Cell-type and Donor-specific Transcriptional Responses to Interferon-α

Schlaak, Joerg F.; Hilkens, Catharien M. U.; Costa-Pereira, Ana P.; Strobl, Birgit; Aberger, Fritz; Frischauf, Anna‐Maria; Kerr, Ian M.

doi:10.1074/jbc.m205571200

Cited by 76 publications

(81 citation statements)

References 54 publications

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“…IFNs are known inducers of transcriptional changes, and their effects on the transcriptome of several cell types have been investigated in a number of studies (12,(15)(16)(17)(18). The transcriptional effects of these cytokines on EC, however, have been only partially addressed (31) despite the broad evidence for their antiangiogenic effects (32)(33)(34).…”

Section: Discussionmentioning

confidence: 99%

“…To date, the gene expression profile induced by IFN-␣ has been predominantly studied in tumor cell lines (12)(13)(14) and some primary cells, including PBMC, T lymphocytes, and dendritic cells (15)(16)(17)(18); little is known about the transcriptional profile induced by IFN-␣ in EC. The definition of cell type-specific profiles is likely central to a full understanding of the biology of IFNs and their antiangiogenic activity and may also be of potential clinical importance given the broad use of these cytokines in patients.…”

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confidence: 99%

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Identification of Genes Selectively Regulated by IFNs in Endothelial Cells

Indraccolo

Pfeffer

Minuzzo

et al. 2007

The Journal of Immunology

151

120

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IFNs are highly pleiotropic cytokines also endowed with marked antiangiogenic activity. In this study, the mRNA expression profiles of endothelial cells (EC) exposed in vitro to IFN-α, IFN-β, or IFN-γ were determined. We found that in HUVEC as well as in other EC types 175 genes were up-regulated (>2-fold increase) by IFNs, including genes involved in the host response to RNA viruses, inflammation, and apoptosis. Interestingly, 41 genes showed a >5-fold higher induction by IFN-α in EC compared with human fibroblasts; among them, the gene encoding the angiostatic chemokine CXCL11 was selectively induced by IFN-α in EC along with other genes associated with angiogenesis regulation, including CXCL10, TRAIL, and guanylate-binding protein 1. These transcriptional changes were confirmed and extended by quantitative PCR analysis and ELISA; whereas IFN-α and IFN-β exerted virtually identical effects on transcriptome modulation, a differential gene regulation by type I and type II IFN emerged, especially as far as quantitative aspects were concerned. In vivo, IFN-α-producing tumors overexpressed murine CXCL10 and CXCL11, guanylate-binding protein 1, and TRAIL, with evidence of CXCL11 production by tumor-associated EC. Overall, these findings improve our understanding of the antiangiogenic effects of IFNs by showing that these cytokines trigger an antiangiogenic transcriptional program in EC. Moreover, we suggest that quantitative differences in the magnitude of the transcriptional activation of IFN-responsive genes could form the basis for cell-specific transcriptional signatures.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Identification of Genes Selectively Regulated by IFNs in Endothelial Cells

Indraccolo

Pfeffer

Minuzzo

et al. 2007

The Journal of Immunology

151

120

View full text Add to dashboard Cite

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“…These observations raise the possibility that individuals that express the Pro 72 form of p53 express relatively higher levels of the IFI16 protein. Because the Pro/Pro genotype has a 41% increased survival of individuals (despite a 2.54-fold increased proportional mortality from cancer) compared with the individuals with the Arg/Arg genotype (40) and steady-state levels of the IFI16 mRNA vary among individuals (21,41), further work will be needed to determine whether a particular genotype of p53 is associated with cellular expression levels of the IFI16 protein. Differences in the expression levels of the IFI16 protein among individuals could account for certain aging-dependent diseases, including certain human cancers (21).…”

Section: Ifi16 Is a Transcriptional Target Of P53mentioning

confidence: 99%

Expression of an IFN-Inducible Cellular Senescence Gene, IFI16, Is Up-Regulated by p53

Song

Alimirah

Panchanathan

et al. 2008

Molecular Cancer Research

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IFN-inducible IFI16 protein (encoded by IFI16 gene at 1q23.1) is the human member of the IFN-inducible structurally related p200 family proteins. Increased expression of the IFI16 protein, a positive modulator of p53-mediated transcription, in normal old human diploid fibroblasts (HDF) is associated with cellular senescence-mediated cell growth arrest. However, the underlying mechanisms that contribute to transcriptional activation of the IFI16 gene in old HDFs remain to be elucidated. Here, we reported that functional activation of p53 in normal young HDFs and p53-null Saos2 cell line resulted in transcriptional activation of the IFI16 gene. We identified a potential p53 DNA-binding site (indicated as IFI16-p53-BS) in the 5 ¶-regulatory region of the IFI16 gene. Importantly, p53 bound to IFI16-p53-BS in a sequence-specific manner in gel-mobility shift assays. Furthermore, p53 associated with the 5 ¶-regulatory region of the IFI16 gene in chromatin immunoprecipitation assays. Interestingly, p53 associated with the regulatory region of the IFI16 gene only on treatment of cells with DNA-damaging agents or in the old, but not in the young, HDFs. Importantly, our promoter-reporter assays, which were coupled with site-directed mutagenesis of IFI16-p53-BS, showed that p53 activates transcription of the IFI16 gene in HDFs through the p53 DNA-binding site. Together, our observations provide support for the idea that up-regulation of IFI16 expression by p53 and functional interactions between IFI16 protein and p53 contribute to cellular senescence.

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“…Importantly, recent analyses of IFI 16 expression in several human tissues by immunohistochemistry revealed that expression of IFI 16 is not restricted to cells of hematopoietic origin (Gariglio et al, 2002;Wei et al, 2003). Of note, IFN induction of IFI 16 in hematopoietic cells appears to be cell-type-and donor-specific (Schlaak et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Role of IFI 16, a member of the interferon-inducible p200-protein family, in prostate epithelial cellular senescence

et al. 2003

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Recent studies have implicated interferon signaling in the regulation of cellular senescence. However, the role of specific interferon-inducible proteins in cellular senescence remains to be defined. Here we report that IFI 16, an interferon-inducible transcriptional modulator from the p200-protein family, contributes to cellular senescence of prostate epithelial cells. Normal human prostate epithelial cells (PrEC) in culture expressed detectable levels of IFI 16, and the levels increased more than fourfold when cells approached cellular senescence. Consistent with a role of IFI 16 in cellular senescence, human prostate cancer cell lines either did not express IFI 16 or expressed a variant form, which was primarily detected in the cytoplasm of prostate cancer cells and not in the nucleus. Moreover, overexpression of functional IFI 16 in human prostate cancer cell lines inhibited colony formation. Additionally, ectopic expression of IFI 16 in clonal prostate cancer cell lines was associated with a senescence-like phenotype, production of senescence-associated b-galactosidase (a biochemical marker for cellular senescence), and reduction of S-phase cells in culture. Importantly, upregulation of p21 WAF1 and inhibition of E2F-stimulated transcription accompanied inhibition of cell growth by IFI 16 in prostate cancer cell lines. Collectively, our observations support the idea that increased levels of IFI 16 in PrECs contribute to senescence-associated irreversible cell growth arrest.

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Cell-type and Donor-specific Transcriptional Responses to Interferon-α

Cited by 76 publications

References 54 publications

Identification of Genes Selectively Regulated by IFNs in Endothelial Cells

Identification of Genes Selectively Regulated by IFNs in Endothelial Cells

Expression of an IFN-Inducible Cellular Senescence Gene, IFI16, Is Up-Regulated by p53

Role of IFI 16, a member of the interferon-inducible p200-protein family, in prostate epithelial cellular senescence

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