Identification and Characterization of a Small‐Molecule Inhibitor of Death‐Associated Protein Kinase 1

Wilbek, Theis S.; Skovgaard, Tine; Sorrell, F.J.; Knapp, Stefan; Berthelsen, Jens; Strømgaard, Kristian

doi:10.1002/cbic.201402512

Cited by 23 publications

(17 citation statements)

References 35 publications

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“…In this pathway, the apoptosis regulator BCL-2 (PC-3p-36625_60-BCL2), Von Hippel-Lindau disease tumour-suppressor (miR-338-Vhl), transferrin receptor (miR-16a/20a-TFRC), MFS transporter, SP family, solute carrier family 2 (facilitated glucose transporter), member 1 (miR-3618-SLC2A1), VEGF, and erythropoietin (EPO) expression were significantly up-regulated, which is additional evidence of an up-regulated HIF-1 signaling pathway. The death-associated protein kinase (miR-27b-DAPK) is a stress-regulated protein kinase that mediates a range of processes, including signal-induced cell death and autophagy 41 . Transcription factor AP-1 (miR-301a/301c-JUN) is an important transcription factor that regulates the expression of VEGF in response to hypoxic conditions, in turn affecting angiogenesis 42 .…”

Section: Discussionmentioning

confidence: 99%

Integrated analysis of mRNA-seq and miRNA-seq in the liver of Pelteobagrus vachelli in response to hypoxia

Zhang

Yin

Mao³

et al. 2016

Sci Rep

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Pelteobagrus vachelli is a well-known commercial species in Asia. However, a sudden lack of oxygen will result in mortality and eventually to pond turnover. Studying the molecular mechanisms of hypoxia adaptation in fishes will not only help us to understand fish speciation and the evolution of the hypoxiasignaling pathway, but will also guide us in the breeding of hypoxia-tolerant fish strains. Despite this, the genetic regulatory network for miRNA-mRNA and the signaling pathways involved in hypoxia responses in fish have remained unexamined. In the present study, we used next-generation sequencing technology to characterise mRNA-seq and miRNA-seq of control-and hypoxia-treated P. vachelli livers to elucidate the molecular mechanisms of hypoxia adaptation. We were able to find miRNA-mRNA pairs using bioinformatics analysis and miRNA prediction algorithms. Furthermore, we compared several key pathways which were identified as involved in the hypoxia response of P. vachelli. Our study is the first report on integrated analysis of mRNA-seq and miRNA-seq in fishes and offers a deeper insight into the molecular mechanisms of hypoxia adaptation. qRT-PCR analysis further confirmed the results of mRNASeq and miRNA-Seq analysis. We provide a good case study for analyzing mRNA/miRNA expression and profiling a non-model fish species using next-generation sequencing technology.Oxygen serves as the terminal electron acceptor in oxidative phosphorylation. Moreover, several enzymatic processes in vivo require molecular oxygen as the direct substrate 1 . Aquatic organisms are usually exposed to oxygen at various concentrations. For example, the natural oxygen level in fresh water can vary widely over the course of 24 hours, from a low level at night to oversaturation during the day. In order to thrive in this environment, fish have adapted and developed various survival strategies (e.g., depression of the metabolic rate, shifting of blood flow mainly to the brain and heart, and efficient production of energy) 2 . Unearthing the molecular mechanisms of hypoxia adaptation in fishes will not only help us to understand fish speciation and the evolution of the hypoxia-signaling pathway but will also guide us in the breeding of hypoxia-tolerant fish strains.Pelteobagrus vachelli has delicious taste with little bone in muscle and high nutritional value. Moreover, it is omnivorous and has a remarkable ability to adapt to environment 3,4 . The relatively high yield of P. vachelli coupled with an affordable price for consumers thus make it a very popular commercial species in Asia. However, the species is only distributed in some of Asia's larger rivers, such as the Liaohe, Huaihe, Yangtze, Xiangjiang, Minjiang and Pearl. It is not suitable for high-density pond farming because of the relatively high oxygen-consumption rate and low oxygen threshold; a sudden lack of oxygen will result in mortality among the fish and will eventually lead to pond turnover 5 . These special characteristics of P. vachelli suggest that it is not only a signi...

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Section: Discussionmentioning

confidence: 99%

Integrated analysis of mRNA-seq and miRNA-seq in the liver of Pelteobagrus vachelli in response to hypoxia

Zhang

Yin

Mao³

et al. 2016

Sci Rep

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“…In glial cells, compound 1 inhibited iNOS and consequently the production of NO in a dose‐dependent manner, thus inhibiting the release of several inflammatory mediators without affecting cyclooxygenase‐2 or apolipoprotein E levels. Additionally, it decreased neuronal loss, and diminished amyloid plaque deposition in vivo proving that inhibition of inflammatory mediators in the hippocampus can reduce neuronal loss …”

Section: Dapks Inhibitorsmentioning

confidence: 96%

Death‐associated protein kinase (DAPK) family modulators: Current and future therapeutic outcomes

Farag

Roh

2018

Medicinal Research Reviews

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Serine/threonine kinases (STKs) represent the majority of discovered kinases to date even though a few Food and Drug Administration approved STKs inhibitors are reported. The third millennium came with the discovery of an important group of STKs that reshaped our understanding of several biological signaling pathways. This family was named death-associated protein kinase family (DAPK family). DAPKs comprise five members (DAPK1, DAPK2, DAPK3, DRAK1, and DRAK2) and belong to the calcium/calmodulin-dependent kinases domain. As time goes on, the list of biological functions of this family is constantly updated. The most extensively studied member is DAPK1 (based on the publications number and Protein Data Bank reported crystal structures) that plays fundamental biological roles depending on the cellular context. DAPK1 regulates apoptosis, autophagy, contributes to the pathogenesis of Alzheimer's disease, acts as a tumor suppressor, inhibits metastasis, mediates the body responses to viral infections, and regulates the synaptic plasticity and depression. For their biological roles, several DAPKs' modulators have been reported for treatment of many diseases as well as acting as probe compounds to facilitate the understanding of the biological functions elicited by this family. Despite that, the number of reported modulators is still limited and more research needs to be conducted on the discovery of novel strategies to activate or inhibit this family. In this report, we aim at drawing more attention to this family by reviewing the recent updates regarding the structure, biological roles, and regulation of this family. In addition, the small-molecule modulators of this family are reviewed in details with their potential therapeutic outcomes evaluated to help medicinal chemists develop more potent and selective possible drug candidates.

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“…In addition, a novel small-molecule imidazo-pyramidazine inhibitor was identified by a GluN2B peptide-based method using a caliper microfluidics capillary electrophoresis system, and this molecule was found to have a potent inhibitory effect on DAPK1 (IC 50 = 0.247 μM) [136]. Recently, the potential lead compound 11 has been developed that interrupts DAPK1-GluN2B interaction [137].…”

Section: Dapk1 As a Potential Target For Neurodegenerative Diseasesmentioning

confidence: 99%

Death-Associated Protein Kinase 1 Phosphorylation in Neuronal Cell Death and Neurodegenerative Disease

Kim

Chen

Zhou

et al. 2019

IJMS

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Regulated neuronal cell death plays an essential role in biological processes in normal physiology, including the development of the nervous system. However, the deregulation of neuronal apoptosis by various factors leads to neurodegenerative diseases such as ischemic stroke and Alzheimer’s disease (AD). Death-associated protein kinase 1 (DAPK1) is a calcium/calmodulin (Ca2+/CaM)-dependent serine/threonine (Ser/Thr) protein kinase that activates death signaling and regulates apoptotic neuronal cell death. Although DAPK1 is tightly regulated under physiological conditions, DAPK1 deregulation in the brain contributes to the development of neurological disorders. In this review, we describe the molecular mechanisms of DAPK1 regulation in neurons under various stresses. We also discuss the role of DAPK1 signaling in the phosphorylation-dependent and phosphorylation-independent regulation of its downstream targets in neuronal cell death. Moreover, we focus on the major impact of DAPK1 deregulation on the progression of neurodegenerative diseases and the development of drugs targeting DAPK1 for the treatment of diseases. Therefore, this review summarizes the DAPK1 phosphorylation signaling pathways in various neurodegenerative diseases.

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Identification and Characterization of a Small‐Molecule Inhibitor of Death‐Associated Protein Kinase 1

Cited by 23 publications

References 35 publications

Integrated analysis of mRNA-seq and miRNA-seq in the liver of Pelteobagrus vachelli in response to hypoxia

Integrated analysis of mRNA-seq and miRNA-seq in the liver of Pelteobagrus vachelli in response to hypoxia

Death‐associated protein kinase (DAPK) family modulators: Current and future therapeutic outcomes

Death-Associated Protein Kinase 1 Phosphorylation in Neuronal Cell Death and Neurodegenerative Disease

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