Phosphatidylinositol 3-Kinase Confers Resistance to Encephalomyocarditis and Herpes Simplex Virus-Induced Cell Death Through the Activation of Distinct Downstream Effectors

Prejean, Christine; Sarma, Tulika; Kurnasov, Oleg V.; Usacheva, Anna; Hemmings, Brian A.; Cantley, Lewis C.; Fruman, David A.; Morrison, Lisa; Buller, R. Mark; Colamonici, Oscar R.

doi:10.4049/jimmunol.167.8.4553

Cited by 25 publications

(15 citation statements)

References 39 publications

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“…In some cell types, PI3K, however, seems to play an essential role in mediating IFN-␥-induced cellular responses. For example, PI3K mediates STAT-1 activation and gene expression induced by IFN-␥ in T98G glioblastoma cells (27) or participates in IFN-␥-induced cellular protection from viral infections in mouse fibro- blasts (37). In addition, activation of PI3K by IFN-␥ may regulate integrin-dependent migration in B cells (10).…”

Section: Discussionmentioning

confidence: 99%

IFN-γ inhibits human airway smooth muscle cell proliferation by modulating the E2F-1/Rb pathway

Amrani

Tliba

Choubey

et al. 2003

American Journal of Physiology-Lung Cellular and Molecular Phys

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Elucidating the factors that inhibit the increase in airway smooth muscle (ASM) mass may be of therapeutic benefit in asthma. Here, we investigated whether interferon-γ (IFN-γ), a potent inducer of growth arrest in various cell types, regulates mitogen-induced ASM cell proliferation. IFN-γ (1–100 U/ml) was found to markedly decrease both DNA synthesis and ASM cell number induced by the mitogens epidermal growth factor (EGF) and thrombin. Interestingly, IFN-γ had no effect on mitogen-induced activation of three major mitogenic signaling pathways, phosphatidylinositol 3-kinase, p70S6k, or mitogen-activated protein kinases. Mitogen-induced expression of cell cycle regulator cyclin D1 was increased by IFN-γ, whereas no effect was observed on degradation of p27Kip1. Expression array analysis of 23 cell cycle-related genes showed that IFN-γ inhibited EGF-induced increases in E2F-1 expression, whereas induction of c- myc, cyclin D2, Egr-1, and mdm2 were unaffected. Induction of E2F-1 protein and Rb hyperphosphorylation after mitogen stimulation was also suppressed by IFN-γ. In addition, IFN-γ decreased activation of cdk2 and expression of cyclin E, upstream signaling molecules responsible for Rb hyperphosphorylation in the late G1 phase. IFN-γ also increased levels of IFI 16 protein, whose mouse homolog p202 has been associated with growth inhibition. Together, our data indicate that IFN-γ is an effective inhibitor of ASM cell proliferation by blocking transition from G1-to-S phase by acting at two different levels: modulation of cdk2/cyclin E activation and inhibition of E2F-1 gene expression.

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Section: Discussionmentioning

confidence: 99%

IFN-γ inhibits human airway smooth muscle cell proliferation by modulating the E2F-1/Rb pathway

Amrani

Tliba

Choubey

et al. 2003

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…B, immunoblot analysis of total cell lysates from U266 cells that were either left untreated (control) or were treated with either IFN␣ alone or in the presence of Ly294002 or rapamycin as indicated. The membranes were probed with antibodies against total or Thr(P) 37/46 4E-BP1 protein. Protein loading was monitored by probing points (Fig.…”

Section: Ifn␣-induced Apoptosis Is Blocked By Inhibition Of the Pi3k/mentioning

confidence: 99%

Interferon α-induced Apoptosis in Tumor Cells Is Mediated through the Phosphoinositide 3-Kinase/Mammalian Target of Rapamycin Signaling Pathway

Thyrell¹,

Hjortsberg²,

Arulampalam

et al. 2004

Journal of Biological Chemistry

114

102

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Interferon (IFN) ␣ induces a caspase-dependent apoptosis that is associated with activation of the proapoptotic Bak and Bax, loss of mitochondrial membrane potential, and release of cytochrome c. In addition to the onset of the classical Jak-STAT pathway, IFN␣ also induced phosphoinositide 3-kinase (PI3K) activity. Pharmacological inhibition of PI3K activity by Ly294002 disrupted IFN-induced apoptosis upstream of mitochondria. Inhibition of mTOR by rapamycin or by overexpression of a kinase dead mutant of mTOR, efficiently blocked IFN␣-induced apoptosis. A PI3K and mTOR-dependent phosphorylation of p70S6 kinase and 4E-BP1 repressor was induced by IFN␣ treatment of cells and was strongly inhibited by Ly294002 or rapamycin. The activation of Jak-STAT signaling upon IFN␣ stimulation was not affected by abrogating PI3K/mTOR pathway. Neither was the expression of several IFN␣ target genes affected, nor the ability of IFN␣ to protect against virus-induced cell death affected by inhibition of the PI3K/mTOR pathway. These data demonstrate that an intact PI3K/ mTOR pathway is necessary for the ability of IFN␣ to induce apoptosis, whereas activation of the Jak-STAT pathway alone appears to be insufficient for this specific IFN␣-induced effect.

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“…F, the blot shown in E was stripped and re-probed with an anti-STAT1 antibody to control for loading. viral infection (59). However, the precise mechanisms that ultimately lead to the generation of IFN biological effects through this signaling cascade are not known.…”

Section: Fig 7 the Ifn␣-dependent Formation Of Isgf3 And Sif Dna Bimentioning

confidence: 99%

Activation of the p70 S6 Kinase and Phosphorylation of the 4E-BP1 Repressor of mRNA Translation by Type I Interferons

Lekmine

Uddin

Sassano

et al. 2003

Journal of Biological Chemistry

114

134

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The Type I IFN receptor-generated signals required for initiation of mRNA translation and, ultimately, induction of protein products that mediate IFN responses, remain unknown. We have previously shown that IFN␣ and IFN␤ induce phosphorylation of insulin receptor substrate proteins and downstream engagement of the phosphatidylinositol (PI) 3-kinase pathway. In the present study we provide evidence for the existence of a Type I IFN-dependent signaling cascade activated downstream of PI 3-kinase, involving p70 S6 kinase. Our data demonstrate that p70 S6K is rapidly phosphorylated on threonine 421 and serine 424 and is activated during treatment of cells with IFN␣ or IFN␤. Such activation of p70 S6K is blocked by pharmacological inhibitors of the PI 3-kinase or the FKBP 12-rapamycin-associated protein/mammalian target of rapamycin (FRAP/ mTOR). Consistent with this, the Type I IFN-dependent phosphorylation/activation of p70 S6K is defective in embryonic fibroblasts from mice with targeted disruption of the p85␣ and p85␤ subunits of the PI 3-kinase (p85␣؊/؊␤؊/؊). Treatment of sensitive cell lines with IFN␣ or IFN␤ also results in phosphorylation/inactivation of the 4E-BP-1 repressor of mRNA translation. Such 4E-BP1 phosphorylation is also PI3-kinase-dependent and rapamycin-sensitive, indicating that the Type I IFNinducible activation of PI3-kinase and FRAP/mTOR results in dissociation of 4E-BP1 from the eukaryotic initiation factor-4E (eIF4E) complex. Altogether, our data establish that the Type I IFN receptor-activated PI 3-kinase pathway mediates activation of the p70 S6 kinase and inactivation of 4E-BP1, to regulate mRNA translation and induction of Type I IFN responses.

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Phosphatidylinositol 3-Kinase Confers Resistance to Encephalomyocarditis and Herpes Simplex Virus-Induced Cell Death Through the Activation of Distinct Downstream Effectors

Cited by 25 publications

References 39 publications

IFN-γ inhibits human airway smooth muscle cell proliferation by modulating the E2F-1/Rb pathway

IFN-γ inhibits human airway smooth muscle cell proliferation by modulating the E2F-1/Rb pathway

Interferon α-induced Apoptosis in Tumor Cells Is Mediated through the Phosphoinositide 3-Kinase/Mammalian Target of Rapamycin Signaling Pathway

Activation of the p70 S6 Kinase and Phosphorylation of the 4E-BP1 Repressor of mRNA Translation by Type I Interferons

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