PKR Senses Nuclear and Mitochondrial Signals by Interacting with Endogenous Double-Stranded RNAs

Kim, Yoosik; Park, Joha; Kim, Sujin; Kim, Min A; Kang, Minchul; Kim, Baekgyu; Rhee, Hyun‐Woo; Kim, V. Narry

doi:10.2139/ssrn.3155545

Cited by 22 publications

(31 citation statements)

References 57 publications

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“…The immunoblots signals were acquired with a GeneGnome XRQ chemiluminescence imaging system (Syngene) and the intensity of the detected bands quantified with GeneTools software (Syngene; Martinez-Leon et al, 2019). The Subcellular Protein Fractionation Kit for Cultured Cells from Thermo Fisher Scientific (part # 78840), MA, a widely employed kit to separate cytosolic and membrane fractions-enriched in integral and membrane-associated proteins (Frescas et al, 2017;Y. Kim et al, 2018;Liao et al, 2011;Rosenberg et al, 2018;Roy, Placzek, & Scanlan, 2012;Schernthaner-Reiter, Trivellin, & Stratakis, 2018), was employed according to manufacturer's recommendations.…”

Section: Immunocytochemistry Western Blot Subcellular Fractionatimentioning

confidence: 99%

Metformin inhibition of colorectal cancer cell migration is associated with rebuilt adherens junctions and FAK downregulation

Amable

Martínez‐León

Picco

et al. 2020

Journal Cellular Physiology

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E‐cadherin, a central component of the adherens junction (AJ), is a single‐pass transmembrane protein that mediates cell–cell adhesion. The loss of E‐cadherin surface expression, and therefore cell–cell adhesion, leads to increased cell migration and invasion. Treatment of colorectal cancer (CRC)‐derived cells (SW‐480 and HT‐29) with 2.0 mM metformin promoted a redistribution of cytosolic E‐cadherin to de novo formed puncta along the length of the contacting membranes of these cells. Metformin also promoted translocation from the cytosol to the plasma membrane of p120‐catenin, another core component of the AJs. Furthermore, E‐cadherin and p120‐catenin colocalized with β‐catenin at cell–cell contacts. Western blot analysis of lysates of CRC‐derived cells revealed a substantial metformin‐induced increase in the level of p120‐catenin as well as E‐cadherin phosphorylation on Ser838/840, a modification associated with β‐catenin/E‐cadherin interaction. These modifications in E‐cadherin, p120‐catenin and β‐catenin localization suggest that metformin induces rebuilding of AJs in CRC‐derived cells. Those modifications were accompanied by the inhibition of focal adhesion kinase (FAK), as revealed by a significant decrease in the phosphorylation of FAK at Tyr397 and paxillin at Tyr118. These changes were associated with a reduction in the numbers, but an increase in the size, of focal adhesions and by the inhibition of cell migration. Overall, these observations indicate that metformin targets multiple pathways associated with CRC development and progression.

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Section: Immunocytochemistry Western Blot Subcellular Fractionatimentioning

confidence: 99%

Metformin inhibition of colorectal cancer cell migration is associated with rebuilt adherens junctions and FAK downregulation

Amable

Martínez‐León

Picco

et al. 2020

Journal Cellular Physiology

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“…5a). This suggests that unedited or partially edited genomic dsRNAs or mitochondrial dsRNAs could be transported to the cytoplasm 24,62 and DDX3X may be important to maintain the endogenous dsRNAs in the cytoplasm at a minimum level. There are several possibilities of how DDX3X could be involved in cellular dsRNA regulation.…”

Section: Discussionmentioning

confidence: 99%

“…Of note, ERVs constitute more than 8% of the human genome and their bi-directional transcription has been shown to increase the formation of dsRNAs [19][20][21] . DNA methylation silences most ERVs in normal somatic cells, but some cancers exhibit loss of ERV DNA methylation and consequent aberrant overexpression of ERVs [22][23][24][25] . In particular, treatment of cancer cells with epigenetic inhibitors increases the expression of ERVs and subsequently induces IFN pathway activation 14,18,23,26,27 .…”

Section: Introductionmentioning

confidence: 99%

Inhibiting DDX3X triggers tumor-intrinsic type I interferon response and enhances anti-tumor immunity

Choi

Kwon

Sun

et al. 2020

Preprint

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Accumulating evidence has shown that cellular double-stranded RNAs (dsRNAs) induce antiviral innate immune responses in human normal and malignant cancer cells. However, it is not fully understood how endogenous ‘self’ dsRNA homeostasis is regulated in the cell. Here, we show that an RNA-binding protein, DEAD-box RNA helicase 3X (DDX3X), prevents the aberrant accumulation of cellular dsRNAs. Loss of DDX3X induces dsRNA sensor-mediated type I interferon signaling and innate immune response in breast cancer cells due to abnormal cytoplasmic accumulation of dsRNAs. Dual depletion of DDX3X and a dsRNA-editing protein, ADAR1 synergistically activates the cytosolic dsRNA pathway in breast cancer cell. Moreover, inhibiting DDX3X enhances the antitumor activity by increasing tumor intrinsic-type I interferon response, antigen presentation, and tumor-infiltration of cytotoxic T cells as well as dendritic cells in breast tumors, which may lead to the development of breast cancer therapy by targeting DDX3X in combination with immune checkpoint blockade.

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“…Lastly, mtRNA has recently been shown to occupy and activate a large portion of endogenous PKR, which could be released as a result of mitochondrial rupture or facilitated export [75]. Supporting this notion, recent research has revealed that mitochondrial stress leads to the cytosolic accumulation of mtDNA [76,76,78].…”

Section: The Mtupr______________________________________mentioning

confidence: 95%

Proteostatic Signaling & Control of Protein Synthesis

Keefe¹

2018

Preprint

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The tremendous diversity and complexity of proteins invariably results in protein misfolding, to which cells have evolved numerous mechanisms of mitigating. Degrading misfolded proteins is perhaps the most intuitive strategy, but also critical to managing proteostasis are the elaborate mechanisms of translational control. Attenuated rates of translation ameliorate protein misfolding by downregulating the flux of new protein and conserving ATP. Loss of translational control, particularly in neurons, constitutes a major proteostatic dysfunction capable of causing or exacerbating neurodegeneration, while interventions aimed at downregulating protein synthesis are generally neuroprotective. In this review, I examine the critical neuronal signaling networks employed to control translation with an emphasis on current research. This includes the Unfolded Protein Response (UPR), the mitochondrial UPR (mtUPR), mTORC1 signaling, and stress granule formation.

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PKR Senses Nuclear and Mitochondrial Signals by Interacting with Endogenous Double-Stranded RNAs

Cited by 22 publications

References 57 publications

Metformin inhibition of colorectal cancer cell migration is associated with rebuilt adherens junctions and FAK downregulation

Metformin inhibition of colorectal cancer cell migration is associated with rebuilt adherens junctions and FAK downregulation

Inhibiting DDX3X triggers tumor-intrinsic type I interferon response and enhances anti-tumor immunity

Proteostatic Signaling & Control of Protein Synthesis

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PKR Senses Nuclear and Mitochondrial Signals by Interacting with Endogenous Double-Stranded RNAs

Cited by 22 publications

References 57 publications

Metformin inhibition of colorectal cancer cell migration is associated with rebuilt adherens junctions and FAK downregulation

Metformin inhibition of colorectal cancer cell migration is associated with rebuilt adherens junctions and FAK downregulation

Inhibiting DDX3X triggers tumor-intrinsic type I interferon response and enhances anti-tumor immunity

Proteostatic Signaling &amp; Control of Protein Synthesis

Contact Info

Product

Resources

About

Proteostatic Signaling & Control of Protein Synthesis