Silencing of Doublecortin-Like (DCL) Results in Decreased Mitochondrial Activity and Delayed Neuroblastoma Tumor Growth

Veríssimo, Carla S.; Elands, Rachel; Cheng, Sou; Saaltink, Dirk-Jan; Horst, Judith P. ter; Alme, Maria Nordheim; Pont, Chantal; Water, Bob van de; Håvik, Bjarte; Fitzsimons, Carlos P.; Vreugdenhil, Erno

doi:10.1371/journal.pone.0075752

Cited by 13 publications

(12 citation statements)

References 64 publications

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“…The next day cells were transfected with FLAG-tagged human BCL2L13, a kind gift from Dr. Jürg Tschopp, Institute of Biochemistry, University of Lausanne (Kataoka et al , 2001), using Attractene (Qiagen) or empty vector and were incubated for 48 h. In the last 7 h of the incubation cells were treated with varying concentrations of KA ranging from 0–300 μM KA or vehicle 46 . Cells were treated with 250 nM MitoTracker® Red CMXRos (Invitrogen) for 5 minutes to specifically stain mitochondria 69 and fixed for 15 minutes in 4% PFA. Subsequently, cells were stained with polyclonal sheep anti-CytC (Sigma-Aldrich, 1:100) in combination with donkey anti-sheep Alexa488 (Invitrogen, 1:1000) and coverslips were mounted in vectashield mounting medium (Vector Labs).…”

Section: Methodsmentioning

confidence: 99%

MicroRNA-124 and -137 cooperativity controls caspase-3 activity through BCL2L13 in hippocampal neural stem cells

Schouten

Fratantoni²,

Hubens

et al. 2015

Sci Rep

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Adult neurogenesis continuously contributes new neurons to hippocampal circuits and the programmed death of a subset of immature cells provides a primary mechanism controlling this contribution. Epileptic seizures induce strong structural changes in the hippocampus, including the induction of adult neurogenesis, changes in gene expression and mitochondrial dysfunction, which may all contribute to epileptogenesis. However, a possible interplay between this factors remains largely unexplored. Here, we investigated gene expression changes in the hippocampal dentate gyrus shortly after prolonged seizures induced by kainic acid, focusing on mitochondrial functions. Using comparative proteomics, we identified networks of proteins differentially expressed shortly after seizure induction, including members of the BCL2 family and other mitochondrial proteins. Within these networks, we report for the first time that the atypical BCL2 protein BCL2L13 controls caspase-3 activity and cytochrome C release in neural stem/progenitor cells. Furthermore, we identify BCL2L13 as a novel target of the cooperative action of microRNA-124 and microRNA-137, both upregulated shortly after seizure induction. This cooperative microRNA-mediated fine-tuning of BCL2L13 expression controls casp3 activity, favoring non-apoptotic caspase-3 functions in NSPC exposed to KA and thereby may contribute to the early neurogenic response to epileptic seizures in the dentate gyrus.

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Section: Methodsmentioning

confidence: 99%

MicroRNA-124 and -137 cooperativity controls caspase-3 activity through BCL2L13 in hippocampal neural stem cells

Schouten

Fratantoni²,

Hubens

et al. 2015

Sci Rep

Self Cite

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“…DCX and DCLK1 are important during neurogenesis and neuronal migration (Mizuguchi et al, ; Mizuguchi et al, ; Shu et al, ; Jean et al, ; Liu et al, ; Saaltink et al, ; Shin et al, ; Verissimo et al, ; Lipka et al, ). Certain mutations that cause the neuronal migration disorder lissencephaly have been mapped to the dcx gene (Gleeson et al, ; Pilz et al, ; Gleeson et al, ; Viot et al, ).…”

Section: Introductionmentioning

confidence: 99%

ReMAPping the microtubule landscape: How phosphorylation dictates the activities of microtubule‐associated proteins

Ramkumar

Jong

Ori-McKenney

2017

Developmental Dynamics

156

111

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Classical microtubule-associated proteins (MAPs) were originally identified based on their co-purification with microtubules assembled from mammalian brain lysate. They have since been found to perform a range of functions involved in regulating the dynamics of the microtubule cytoskeleton. Most of these MAPs play integral roles in microtubule organization during neuronal development, microtubule remodeling during neuronal activity, and microtubule stabilization during neuronal maintenance. As a result, mutations in MAPs contribute to neurodevelopmental disorders, psychiatric conditions, and neurodegenerative diseases. MAPs are post-translationally regulated by phosphorylation depending on developmental time point and cellular context. Phosphorylation can affect the microtubule affinity, cellular localization, or overall function of a particular MAP and can thus have profound implications for neuronal health. Here we review MAP1, MAP2, MAP4, MAP6, MAP7, MAP9, tau, and DCX, and how each is regulated by phosphorylation in neuronal physiology and disease. Developmental Dynamics 247:138-155,

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“…Thereafter, investigators reported an important role of DCLK1 in dictating cognitive behavior of mice and humans 16 17 . A possible important role of DCLK1 in maintaining tumorous growths was first learned from experiments with neuroblastomas 18 19 . Only in the past 7–8 years, epithelial expression of DCLK1 was described for the first time in mouse gastric epithelial cells 20 , and the authors speculated that DCLK1 was being expressed by gastric stem cells.…”

mentioning

confidence: 99%

Epigenetic changes and alternate promoter usage by human colon cancers for expressing DCLK1-isoforms: Clinical Implications

O’Connell

Sarkar

Luthra³

et al. 2015

Sci Rep

167

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DCLK1 specifically marks colon/pancreatic cancers in mice, and is expressed by human colon adenocarcinomas (hCRCs). Down-regulation of DCLK1 results in loss of cancer-stem-cells (CSCs), and inhibits spheroidal/xenograft growths from hCRC-cells. The 5′-promoter of DCLK1-gene is reportedly hypermethylated in hCRCs, resulting in loss of expression of DCLK1-transcripts, originating from 5′(α)-promoter (termed DCLK1-L, in here). However, in mouse colon-tumors, 5′-promoter of DCLK1-gene remains unchanged, and DCLK1-L, originating from 5′(α)-promoter, is expressed. We hypothesized that elevated levels of DCLK1-protein in hCRC-cells, may be transcribed/translated from an alternate-promoter. Several in silico and molecular biology approaches were used to test our hypothesis. We report for the first time that majority of hCRCs express short-transcripts of DCLK1 (termed DCLK1-S, in here) from an alternate β-promoter in IntronV of the gene, while normal-colons mainly express DCLK1-L from 5′(α)-promoter. We additionally report an important role of β-catenin and TCF4/LEF binding-sites for activating (α)-promoter, while activated NF-κBp65 (bound to NF-κB-cis-element), activates (β)-promoter in cancer-cells. DCLK1-S expression was examined in a cohort of 92 CRC patients; high-expressors had significantly worse overall-survival compared to low-expressors. Our novel findings’ regarding usage of alternate (β)-promoter by hCRCs, suggests that DCLK1-S may represent an important target for preventing/inhibiting colon-cancers, and for eliminating colon-CSCs.

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Silencing of Doublecortin-Like (DCL) Results in Decreased Mitochondrial Activity and Delayed Neuroblastoma Tumor Growth

Cited by 13 publications

References 64 publications

MicroRNA-124 and -137 cooperativity controls caspase-3 activity through BCL2L13 in hippocampal neural stem cells

MicroRNA-124 and -137 cooperativity controls caspase-3 activity through BCL2L13 in hippocampal neural stem cells

ReMAPping the microtubule landscape: How phosphorylation dictates the activities of microtubule‐associated proteins

Epigenetic changes and alternate promoter usage by human colon cancers for expressing DCLK1-isoforms: Clinical Implications

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