Activation of the dsRNA-Activated Protein Kinase PKR in Mitochondrial Dysfunction and Inflammatory Stress in Metabolic Syndrome

Sud, Neetu; Rutledge, Angela C.; Pan, Kaichao; Su, Qiaozhu

doi:10.2174/1381612822666160202141845

Cited by 26 publications

(18 citation statements)

References 88 publications

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“…PKR is a key constituent of the metaflammasome, activated by nutrients such as fatty acids and by ER stress [147]. The interaction between the PKR, and inflammatory kinases, such as IKK and JNK, IRS1 has also been reported [148]. The absence of PKR leads to decreased activation of JNK and IKKβ which are key kinases in the development of insulin resistance.…”

Section: Rna-activated Protein Kinase (Pkr)mentioning

confidence: 99%

Protein kinases: mechanisms and downstream targets in inflammation-mediated obesity and insulin resistance

2016

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Obesity induced low-grade inflammation (metaflammation) impairs insulin receptor signaling (IRS). This has been implicated in the development of insulin resistance. Insulin signaling in the target tissues is mediated by stress kinases such as p38 mitogen-activated protein kinase (MAPK), c-Jun NH2-terminal kinase (JNK), inhibitor of NF-kB kinase complex beta (IKKβ), AMP activated protein kinase (AMPK), protein kinase C (PKC), Rho associated coiled-coil containing protein kinase (ROCK) and RNA-activated protein kinase (PKR), etc. Most of these kinases phosphorylate several key regulators in glucose homeostasis. The phosphorylation of serine residues in the insulin receptor (IR) and IRS-1 molecule results in diminished enzymatic activity in the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. This has been one of the key mechanisms observed in the tissues that are implicated in insulin resistance especially in Type II Diabetes Mellitus (T2-DM). Identifying the specific protein kinases involved in obesity induced chronic inflammation may help in developing the targeted drug therapies to minimize the insulin resistance. This review is focused on the protein kinases involved in the inflammatory cascade and molecular mechanisms and their downstream targets with special reference to obesity induced T2-DM.

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Section: Rna-activated Protein Kinase (Pkr)mentioning

confidence: 99%

Protein kinases: mechanisms and downstream targets in inflammation-mediated obesity and insulin resistance

2016

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“…24). These PKR-associated processes support the relevance of PKR's regulation; in fact, numerous studies have found PKR to be dysregulated in most type of cancers, neurodegenerative diseases, metabolic disorders and other pathologies (Refs 8,25). Whereas PKR is recognised for its negative effects on neurodegenerative diseases, the role of PKR activation in cancer is complex and remains controversial (reviewed in Ref.…”

Section: Introductionmentioning

confidence: 89%

Clinical and therapeutic potential of protein kinase PKR in cancer and metabolism

García-Ortega

López

Jiménez

et al. 2017

Expert Rev. Mol. Med.

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The protein kinase R (PKR, also called EIF2AK2) is an interferon-inducible double-stranded RNA protein kinase with multiple effects on cells that plays an active part in the cellular response to numerous types of stress. PKR has been extensively studied and documented for its relevance as an antiviral agent and a cell growth regulator. Recently, the role of PKR related to metabolism, inflammatory processes, cancer and neurodegenerative diseases has gained interest. In this review, we summarise and discuss the involvement of PKR in several cancer signalling pathways and the dual role that this kinase plays in cancer disease. We emphasise the importance of PKR as a molecular target for both conventional chemotherapeutics and emerging treatments based on novel drugs, and its potential as a biomarker and therapeutic target for several pathologies. Finally, we discuss the impact that the recent knowledge regarding PKR involvement in metabolism has in our understanding of the complex processes of cancer and metabolism pathologies, highlighting the translational research establishing the clinical and therapeutic potential of this pleiotropic kinase.

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“…HRI) [ 6 , 29 ]. PKR has been implicated in a broad spectrum of infectious and inflammatory processes in addition to its well-known antiviral response [ 30 – 33 ]. PKR is activated in murine colonic epithelial cells during DSS-induced colitis.…”

Section: Cellular Stress Signaling In Gastrointestinal Tractmentioning

confidence: 99%

Cellular Stress Responses and Gut Microbiota in Inflammatory Bowel Disease

Cao

2018

Gastroenterology Research and Practice

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Progresses in the past two decades have greatly expanded our understanding of inflammatory bowel disease (IBD), an incurable disease with multifaceted and challenging clinical manifestations. The pathogenesis of IBD involves multiple processes on the cellular level, which include the stress response signaling such as endoplasmic reticulum (ER) stress, oxidative stress, and hypoxia. Under physiological conditions, the stress responses play key roles in cell survival, mucosal barrier integrity, and immunomodulation. However, they can also cause energy depletion, trigger cell death and tissue injury, promote inflammatory response, and drive the progression of clinical disease. In recent years, gut microflora has emerged as an essential pathogenic factor and therapeutic target for IBD. Altered compositional and metabolic profiles of gut microbiota, termed dysbiosis, are associated with IBD. Recent studies, although limited, have shed light on how ER stress, oxidative stress, and hypoxic stress interact with gut microorganisms, a potential source of stress in the microenvironment of gastrointestinal tract. Our knowledge of cellular stress responses in intestinal homeostasis as well as their cross-talks with gut microbiome will further our understanding of the pathogenesis of inflammatory bowel disease and probably open avenues for new therapies.

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Activation of the dsRNA-Activated Protein Kinase PKR in Mitochondrial Dysfunction and Inflammatory Stress in Metabolic Syndrome

Cited by 26 publications

References 88 publications

Protein kinases: mechanisms and downstream targets in inflammation-mediated obesity and insulin resistance

Protein kinases: mechanisms and downstream targets in inflammation-mediated obesity and insulin resistance

Clinical and therapeutic potential of protein kinase PKR in cancer and metabolism

Cellular Stress Responses and Gut Microbiota in Inflammatory Bowel Disease

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