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

Advanced Review

Yong Sun Lee, Nawapol Kunkeaw, Yeon‐Su Lee

Published Online: Jun 23 2019

DOI: 10.1002/wrna.1558

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Abstract 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

Domain structures of PKR and its regulator proteins harboring dsRBMsPKR and each of its regulator proteins harboring a dsRBM(s) are shown. Sequence numberings are based on the National Center for Biotechnology Information (NCBI) reference sequence of each protein. Domains are identified in the NCBI Conserved Domains database, except that the TD3 domain of TRBP is based on (Daniels & Gatignol, ). Probably TD3's homology to the dsRBM is too weak to be deposited in the database. All proteins and domains are drawn to scale. dsRBM domains are highlighted in red. Z‐DNA BDs and AD of ADAR are Z‐DNA binding domains and adenosine‐deaminase domain, respectively. The DZF domain of ILF3 is “domain in DSRM or ZnF_C2H2 domain containing proteins”

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The tumor surveillance model as compared to PKR's antiviral rolePKR is in a suppressed state by nc886 in normal human cells. The silencing of nc886, the PKR repressor ncRNA, is expected to be the most prevalent cause of PKR activation during tumorigenesis, although PKR can be activated also by up‐ or down‐regulation of PKR activators and other repressors, respectively

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The PKR pathway and its regulatorsThis cartoon depicts the PKR pathway. PKR‐activating stimuli, PKR‐activating RNAs, the PKR‐repressing RNA (nc886), PKR‐activating proteins, and ‐repressing proteins are distinguished by color codes. Downstream pathways with oncogenic and tumor suppressive properties are designated in coral and green colors, respectively. Solid lines indicate direct molecular interaction from concrete evidence; dotted lines indicate the other

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