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

Thyrell, Lena; Hjortsberg, Linn; Arulampalam, Velmurugesan; Panaretakis, Theocharis; Uhles, Sabine; Dagnell, Markus; Zhivotovsky, Boris; Leibiger, Ingo B.; Grandér, Dan; Pokrovskaja, Katja

doi:10.1074/jbc.m312219200

Cited by 114 publications

(106 citation statements)

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“…Work from others has also implicated mTOR in the regulation of IFN-induced apoptosis (10), while in recent studies using cells with targeted deletion of both the Akt1 and Akt2 genes, we established Akt as a critical element of the IFN-signaling pathway required for engagement of mTOR and for mRNA translation of IFN-regulated genes (12,25). Together, the emerging evidence points toward an essential role for mTOR and its effectors in the generation of the biological effects of IFNs.…”

Section: Discussionmentioning

confidence: 91%

“…However, beyond the classic Jak-Stat pathways, there is evidence that IFNs activate several other signaling cascades, including the mTOR-regulated (8)(9)(10)(11)(12) and mitogen-activated protein kinase (MAPK) signaling cascades (13)(14)(15). Such non-Stat pathways play important roles in the induction of IFN-responses, via their ability to promote optimal IFN-dependent gene transcription (13) or mRNA translation of ISGs (12).…”

mentioning

confidence: 99%

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Type I interferon (IFN)-dependent activation of Mnk1 and its role in the generation of growth inhibitory responses

Joshi

Kaur

Redig

et al. 2009

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

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Section: Discussionmentioning

confidence: 91%

mentioning

confidence: 99%

Type I interferon (IFN)-dependent activation of Mnk1 and its role in the generation of growth inhibitory responses

Joshi

Kaur

Redig

et al. 2009

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

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“…On one hand, rapamycin is proved to be proapoptotic, especially in cancers, resulting in apoptotic death of the cancer cells 29. On the other hand, some evidence has demonstrated that rapamycin can be antiapoptotic 30, 31. For example, rapamycin inhibits death of syncytia via inhibition of proapoptotic Bax and inhibition of the mitochondrial cell death pathway 32, 33.…”

Section: Discussionmentioning

confidence: 99%

Rapamycin prevents cerebral stroke by modulating apoptosis and autophagy in penumbra in rats

Zhang

Kai

et al. 2017

Ann Clin Transl Neurol

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ObjectiveWhether activation or inhibition of the mTOR pathway is beneficial to ischemic injury remains controversial. It may result from the different reaction of ischemic penumbra and core to modulation of mTOR pathway after cerebral ischemia–reperfusion injury in rats.MethodsLonga's middle cerebral artery occlusion (MCAO) method was conducted to induce the focal cerebral ischemia–reperfusion. Western blot analysis was used to examine the protein expression involving mTOR pathway, apoptosis, and autophagy‐related proteins. TTC staining and Fluoro‐Jade B staining was conducted to detect the infarct volume and cell apoptosis, respectively. Neurological function was measured by modified neurological severity score and left‐biased swing.Results mTOR signaling pathway was activated in ischemic penumbra and decreased in ischemic core after ischemia and ischemia–reperfusion. Ischemia–reperfusion injury induced the increase in cleaved caspase 9 and caspase 3 both in ischemic penumbra and in ischemic core, whereas the expression of phosphorylated ULK1, Beclin 1 and LC3‐II was decreased. Rapamycin pre or postadministration inhibited the overactivation of mTOR pathway in ischemic penumbra. Ameliorated neurological function and reduced infarct volume were observed after pre or postrapamycin treatment. Rapamycin markedly decreased the number of FJB‐positive cells and the expression of cleaved caspase‐3 and cleaved caspase‐9 proteins as well as increased the activation of autophagy reflected by ULK1, Beclin‐1 and LC3.Interpretation mTOR signaling pathway was activated in ischemic penumbra after cerebral ischemia–reperfusion injury in rats. mTOR inhibitor rapamycin significantly decreased the mTOR activation and infarct volume and subsequently improved neurological function. These results may relate to inhibition of neuron apoptosis and activation of autophagy.

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“…These findings have suggested a potential mechanism by which IFNs regulate translational control of IFN-specific genes, but the precise functional relevance of mTOR and downstream pathways in IFN signaling had not been defined. A recent study has suggested that mTOR signals may play positive roles in the generation of IFN biological responses, as evidenced by the inhibition of IFN␣-induced apoptosis in cells in which a kinase-deficient mTOR mutant was expressed or by treatment of cells with the mTOR inhibitor rapamycin (49). However, the functional relevance of specific effectors downstream of mTOR that may be involved in the generation of IFN responses has remained unknown to date.…”

Section: Discussionmentioning

confidence: 99%

Regulatory Effects of Mammalian Target of Rapamycin-activated Pathways in Type I and II Interferon Signaling

Kaur

Lal

Sassano

et al. 2007

Journal of Biological Chemistry

106

132

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The mechanisms regulating initiation of mRNA translation for the generation of protein products that mediate interferon (IFN) responses are largely unknown. We have previously shown that both Type I and II IFNs engage the mammalian target of rapamycin (mTOR), resulting in downstream phosphorylation and deactivation of the translational repressor 4E-BP1 (eIF4E-binding protein 1). In the current study, we provide direct evidence that such regulation of 4E-BP1 by IFN␣ or IFN␥ results in sequential dissociation of 4E-BP1 from eukaryotic initiation factor-4E and subsequent formation of a functional complex between eukaryotic initiation factor-4E and eukaryotic initiation factor-4G, to allow initiation of mRNA translation. We also demonstrate that the induction of key IFN␣-or IFN␥-inducible proteins (ISG15 (interferon-stimulated Type I (␣, ␤, ␦, ⑀, , and ) and II (␥) interferons (IFNs) 2 are pleiotropic cytokines that exhibit important antiviral, immunomodulatory, and growth inhibitory properties via engagement of widely expressed cell surface-specific receptors (1-5). The IFNs constitute the first line of the immune antiviral defense and are key components of the immune surveillance against tumors (1-5). In addition, because of their important biological properties, different recombinant IFNs (␣, ␤, and ␥) have been used extensively as therapeutic agents in a variety of clinical syndromes in humans, and certain IFN-subtypes are approved for the treatment of human malignancies, viral syndromes, and neurologic diseases (6 -10).Over the years, the mechanisms of IFN signal transduction have been the focus of attention by many research groups and have come under extensive investigation. Since the demonstration of the existence of STAT pathways that regulate transcription of interferon-inducible genes (2, 3), there has been gradual accumulation of evidence pointing toward a complicated network of multiple signaling pathways, whose coordinated function is necessary for the generation of IFN biological responses (4, 5). For instance, it has now become apparent that, in addition to different combinations of IFN-activated JAKs and STATs, the coordinated function of the phosphatidylinositol (PI) 3-kinase and the p38 mitogen-activated protein kinase pathways are essential for optimal IFN-dependent transcriptional regulation (5). The PI 3Ј-kinase pathway appears to be required for IFN-inducible transcriptional activation by regulating phosphorylation of STAT1 on serine 727 (11, 12), probably via intermediate engagement and activation of protein kinase C-␦ (13-16). Activation of the p38 mitogen-activated protein kinase appears to be also necessary for Type I, but not II, * This work was supported by National Institutes of Health Grants CA77816, CA100579, and CA94079 (to L. C. P.), by a grant from the Department of Veterans Affairs (to L. C. P.), and Canadian Institutes of Health Research Grant MOP15094 (to E. N. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article mus...

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

Cited by 114 publications

References 40 publications

Type I interferon (IFN)-dependent activation of Mnk1 and its role in the generation of growth inhibitory responses

Type I interferon (IFN)-dependent activation of Mnk1 and its role in the generation of growth inhibitory responses

Rapamycin prevents cerebral stroke by modulating apoptosis and autophagy in penumbra in rats

Regulatory Effects of Mammalian Target of Rapamycin-activated Pathways in Type I and II Interferon Signaling

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