Stress-induced TRBP phosphorylation enhances its interaction with PKR to regulate cellular survival

Chukwurah, Evelyn; Patel, Rekha C.

doi:10.1038/s41598-018-19360-8

Cited by 34 publications

(25 citation statements)

References 59 publications

(73 reference statements)

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“…One of the first reported functions of PACT and TRBP is to modulate the PKR activity. Earlier studies proposed that PACT directly binds PKR and activates the PKR kinase activity in the absence of dsRNA (172)(173)(174), while TRBP inhibits PKR by directly binding to PKR and/or PACT (175)(176)(177). A homozygous missense mutation (P222L) in PACT was shown to cause hyperactivation of PKR and early-onset dystonia DYT16 (178), supporting the role of PACT in PKR modulation.…”

Section: Pact and Trbpmentioning

confidence: 92%

Double-Stranded RNA Sensors and Modulators in Innate Immunity

Hur

2019

Annu. Rev. Immunol.

291

286

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Detection of double-stranded RNAs (dsRNAs) is a central mechanism of innate immune defense in many organisms. We here discuss several families of dsRNA-binding proteins involved in mammalian antiviral innate immunity. These include RIG-I-like receptors, protein kinase R, oligoadenylate synthases, adenosine deaminases acting on RNA, RNA interference systems, and other proteins containing dsRNA-binding domains and helicase domains. Studies suggest that their functions are highly interdependent and that their interdependence could offer keys to understanding the complex regulatory mechanisms for cellular dsRNA homeostasis and antiviral immunity. This review aims to highlight their interconnectivity, as well as their commonalities and differences in their dsRNA recognition mechanisms. KeywordsdsRNA; RIG-I-like receptor; protein kinase R; oligoadenylate synthase; dsRNA-dependent adenosine deaminase; RNA interference HHS Public Access

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Section: Pact and Trbpmentioning

confidence: 92%

Double-Stranded RNA Sensors and Modulators in Innate Immunity

Hur

2019

Annu. Rev. Immunol.

291

286

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“…Not only PACT (PD3), but also TRBP is phosphorylated. TRBP binds and inhibits PKR more proficiently, when it is phosphorylated upon oxidative stress (Chukwurah & Patel, ) or during the mitotic phase in cell cycle (Kim et al, ). PKR is led to activation in these two conditions (Kim et al, ; Pyo et al, ) and TRBP phosphorylation prevents hyper‐activation of PKR, whose physiological significance appears to be the restriction of PKR activity under the tolerance level so that cells survive these conditions.…”

Section: Cellular Proteins For Pkr Regulationmentioning

confidence: 99%

Protein kinase R and its cellular regulators in cancer: An active player or a surveillant?

2019

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Protein kinase R (PKR), originally known as an antiviral protein, senses various stresses as well as pathogen‐driven double‐stranded RNAs. Thereby activated PKR provokes diverse downstream events, including eIF2α phosphorylation and nuclear factor kappa‐light‐chain‐enhancer of activated B cells activation. Consequently, PKR induces apoptosis and inflammation, both of which are highly important in cancer as much as its original antiviral role. Therefore, cellular proteins and RNAs should tightly control PKR activity. PKR and its regulators are often dysregulated in cancer and it is undoubted that such dysregulation contributes to tumorigenesis. However, PKR's precise role in cancer is still in debate, due to incomprehensible and even contradictory data. In this review, we introduce important cellular PKR regulators and discuss about their roles in cancer. Among them, we pay particular attention to nc886, a PKR repressor noncoding RNA that has been identified relatively recently, because its expression pattern in cancer can explain interesting yet obscure oncologic aspects of PKR. Based on nc886 and its regulation of PKR, we have proposed a tumor surveillance model, which reconciles contradictory data about PKR in cancer. This article is categorized under: Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications

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“…However, the high level of post-translational modifications and regulation of the protein indicated that PKR activity does not necessarily have to correspond to the amount of its messenger RNA. In fact, numerous proteins have been described as regulating their activity (e.g., PACT, trans-activation response (TAR) RNA binding protein (TRBP), nucleophosmin (NPM)) [4,7,8,[46][47][48] and several post-translational modifications have been showed by SUMOylation and ISGylation, among others [49,50]. Nc886 has been described as a PKR inhibitor, being the inhibition of PKR/NF-kB in correlation with its tumour suppressor activity.…”

Section: Discussionmentioning

confidence: 99%

Uncovering Tumour Heterogeneity through PKR and nc886 Analysis in Metastatic Colon Cancer Patients Treated with 5-FU-Based Chemotherapy

Ortega-García

Mesa

Moya

et al. 2020

Cancers

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Colorectal cancer treatment has advanced over the past decade. The drug 5-fluorouracil is still used with a wide percentage of patients who do not respond. Therefore, a challenge is the identification of predictive biomarkers. The protein kinase R (PKR also called EIF2AK2) and its regulator, the non-coding pre-mir-nc886, have multiple effects on cells in response to numerous types of stress, including chemotherapy. In this work, we performed an ambispective study with 197 metastatic colon cancer patients with unresectable metastases to determine the relative expression levels of both nc886 and PKR by qPCR, as well as the location of PKR by immunohistochemistry in tumour samples and healthy tissues (plasma and colon epithelium). As primary end point, the expression levels were related to the objective response to first-line chemotherapy following the response evaluation criteria in solid tumours (RECIST) and, as the second end point, with survival at 18 and 36 months. Hierarchical agglomerative clustering was performed to accommodate the heterogeneity and complexity of oncological patients' data. High expression levels of nc886 were related to the response to treatment and allowed to identify clusters of patients. Although the PKR Cancers 2020, 12, 379 2 of 17 mRNA expression was not associated with chemotherapy response, the absence of PKR location in the nucleolus was correlated with first-line chemotherapy response. Moreover, a relationship between survival and the expression of both PKR and nc886 in healthy tissues was found. Therefore, this work evaluated the best way to analyse the potential biomarkers PKR and nc886 in order to establish clusters of patients depending on the cancer outcomes using algorithms for complex and heterogeneous data.

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Stress-induced TRBP phosphorylation enhances its interaction with PKR to regulate cellular survival

Cited by 34 publications

References 59 publications

Double-Stranded RNA Sensors and Modulators in Innate Immunity

Double-Stranded RNA Sensors and Modulators in Innate Immunity

Protein kinase R and its cellular regulators in cancer: An active player or a surveillant?

Uncovering Tumour Heterogeneity through PKR and nc886 Analysis in Metastatic Colon Cancer Patients Treated with 5-FU-Based Chemotherapy

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