A BCL6/BCOR/SIRT1 Complex Triggers Neurogenesis and Suppresses Medulloblastoma by Repressing Sonic Hedgehog Signaling

Tiberi, Luca; Bonnefont, Jérôme; Ameele, Jelle van den; Bon, Serge-Daniel Le; Herpoel, Adèle; Bilheu, Angéline; Baron, Beverly W.; Vanderhaeghen, Pierre

doi:10.1016/j.ccell.2014.10.021

Cited by 88 publications

(78 citation statements)

References 67 publications

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“…Recent studies have shown that Bcl6 overexpression (Tiberi et al, 2014) or direct FGF injection reduces proliferation of medulloblastoma cells in which Shh is hyperactivated (Emmenegger et al, 2013), supporting the idea that enhancing differentiation effectively prevents medulloblastoma progression in vivo.…”

Section: Pals1 Loss Forces Cell Cycle Exit Despite Hyperactive Shh Simentioning

confidence: 85%

Apical complex protein Pals1 is required to maintain cerebellar progenitor cells in a proliferative state

et al. 2015

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Through their biased localization and function within the cell, polarity complex proteins are necessary to establish the cellular asymmetry required for tissue organization. Well-characterized germinal zones, mitogenic signals and cell types make the cerebellum an excellent model for addressing the crucial function of polarity complex proteins in the generation and organization of neural tissues. Deletion of the apical polarity complex protein Pals1 in the developing cerebellum results in a remarkably undersized cerebellum with disrupted layers in poorly formed folia and strikingly reduced granule cell production. We demonstrate that Pals1 is not only essential for cerebellum organogenesis, but also for preventing premature differentiation and thus maintaining progenitor pools in cerebellar germinal zones, including cerebellar granule neuron precursors in the external granule layer. In the Pals1 mouse mutants, the expression of genes that regulate the cell cycle was diminished, correlating with the loss of the proliferating cell population of germinal zones. Furthermore, enhanced Shh signaling through activated Smo cannot overcome impaired cerebellar cell generation, arguing for an epistatic role of Pals1 in proliferation capacity. Our study identifies Pals1 as a novel intrinsic factor that regulates the generation of cerebellar cells and Pals1 deficiency as a potential inhibitor of overactive mitogenic signaling.

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Section: Pals1 Loss Forces Cell Cycle Exit Despite Hyperactive Shh Simentioning

confidence: 85%

Apical complex protein Pals1 is required to maintain cerebellar progenitor cells in a proliferative state

et al. 2015

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“…Here, our study for the irst time showed that the Smoothened (Smo) agonist purmophamine increased the expression of Sirt1, the Smoothened (Smo) antagonist cyclopamine decreased the expression of Sirt1, and the Sirt1 inhibitor sirtinol decreased the expressions of Shh, Ptc-1, Smo, and Gli-1proteins. Tiberi et al reported that a Sirt1 complex inhibited the Shh signaling in normal and oncogenic neural development [31]. Kong and Yang et al show that Notch signaling tunes neural progenitor responses to Shh by regulating traf icking of the Shh receptor Patched1 and downstream effector Smoothened to primary cilia.…”

Section: Discussionmentioning

confidence: 99%

Resveratrol Enhances Neurite Outgrowth and Synaptogenesis Via Sonic Hedgehog Signaling Following Oxygen-Glucose Deprivation/Reoxygenation Injury

Tang¹,

Guo²,

Liao³

et al. 2017

Cell Physiol Biochem

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Background/Aims: Neurite outgrowth and synaptogenesis are critical steps for functional recovery after stroke. Resveratrol promotes neurite outgrowth and synaptogenesis, but the underlying mechanism is not well understood, although the Sonic hedgehog (Shh) signaling pathway may be involved. Given that resveratrol activates sirtuin (Sirt)1, the present study examined whether this is mediated by Shh signaling. Methods: Primary cortical neuron cultures were pretreated with drugs before oxygen-glucose deprivation/reoxygenation (OGD/R). Cell viability and apoptosis were evaluated with Cell Counting Kit 8 and by terminal deoxynucleotidyl transferase dUTP nick end labeling, respectively. Neurite outgrowth and synaptogenesis were assessed by immunocytochemistry and western blotting, which was also used to examine the expression of Sirt1 and Shh signaling proteins. Results: Resveratrol and the Smoothened (Smo) agonist purmophamine, which activates Shh signaling, increased the expression of growth-associated protein(GAP)-43, synaptophysin, Shh, Patched (Ptc)-1, Smo, glioma-associated oncogene homolog (Gli)-1, and Sirt1 were upregulated under these conditions. These effects were reversed by treatment with the Smo inhibitor cyclopamine, whereas the Sirt1 inhibitor sirtinol reduced the levels of Shh, Ptc-1, Smo, and Gli-1. Conclusions: Resveratrol reduces neuronal injury following OGD/R injury and enhances neurite outgrowth and synaptogenesis by activating Shh signaling, which in turn induces Sirt1.

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“…Tiberi et al [109] recently demonstrated that BCL6 represses GLI1 and GLI2, effectors of the SHH pathway, through recruitment of BCOR and SIRT1 deacetylase. Because the targets of the BCL6/BCOR/SIRT1 complex depend on the cellular context, further studies are necessary to clarify the significance of this mutation in EBVaGC.…”

Section: Molecular Abnormalities Demonstrated By ‘Omics' Studiesmentioning

confidence: 99%

Epstein-Barr Virus-Associated Gastric Carcinoma: Use of Host Cell Machineries and Somatic Gene Mutations

2015

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Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) is a distinct subtype of gastric carcinoma, consisting of clonal growth of EBV-infected epithelial cells. Its unique characteristics have been demonstrated by epidemiological, clinical and pathological studies using in situ hybridization for EBV-encoded small RNAs. An oncogenic process for EBVaGC has also been revealed. EBV uses various host-cell machineries, including cell division machinery to propagate clonal virus genomes, DNA-methylation machinery to epigenetically control infected cells, and microRNA and exosome machineries to modify the behavior and microenvironment of infected cells. Recent comprehensive molecular analyses from The Cancer Genome Atlas project demonstrate that EBVaGC is a representative molecular subtype that is distinct from microsatellite unstable, genomically stable and chromosome unstable subtypes. In addition to having the highest level of DNA methylation in CpG islands of promoter regions, EBVaGC harbors particular gene alterations, including a high frequency of mutations in PIK3CA and ARID1A, mutation in BCOR, and amplification of PD-L1 and PD-L2. Although currently undetermined, the virus might use the altered cellular functions that are induced by these somatic mutations. Further investigation of virus-driven oncogenesis will enable hitherto unknown functions of stomach epithelial cell machineries to be elucidated, which may reveal potential therapeutic targets for EBVaGC.

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A BCL6/BCOR/SIRT1 Complex Triggers Neurogenesis and Suppresses Medulloblastoma by Repressing Sonic Hedgehog Signaling

Cited by 88 publications

References 67 publications

Apical complex protein Pals1 is required to maintain cerebellar progenitor cells in a proliferative state

Apical complex protein Pals1 is required to maintain cerebellar progenitor cells in a proliferative state

Resveratrol Enhances Neurite Outgrowth and Synaptogenesis Via Sonic Hedgehog Signaling Following Oxygen-Glucose Deprivation/Reoxygenation Injury

Epstein-Barr Virus-Associated Gastric Carcinoma: Use of Host Cell Machineries and Somatic Gene Mutations

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