Small molecule modulators of eukaryotic initiation factor 2α kinases, the key regulators of protein synthesis

Joshi, M. P.; Kulkarni, Abhijeet; Pal, Jayanta K.

doi:10.1016/j.biochi.2013.07.030

Cited by 35 publications

(26 citation statements)

References 78 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Four proteins are currently known to induce stress responses through a common pathway by phosphorylation of eIF2α (51,52). These proteins possess homologous kinases but distinct recognition domains that are activated by different stress factors in the endoplasmic reticulum, including dsRNA (PKR), mis- or unfolded proteins (PERK) and low amino acid concentrations (GCN2).…”

Section: Discussionmentioning

confidence: 99%

“…These proteins possess homologous kinases but distinct recognition domains that are activated by different stress factors in the endoplasmic reticulum, including dsRNA (PKR), mis- or unfolded proteins (PERK) and low amino acid concentrations (GCN2). Perhaps there exist one or more additional members of this group that activate the stress response pathway with further recognition motifs (high CpG or UpA RNA) and which are also inhibited by C16 (52). Investigation of cellular binding partners of transfected RNA of different dinucleotide compositions represents a promising future approach to identify what proteins are involved in this recognition process.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

The influence of CpG and UpA dinucleotide frequencies on RNA virus replication and characterization of the innate cellular pathways underlying virus attenuation and enhanced replication

Atkinson

Witteveldt

Evans

et al. 2014

Nucleic Acids Research

170

209

View full text Add to dashboard Cite

Most RNA viruses infecting mammals and other vertebrates show profound suppression of CpG and UpA dinucleotide frequencies. To investigate this functionally, mutants of the picornavirus, echovirus 7 (E7), were constructed with altered CpG and UpA compositions in two 1.1–1.3 Kbase regions. Those with increased frequencies of CpG and UpA showed impaired replication kinetics and higher RNA/infectivity ratios compared with wild-type virus. Remarkably, mutants with CpGs and UpAs removed showed enhanced replication, larger plaques and rapidly outcompeted wild-type virus on co-infections. Luciferase-expressing E7 sub-genomic replicons with CpGs and UpAs removed from the reporter gene showed 100-fold greater luminescence. E7 and mutants were equivalently sensitive to exogenously added interferon-β, showed no evidence for differential recognition by ADAR1 or pattern recognition receptors RIG-I, MDA5 or PKR. However, kinase inhibitors roscovitine and C16 partially or entirely reversed the attenuated phenotype of high CpG and UpA mutants, potentially through inhibition of currently uncharacterized pattern recognition receptors that respond to RNA composition. Generating viruses with enhanced replication kinetics has applications in vaccine production and reporter gene construction. More fundamentally, the findings introduce a new evolutionary paradigm where dinucleotide composition of viral genomes is subjected to selection pressures independently of coding capacity and profoundly influences host–pathogen interactions.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The influence of CpG and UpA dinucleotide frequencies on RNA virus replication and characterization of the innate cellular pathways underlying virus attenuation and enhanced replication

Atkinson

Witteveldt

Evans

et al. 2014

Nucleic Acids Research

170

209

View full text Add to dashboard Cite

show abstract

“…In addition, data showing PKR involvement in learning and memory suggest that PKR inhibition could benefit humans, especially those experiencing age‐related memory loss or the most devastating memory loss associated with AD (33, 34). Although different chemical compounds containing a 3'‐substituted indolone core protect neurons from apoptosis by inhibiting PKR, unfortunately they also display high toxicity (35). A derivate with low toxicity called PKR inhibitor (PKRi), or C16, decreased the neuronal apoptosis in mice but induced undesirable effects on organs and cells outside the nervous system (36).…”

Section: Impact Of Pkr In Neurodegenerative Diseases and Therapeutic mentioning

confidence: 99%

The impact of PKR activation: from neurodegeneration to cancer

et al. 2014

View full text Add to dashboard Cite

An inverse association between cancer and neurodegeneration is plausible because these biological processes share several genes and signaling pathways. Whereas uncontrolled cell proliferation and decreased apoptotic cell death governs cancer, excessive apoptosis contributes to neurodegeneration. Protein kinase R (PKR), an interferon-inducible double-stranded RNA protein kinase, is involved in both diseases. PKR activation blocks global protein synthesis through eIF2α phosphorylation, leading to cell death in response to a variety of cellular stresses. However, PKR also has the dual role of activating the nuclear factor κ-B pathway, promoting cell proliferation. Whereas PKR is recognized for its negative effects on neurodegenerative diseases, in part, inducing high level of apoptosis, the role of PKR activation in cancer remains controversial. In general, PKR is considered to have a tumor suppressor function, and some clinical data show a correlation between suppressed or inactivated PKR and a poor prognosis for several cancers. However, other studies show high PKR expression and activation levels in various cancers, suggesting that PKR might contribute to neoplastic progression. Understanding the cellular factors and signals involved in the regulation of PKR in these age-related diseases is relevant and may have important clinical implications. The present review highlights the current knowledge on the role of PKR in neurodegeneration and cancer, with special emphasis on its regulation and clinical implications.

show abstract

“…PERK is a type 1 transmembrane protein kinase residing in the ER which is activated in response to perturbation of protein folding and constitutes a signal transducer of the earliest phase of stress response (Liu et al 2016). UPR first alleviates the ER stress by diminishing the overall protein load via PERK-mediated phosphorylation of the α subunit of eukaryotic translation initiation factor 2 (eIF2α) (Mahdi et al 2016; Liu et al 2016; Joshi et al 2013; Zhang et al 2013). In turn, the decrease in eIF2 activity promotes the translation of activating transcription factor 4 (ATF4) resulting in the activation of CCAAT/enhancer binding protein (C/EBP) homologous protein (CHOP) production, which promotes ER stress-induced apoptosis (Ron and Walter 2007; Walter and Ron 2011; Fawcett et al 1999; Jiang et al 2004).…”

Section: Endoplasmic Reticulum Stressmentioning

confidence: 99%

Endoplasmic reticulum stress in chondrodysplasias caused by mutations in collagen types II and X

Gawron

2016

Cell Stress and Chaperones

View full text Add to dashboard Cite

The endoplasmic reticulum is primarily recognized as the site of synthesis and folding of secreted, membrane-bound, and some organelle-targeted proteins. An imbalance between the load of unfolded proteins and the processing capacity in endoplasmic reticulum leads to the accumulation of unfolded or misfolded proteins and endoplasmic reticulum stress, which is a hallmark of a number of storage diseases, including neurodegenerative diseases, a number of metabolic diseases, and cancer. Moreover, its contribution as a novel mechanistic paradigm in genetic skeletal diseases associated with abnormalities of the growth plates and dwarfism is considered. In this review, I discuss the mechanistic significance of endoplasmic reticulum stress, abnormal folding, and intracellular retention of mutant collagen types II and X in certain variants of skeletal chondrodysplasia.

show abstract

Small molecule modulators of eukaryotic initiation factor 2α kinases, the key regulators of protein synthesis

Cited by 35 publications

References 78 publications

The influence of CpG and UpA dinucleotide frequencies on RNA virus replication and characterization of the innate cellular pathways underlying virus attenuation and enhanced replication

The influence of CpG and UpA dinucleotide frequencies on RNA virus replication and characterization of the innate cellular pathways underlying virus attenuation and enhanced replication

The impact of PKR activation: from neurodegeneration to cancer

Endoplasmic reticulum stress in chondrodysplasias caused by mutations in collagen types II and X

Contact Info

Product

Resources

About