, a reduced or even an absence of tumorigenicity of initially highly malignant cells could be discerned. These data indicate that both the absence of interferon signaling and the ability to form tumors were reversed in a minority of cells. We provide a paradigm for the existence of innate genetic redundancy mechanisms, where a particular phenotype persists and can be isolated without application of drugs generally changing the epigenetic context. ' 2007 Wiley-Liss, Inc.Key words: human papillomaviruses; interferon-b regulation; EMCVcytolysis; tumor necrosis factor alpha; redundancy mechanisms; oscillation; chaotic cell systems; tumorigenicity Infections with certain types of human papillomaviruses (HPV) are the major cause for the development of cervical cancer. 1 Epidemiological studies show that immunodeficient women have a significantly higher risk of developing a tumor than age-matched controls. Hence, cancer of the cervix uteri is the final outcome of a long term selection and escape process, where HPV positive cells are no longer controlled by immunological surveillance. 2 Consequently, a physiological intact communication route between inflammatory and HPV-containing cells is an indispensable prerequisite for a proper antiviral response. 3 Targeting IFN-signaling actually provides a general selective advantage for tumor formation, because it favors the disruption of the intercellular cross-talk between HPV positive and immunological effector cells. 4 In a previous investigation, we demonstrated that the antiviral effect of TNF-a, which is mediated by IFN-b gene activation, 5 is disturbed in HPV positive cervical carcinoma cells. 6 The reason for this failure is the lack of interferon-regulatory factor (IRF)-1 and p48 (IRF-9) expression, two key regulators, tightly involved in the transcriptional control of the intermediate and the delayed interfero...

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Section: Discussionmentioning

confidence: 62%

Genetic redundancy in human cervical carcinoma cells: Identification of cells with “normal” properties

Bachmann

Zawatzky

Rösl

2007

Intl Journal of Cancer

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“…We reasoned that combining a viral therapeutic with a compound that reversibly compromises host antiviral genetic programs could provide a means to enhance OV growth in tumor cells. Histone deacetylase inhibitors (HDIs) are small molecules currently in clinical development that have demonstrated potent anti-tumor activity but are also known to prevent the transcriptional activation of antiviral genes after IFN stimulation or virus infection (12)(13)(14)(15)(16)(17)(18)(19). Here, we demonstrate that a variety of HDIs markedly enhance OV killing of tumor cells in vitro and in vivo but do not increase OV growth in normal tissues.…”

Section: Hdac Inhibitor ͉ Oncolytic Virus ͉ Refractory Tumors ͉ Combimentioning

confidence: 77%

Chemical targeting of the innate antiviral response by histone deacetylase inhibitors renders refractory cancers sensitive to viral oncolysis

Nguyên

Abdelbary

Arguello

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

164

176

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“…IFN-␤ mRNA expression peaked at 6 h and preceded the induction of IFN-␣ transcription at 18 -24 h post V 2 O 5 exposure. IFN-␤ stimulates the JAK-STAT pathway through the IFN receptor, resulting in activation of the transcription factor IFN-stimulated gene factor 3 (ISGF3) that in turn increases IFN regulatory factor 7 protein synthesis (22). IFN regulatory factor 7 has been shown to amplify IFN-␣ expression through a positive feedback loop (23).…”

Section: Discussionmentioning

confidence: 99%

STAT-1 Signaling in Human Lung Fibroblasts Is Induced by Vanadium Pentoxide through an IFN-β Autocrine Loop

Antao-Menezes

Turpin

Bost

et al. 2008

The Journal of Immunology

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The inhalation of vanadium pentoxide (V2O5) results in bronchitis and airway fibrosis. The lung fibrotic response to V2O5 partially resolves where fibroblasts first proliferate and deposit collagen, but then undergo growth arrest and apoptosis. STAT-1 mediates fibroblast growth arrest and apoptosis. We previously reported that STAT-1 is a protective factor and mice lacking STAT-1 are more susceptible to lung fibrosis. We also reported that V2O5-induced STAT-1 phosphorylation in lung fibroblasts requires H2O2 and de novo protein synthesis. In this study, we identified IFN-β as the protein that mediates STAT-1 activation by V2O5 in normal human lung fibroblasts and identified NADPH and xanthine oxidase systems as sources of H2O2 that drive IFN-β gene expression. STAT-1 phosphorylation was decreased with neutralizing Abs to IFN-β as well as an inhibitor of JAK. V2O5 also increased transcription of an IFN-inducible and STAT-1-dependent chemokine, CXCL10. Inhibition of H2O2-generating enzyme systems NADPH oxidase by apocynin and xanthine oxidase by allopurinol individually reduced STAT-1 phosphorylation. Apocynin and allopurinol also decreased V2O5-induced IFN-β mRNA levels and CXCL10 expression. IFN-α transcription was inhibited only by allopurinol. Taken together, these data indicate that fibroblasts play a role in the innate immune response to vanadium-induced oxidative stress by synthesizing IFN-β and activating STAT-1 to cause growth arrest and increase levels of CXCL10, a potent antifibrotic factor. This mechanism is postulated to counterbalance profibrogenic mechanisms that follow V2O5 injury.

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Impairment of Interferon-Induced IRF-7 Gene Expression due to Inhibition of ISGF3 Formation by Trichostatin A

Cited by 50 publications

References 40 publications

Genetic redundancy in human cervical carcinoma cells: Identification of cells with “normal” properties

Genetic redundancy in human cervical carcinoma cells: Identification of cells with “normal” properties

Chemical targeting of the innate antiviral response by histone deacetylase inhibitors renders refractory cancers sensitive to viral oncolysis

STAT-1 Signaling in Human Lung Fibroblasts Is Induced by Vanadium Pentoxide through an IFN-β Autocrine Loop

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