Interferon Induction by Viruses. XVI. 2-Aminopurine Blocks Selectively and Reversibly an Early Stage in Interferon Induction

Marcus, Philip I.; Sekellick, Margaret J.

doi:10.1099/0022-1317-69-7-1637

Cited by 80 publications

(37 citation statements)

References 33 publications

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“…2-Aminopurine has been shown to inhibit the doublestranded RNA-dependent protein kinase in vitro (21) and also blocks gene induction by double-stranded RNA (41,61,68). It is attractive to speculate that 2-aminopurine inhibition of gene induction by IFN-y and double-stranded RNA reflects the involvement of the same kinase in these two signal transduction pathways.…”

Section: -Aminopurine Selectively Blocks Gbp Induction By Ifn-ymentioning

confidence: 99%

“…In addition, similarities have been noted between the promoter elements conferring responsiveness to these agents (18,30,63). Recently, on the basis of inhibition by 2-aminopurine, three groups of investigators (41,61,68) have suggested that a kinase is involved in gene induction by double-stranded RNA. We tested the effect of 2-aminopurine on induction of GBP transcription by IFN-a and IFN--y (Fig.…”

Section: -Aminopurine Selectively Blocks Gbp Induction By Ifn-ymentioning

confidence: 99%

See 1 more Smart Citation

Alpha interferon and gamma interferon stimulate transcription of a single gene through different signal transduction pathways.

Lew¹,

Decker²,

Darnell³

1989

Mol. Cell. Biol.

104

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Interferons (IFNs) play a key role in the defense against virus infection and the regulation of cell growth and differentiation, in part through changes in specific gene transcription in target cells. We describe several differences between the signal transduction events that result in transcriptional activation of the human gene coding for a guanylate-binding protein (GBP) by alpha interferon (IFN-a) and gamma interferon (IFN--y (2,12,16,24,25,31,36,37,43,44,50) induce alterations in the expression of specific sets of genes in responsive cells. In some cases, extracellular polypeptides have been shown to induce transcriptional activation of target genes within minutes (2, 12, 16, 23-25, 31, 35-37, 43, 44, 50). Binding of growth factors to their cell surface receptors also results in immediate changes in the cytoplasmic levels of one or more second messengers (Ca2+, cyclic AMP [cAMP], diacylglycerol), which are thought to act through specific protein kinases to produce intracellular responses, including altered transcription (56, 57). The strongest support for the idea that second messengers function physiologically in transcriptional regulation is that agents which artificially perturb intracellular second messenger levels can mimic the effects of growth factors on the transcription of certain genes (22,26,31,55,56). However, it is difficult to see how changes in the intracellular concentrations of only a few second messengers can generate the specific transcriptional responses that are elicited by the wide variety of ligands that exist in the developing and adult organism.We have been examining the mechanisms of extracellular ligand-dependent gene activation by studying the events that follow interferon (IFN) (6,47,54,60). We have recently demonstrated that the gene encoding a cytoplasmic guanylate-binding protein (GBP) (7-9) is activated within minutes by either IFN-a or IFN--y in human fibroblasts (15). In this report, we describe several differences between the signal transduction events leading to the transcriptional response of this gene to IFN-a and IFN--y in HeLa cells. Neither of these pathways appear to involve known second messengers.* Corresponding author. Plasmid DNAs. Probes used in run-on assays were as follows: pGEM, pGEM-1 (Promega Biotec, Madison, Wis.); actin, chicken P-actin PstI cDNA fragment (11) subcloned into pGEM-1; GBP, full-length 2.7-kilobase GBP cDNA cloned into pTZ18R (8); fos, 2.2-kilobase fragment of human c-fos gene cloned into pUC19 (pF4 [50]); tubulin, fragment of human ,-tubulin pseudogene (64). y-Actin (used to measure steady-state actin mRNA levels, see below) is a subcloned cDNA fragment of human -y-actin described in reference 17. GT7 (used to measure steady-state GBP mRNA levels) is a 138-base-pair HindIII-XbaI fragment of the GBP cDNA encoding amino acids 244 to 290 cloned into the respective sites of pGEM-1. MATERIALS AND METHODS CellsMeasurement of transcription rate (run-on assay). Isolation of nuclei, elongation reactions in the presence of radiolabeled UTP, and ...

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Section: -Aminopurine Selectively Blocks Gbp Induction By Ifn-ymentioning

confidence: 99%

Section: -Aminopurine Selectively Blocks Gbp Induction By Ifn-ymentioning

confidence: 99%

Alpha interferon and gamma interferon stimulate transcription of a single gene through different signal transduction pathways.

Lew¹,

Decker²,

Darnell³

1989

Mol. Cell. Biol.

104

View full text Add to dashboard Cite

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“…poly(rC) as an inducer (Cesario et al, 1988). A role for dsRNA-dependent protein kinase has been suggested in the induction of IFN-fl (Marcus & Sekellick, 1988;Zinn et al, 1988). Evidence for the latter, however, is based on the inhibition of IFN-fl induction by 2-aminopurine, without demonstration of a direct effect of the drug on dsRNA-dependent protein kinase or on cellular protein kinases.…”

Section: Introductionmentioning

confidence: 99%

Effect of Protein Kinase C Inhibitors on Interferon-beta Production by Viral and Non-viral Inducers

Thacore¹,

Lin²,

Davis

et al. 1990

Journal of General Virology

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Induction of interferon-fl (IFN-fl) in human (BG-9), simian (CV-1) and mouse (L-929) cell lines by Sendai virus and by poly(rI), poly(rC) has been studied for its possible dependence on protein kinase C (PKC) through the use of pharmacological inhibitors (K252a and H-7) of PKC. Exposure of BG-9, CV-1 or L-929 cells to K252a (>10.025 ~tM), a staurosporine derivative, 24 h before or after induction of IFN with poly(rl).poly(rC), inhibited by > 95 % the production of IFN-fl. In contrast, virus-induced 1FN production was enhanced threefold or more by K252a in BG-9 and L-929 but not in CV-1 cells. A naphthalene sulphonamide inhibitor of PKC, H-7, at >/5 ~tM, decreased poly(rI).poly(rC)-induced IFN production in BG-9 and CV-1 cells by 75 to 94%, but had no effect on IFN production in L-929 cells. Viral induction of IFN was not affected significantly by H-7 in BG-9, CV-1 and L-929 cells. In contrast to these results, the calmodulin inhibitor, trifluoperazine (5 to 15 ~tM) did not affect IFN-fl production by poly(rI).poly(rC) but significantly enhanced IFN production by Sendai virus in both human and murine cell lines. Thus, in human and simian fibroblasts the induction of IFN-fl by poly(rI).poly(rC) appears to be PKC-dependent, whereas viral induction of IFN-fl is not. Results with K252a implicate PKC in non-viral induction of IFN in mouse fibroblasts, as well. Direct measurements of PKC activity in BG-9 cells exposed to several concentrations of K252a showed that the membrane PKC activity is significantly more sensitive to inhibition by K252a than is cytosolic PKC activity. In L-929 cells, K252a inhibited membrane PKC activity similarly, but was less effective as an inhibitor of cytosolic enzyme activity than in BG-9. These studies support an intregral role for PKC activity, particularly membraneassociated activity, in non-viral [poly(rI).poly(rC)] induction of IFN-fl in human, simian and mouse fibroblasts.

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“…Other consequences of virus infection or exposure to dsRNA are prevented by 2-AP, which may provide a clue to its mechanism of action. It prevents induction by virus or dsRNA of beta interferon, c-fos, c-myc, and tumor necrosis factor alpha by selectively blocking transcription of these genes rather than their translation (7,14,26,41,45). 2-AP may enhance gene expression at a translational level by inhibiting DAI kinase activated when plasmids are transfected into mammalian cells (17,19).…”

Section: Discussionmentioning

confidence: 99%

Inducible transcriptional activation of the human immunodeficiency virus long terminal repeat by protein kinase inhibitors.

et al. 1993

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The protein kinase inhibitor 2-aminopurine (2-AP) greatly stimulated expression in human promonocytesmacrophages of plasmid constructs carrying various reporter genes (chloramphenicol acetyltransferase, lacZ, firefly luciferase [luc], and SalmoneUla typhimurum histidinol dehydrogenase [his]) driven by the human immunodeficiency virus type 1 (HIV-1) long terminal repeat. Adenine, adenosine, and caffeine were also effective inducers, but other purine or pyrimidine derivatives were ineffective. Experiments with mutant derivatives of the HIV-1 long terminal repeat revealed no specific eukaryotic promoter elements necessary for 2-AP induction but indicated the need for some minimum combination of such elements. Induction of HIV-1-directed gene expression appeared not to require action of the transcription factor NF-KB. The mechanism of induction was investigated by using the luc and his genes linked to the HIV-1 long terminal repeat. 2-AP induced marked, steady rises in mRNA accumulation from both transfected and chromosomally integrated HIV-1 constructs but no increases from an endogenous gene encoding 'y-actin or glucose 6-phosphate dehydrogenase. Thus, induction is selective and not an artifact induced by transfecting DNA into cells. In run-on transcription experiments, the rates of transcription initiation of both transfected and integrated copies of the his gene increased about sixfold in cells treated with 2-AP. Thus, while increased initiation accounted for a portion of 2-AP induction, it could not cause the far greater increase in steady-state mRNA levels. 2-AP induction did not change mRNA decay rates and differed from the phorbol ester (phorbol myristate acetate)-induced activation of the protein kinase C-NF-KB pathway in its time course and in its requirement for new protein synthesis. Gel retardation assays showed that unlike phorbol myristate acetate induction, 2-AP induction is enhancer independent. Whereas many previous studies have implicated the activation of various protein kinases in gene induction, we here describe a mechanism of gene activation that appears to involve protein kinase inhibition as a component of the induction response.

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Interferon Induction by Viruses. XVI. 2-Aminopurine Blocks Selectively and Reversibly an Early Stage in Interferon Induction

Cited by 80 publications

References 33 publications

Alpha interferon and gamma interferon stimulate transcription of a single gene through different signal transduction pathways.

Alpha interferon and gamma interferon stimulate transcription of a single gene through different signal transduction pathways.

Effect of Protein Kinase C Inhibitors on Interferon-beta Production by Viral and Non-viral Inducers

Inducible transcriptional activation of the human immunodeficiency virus long terminal repeat by protein kinase inhibitors.

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