Antiproliferative action of interferon-α requires components of T-cell-receptor signalling

Petricoin, Emanuel F.; Ito, Satoshi; Williams, Brandi L.; Audet, Susette; Stancato, Louis F.; Gamero, Ana M.; Clouse, Kathleen A.; Grimley, Philip M.; Weiss, Arthur; Beeler, Judy A.; Finbloom, D S; Shores, Elizabeth W.; Abraham, Robert T.; Larner, Andrew C.

doi:10.1038/37648

Cited by 146 publications

(110 citation statements)

References 9 publications

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“…Our preliminary experiments with anti-phosphotyrosine mAb specific for TEY suggested that short-term PMA stimulation caused phosphorylation of TEY on Jak1 molecules (data not shown). Recently, Petricoin et al (33) reported that the antiproliferative action of IFN-␣ required components of the TCR signaling cascade, such as Lck and ZAP-70. Here, we present evidence that the TCR-mediated Ras͞MAPK activation controls IL-4R-mediated signaling and determines the direction of helper T cell differentiation.…”

Section: Resultsmentioning

confidence: 99%

T cell antigen receptor-mediated activation of the Ras/mitogen-activated protein kinase pathway controls interleukin 4 receptor function and type-2 helper T cell differentiation

Yamashita

Kimura

Kubo

et al. 1999

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

187

174

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Section: Resultsmentioning

confidence: 99%

T cell antigen receptor-mediated activation of the Ras/mitogen-activated protein kinase pathway controls interleukin 4 receptor function and type-2 helper T cell differentiation

Yamashita

Kimura

Kubo

et al. 1999

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

187

174

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“…Further in vivo studies will be needed to fully characterize the functional relation between Nras and the immune defense system in the knockout mice. In this regard, it is worth mentioning that the transcriptional data reported here are fully derived from analysis of fibroblasts rather than lymphocytes, and that the available literature indicates that IFN/STAT signaling is mostly independent of T-cell receptor-dependent gene expression or signal-transduction processes (Beadling et al, 1994;Petricoin et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Transcriptional networks of knockout cell lines identify functional specificities of H-Ras and N-Ras: significant involvement of N-Ras in biotic and defense responses

et al. 2006

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We characterized differential gene expression profiles of fibroblast cell lines harboring single or double-homozygous null mutations in H-ras and N-ras. Whereas the expression level of the individual H-, N-and K-ras genes appeared unaffected by the presence or absence of the other ras loci, significant differences were observed between the expression profiles of cells missing N-ras and/or H-ras. Absence of N-ras produced much stronger effects than absence of H-ras over the profile of the cellular transcriptome. N-ras À/À and H-ras À/À fibroblasts displayed rather antagonistic expression profiles and the transcriptome of H-ras À/À cells was significantly closer to that of wild-type fibroblasts than to that of N-ras À/À cells. Classifying all differentially expressed genes into functional categories suggested specific roles for H-Ras and N-Ras. It was particularly striking in N-ras À/À cells the upregulation of a remarkable number of immunity-related genes, as well as of several loci involved in apoptosis. Reverse-phase protein array assays demonstrated in the same N-ras À/À cells the overexpression and nuclear migration of tyrosine phosphorylated signal transducer and activator of transcription 1 (Stat1) which was concomitant with transcriptional activation mediated by interferon-stimulated response elements. Significantly enhanced numbers of apoptotic cells were also detected in cultures of N-ras À/À cells. Our data support the notion that different Ras isoforms play functionally distinct cellular roles and indicate that N-Ras is significantly involved in immune modulation/host defense and apoptotic responses. Oncogene (2007) 26, 917-933.

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“…These components were associated with IFNaR1, as judged by co-immunoprecipitation experiments and are essential for signaling via the T-cell receptor (57). Requirement of T-cell receptor signaling components was also reported by other groups, who showed that Stat5, which is constitutively associated with Tyk2, provides upon phosphorylation a docking site for the SH2 domain of CrkL, a protein that is located upstream of the T-cell receptor induced growth-inhibitory C3G/Rap-1 cascade.…”

Section: Discussionmentioning

confidence: 99%

Dimerization of the Interferon Type I Receptor IFNaR2–2 Is Sufficient for Induction of Interferon Effector Genes but Not for Full Antiviral Activity

Pattyn¹,

Ostade²,

Schauvliege³

et al. 1999

Journal of Biological Chemistry

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We constructed chimeric receptors wherein the extracellular domain of the erythropoietin receptor (EpoR) was fused to the transmembrane and intracellular domains of the interferon (IFN) type I receptor subunits, IFNaR1 or IFNaR2-2. Transfection into 2fTGH and Tyk2-deficient 11,1 cells showed that EpoR/IFNaR2-2 alone was able to transduce a signal upon stimulation with erythropoietin (Epo), as judged by induction of the interferon type I-inducible 6-16 promoter. In contrast, protection against infection with encephalomyocarditis virus or vesicular stomatitis virus was reduced or absent, respectively. To further investigate the role of IFNaR1 in the induction of an antiviral state, we analyzed the Epo-versus IFN␣-induced transcription of a set of genes, involved in antiviral protection. Up to 24 h after stimulation with Epo or IFN␣, comparable transcription of the p56, dsRNA-dependent protein kinase, 2-5A synthetase, and MxA genes was seen. However, at later time points, only in the case of Epo induction, a sharp decrease of mRNA levels was observed. Western blotting analysis of dsRNA-dependent protein kinase showed a similar pattern at the protein level. Taken together, our results imply a role for IFNaR1 in the induction of sustained mRNA and protein levels that are likely required for optimal antiviral activity.It is generally accepted that activation of a cell by a cytokine is initiated by ligand-induced clustering of receptor subunits, which can occur as di-, tri-, or higher order oligomers, involving identical or related subunits. With the exception of the heptamembrane-spanning receptors, members from the hematopoietin/IFN, 1 tumor necrosis factor/nerve growth factor, and tyrosine kinase receptor families are all activated by this mechanism of cytokine-driven multimerization. Ligand binding to the first receptor component induces the association with additional receptor subunits eventually resulting in an increase of affinity for the ligand (1, 2). Alternatively, preformed receptor complexes may also exist on the cell membrane (3). Interferons belong to the class I cytokine family and are divided into type I interferons (at least 14 IFN␣ subtypes, IFN␤, IFN, and the bovine embryonic IFN) that have antiviral, cytostatic, and hematopoietic activities on many cell types, and the type II interferon or IFN␥ that is also involved in many immune functions. Both types of interferons bind to distinct receptors that belong to the class I cytokine receptors. The interferon type I receptor (IFNaR) is composed of two subunits, IFNaR1 and IFNaR2-2. As a result of alternative splicing, subtypes of the latter subunit do also exist: a cytoplasmic truncated transmembrane form (IFNaR2-1) and a soluble form (IFNaR2-3) (4 -8).A large body of evidence has shown that the class I cytokine receptors make use of associated kinases (JAKs) to start intracellular tyrosine phosphorylation, resulting in the activation of the so-called Stat proteins. This JAK/Stat pathway is essential for transcription of many of the cytokine-inducible ge...

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Antiproliferative action of interferon-α requires components of T-cell-receptor signalling

Cited by 146 publications

References 9 publications

T cell antigen receptor-mediated activation of the Ras/mitogen-activated protein kinase pathway controls interleukin 4 receptor function and type-2 helper T cell differentiation

T cell antigen receptor-mediated activation of the Ras/mitogen-activated protein kinase pathway controls interleukin 4 receptor function and type-2 helper T cell differentiation

Transcriptional networks of knockout cell lines identify functional specificities of H-Ras and N-Ras: significant involvement of N-Ras in biotic and defense responses

Dimerization of the Interferon Type I Receptor IFNaR2–2 Is Sufficient for Induction of Interferon Effector Genes but Not for Full Antiviral Activity

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