Kooperativer Bibliotheksverbund

Berlin Brandenburg

and
and

Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
Filter
Type of Medium
Language
Year
  • 1
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 29 July 2014, Vol.111(30), pp.11061-6
    Description: Hedgehog (Hh) pathway activation and Gli-dependent transcription play critical roles in embryonic patterning, tissue homeostasis, and tumorigenesis. By conducting a genome-scale cDNA overexpression screen, we have identified the Rho GAP family member Arhgap36 as a positive regulator of the Hh pathway in vitro and in vivo. Arhgap36 acts in a Smoothened (Smo)-independent manner to inhibit Gli repressor formation and to promote the activation of full-length Gli proteins. Arhgap36 concurrently induces the accumulation of Gli proteins in the primary cilium, and its ability to induce Gli-dependent transcription requires kinesin family member 3a and intraflagellar transport protein 88, proteins that are essential for ciliogenesis. Arhgap36 also functionally and biochemically interacts with Suppressor of Fused. Transcriptional profiling further reveals that Arhgap36 is overexpressed in murine medulloblastomas that acquire resistance to chemical Smo inhibitors and that ARHGAP36 isoforms capable of Gli activation are up-regulated in a subset of human medulloblastomas. Our findings reveal a new mechanism of Gli transcription factor activation and implicate ARHGAP36 dysregulation in the onset and/or progression of GLI-dependent cancers.
    Keywords: Gtpase-Activating Proteins -- Metabolism ; Kruppel-Like Transcription Factors -- Metabolism ; Medulloblastoma -- Metabolism ; Nuclear Proteins -- Metabolism ; Transcription Factors -- Metabolism ; Zebrafish -- Metabolism ; Zebrafish Proteins -- Metabolism
    ISSN: 00278424
    E-ISSN: 1091-6490
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 2
    Language: English
    In: Cell, 24 April 2014, Vol.157(3), pp.525-527
    Description: Hierarchical cell state models, wherein a few stem-like tumor-propagating cells repopulate the tumor after therapy, are often invoked in cancer. Suvà et al. demonstrate a plastic developmental hierarchy in glioma cell populations by characterizing the epigenetic states of phenotypically distinct cells and identifying four factors sufficient to reprogram differentiated cells into a tumorigenic stem-like state.
    Keywords: Biology
    ISSN: 0092-8674
    E-ISSN: 1097-4172
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 3
    In: International Journal of Cancer, 01 February 2014, Vol.134(3), pp.703-716
    Description: Based on extensive pre‐clinical studies, the oncolytic parvovirus H‐1 (H‐1PV) is currently applied to patients with recurrent glioblastoma in a phase I/IIa clinical trial (ParvOryx01, NCT01301430). Cure rates of about 40% in pediatric high‐risk medulloblastoma (MB) patients also indicate the need of new therapeutic approaches. In order to prepare a future application of oncolytic parvovirotherapy to MB, the present study preclinically evaluates the cytotoxic efficacy of H‐1PV on MB cells and characterizes cellular target genes involved in this effect. Six MB cell lines were analyzed by whole genome oligonucleotide microarrays after treatment and the results were matched to known molecular and cytogenetic risk factors. In contrast to non‐transformed infant astrocytes and neurons, in five out of six MB cell lines lytic H‐1PV infection and efficient viral replication could be demonstrated. The cytotoxic effects induced by H‐1PV were observed at LD50s below 0.05 p. f. u. per cell indicating high susceptibility. Gene expression patterns in the responsive MB cell lines allowed the identification of candidate target genes mediating the cytotoxic effects of H‐1PV. H‐1PV induced down‐regulation of key regulators of early neurogenesis shown to confer poor prognosis in MB such as ZIC1, FOXG1B, MYC, and NFIA. In MB cell lines with genomic amplification of MYC, expression of MYC was the single gene most significantly repressed after H‐1PV infection. H‐1PV virotherapy may be a promising treatment approach for MB since it targets genes of functional relevance and induces cell death at very low titers of input virus. What's new? Medulloblastoma, the most frequent pediatric brain cancer, causes death in about 60 percent of high‐risk patients, and so there is a major need for novel, highly effective therapies. One therapy of interest is parvovirus H‐1 (H‐1PV), which was found in this study to produce marked cytotoxic effects in six medulloblastoma cell lines. Gene expression profiling revealed that H‐1PV infection causes down‐regulation of key regulatory genes involved in early neurogenesis, with significant repression of . The master regulators affected may represent putative direct or indirect H‐1PV target genes.
    Keywords: Medulloblastoma ; Oncolytic Virus ; Parvovirus H‐1pv ; Cellular Targets ; Myc ; Master Regulators Of Neurogenesis
    ISSN: 0020-7136
    E-ISSN: 1097-0215
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 4
    In: International Journal of Cancer, 01 January 2014, Vol.134(1), pp.21-31
    Description: The canonical Sonic Hedgehog (Shh)/Gli pathway plays multiples roles during central nervous system (CNS) development. To elucidate the molecular repertoire of Shh mediators, we have recently described novel transcriptional targets in response to Shh pathway modulation. Among them, we were able to identify Neogenin1 (Neo1), a death dependence receptor, as a new direct Shh downstream regulator in neural precursor proliferation. As appropriate Shh signaling is required for cerebellar growth and alterations cause Shh‐driven medulloblastoma (MB), here we have addressed the role of the Shh/Neogenin1 interaction in the context of cerebellar development and cancer. We demonstrate that the Shh pathway regulates Neogenin1 expression in mouse models that recapitulate the Shh MB subtype. We show that the canonical Shh pathway directly regulates the gene acting through an upstream sequence in its promoter both and in granule neuron precursor cells. We also identified and characterized a functional Gli‐binding site in the first intron of the human gene. Gene expression profiling of more than 300 MB shows that is indeed upregulated in SHH tumors compared to the other MB subgroups. Finally, we provide evidence that NEO1 is necessary for cell cycle progression in a human MB cell line, because a loss of function of arrests cells in the G2/M phase. Taken together, these results highlight Neogenin1 as a novel downstream effector of the Shh pathway in MB and a possible therapeutic target. What's new? Abnormal activation of the canonical Sonic Hedgehog (Shh)/Gli pathway has been associated with up to 30% of the human cases of medulloblastoma, which represents the most common malignant primary brain tumor in children. A greater knowledge of the cellular response to Shh pathway activation in the cerebellum is critical for both understanding disease formation and developing new treatments. In this study, the authors identified Neogenin‐1 as a novel downstream effector of the Shh pathway that mediates proliferation in both cultured cerebellar progenitors and shh‐driven medulloblastoma. The data suggest that targeting Neogenin‐1 could offer a promising alternative to current anti‐medulloblastoma therapies.
    Keywords: Medulloblastoma ; Sonic Hedgehog ; Neogenin 1 ; Gli ; Cancer
    ISSN: 0020-7136
    E-ISSN: 1097-0215
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 5
    Language: English
    In: Cancer Research, 10/01/2014, Vol.74(19 Supplement), pp.LB-198-LB-198
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 6
    Language: English
    In: Clinical cancer research : an official journal of the American Association for Cancer Research, 15 November 2014, Vol.20(22), pp.5630-40
    Description: High-throughput genomic technologies have shed light on the biologic heterogeneity of several pediatric brain tumors. The biology of the four common pediatric brain tumors-namely medulloblastoma; ependymoma; high-grade glioma (HGG), including diffuse intrinsic pontine glioma; and low-grade glioma-is highlighted in this CCR Focus article. The discovery that medulloblastoma consists of four different subgroups, namely WNT, SHH, Group 3, and Group 4, each with distinct clinical and molecular features, has affected the treatment of children with medulloblastoma. Prospective studies have documented the efficacy of SMO inhibitors in a subgroup of patients with SHH medulloblastoma. Efforts are ongoing to develop specific therapies for each of the subgroups of medulloblastoma. Similar efforts are being pursued for ependymoma, HGG, and diffuse intrinsic pontine glioma where the disease outcome for the latter two tumors has not changed over the past three decades despite several prospective clinical trials. Developing and testing targeted therapies based on this new understanding remains a major challenge to the pediatric neuro-oncology community. The focus of this review is to summarize the rapidly evolving understanding of the common pediatric brain tumors based on genome-wide analysis. These novel insights will add impetus to translating these laboratory-based discoveries to newer therapies for children diagnosed with these tumors.
    Keywords: Molecular Targeted Therapy ; Translational Medical Research ; Brain Neoplasms -- Drug Therapy
    ISSN: 1078-0432
    E-ISSN: 15573265
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 7
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States, July 29, 2014, Vol.111(30), p.11061(6)
    Description: Hedgehog (Hh) pathway activation and Gli-dependent transcription play critical roles in embryonic patterning, tissue homeostasis, and tumorigenesis. By conducting a genome-scale cDNA overexpression screen, we have identified the Rho GAP family member Arhgap36 as a positive regulator of the Hh pathway in vitro and in vivo. Arhgap36 acts in a Smoothened (Smo)-independent manner to inhibit Gli repressor formation and to promote the activation of full-length Gli proteins. Arhgap36 concurrently induces the accumulation of Gli proteins in the primary cilium, and its ability to induce Gli-dependent transcription requires kinesin family member 3a and intraflagellar transport protein 88, proteins that are essential for ciliogenesis. Arhgap36 also functionally and biochemically interacts with Suppressor of Fused. Transcriptional profiling further reveals that Arhgap36 is overexpressed in murine medulloblastomas that acquire resistance to chemical Smo inhibitors and that ARHGAP36 isoforms capable of Gli activation are upregulated in a subset of human medulloblastomas. Our findings reveal a new mechanism of Gli transcription factor activation and implicate ARHGAP36 dysregulation in the onset and/or progression of GLI-dependent cancers. www.pnas.org/cgi/doi/10.1073/pnas.1322362111
    Keywords: Genes -- Research ; Genes -- Physiological Aspects ; Transcription Factors -- Physiological Aspects ; Transcription Factors -- Research ; Carcinogenesis -- Research ; Carcinogenesis -- Genetic Aspects
    ISSN: 0027-8424
    Source: Cengage Learning, Inc.
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 8
    Language: English
    In: Cancer Research, 10/01/2014, Vol.74(19 Supplement), pp.LB-203-LB-203
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 9
    Language: English
    In: Cancer Research, 07/15/2016, Vol.76(14 Supplement), pp.SY15-02-SY15-02
    Description: Malignant pediatric brain tumors, including ependymoma, medulloblastoma and atypical teratoidrhabdoid tumors, frequently demonstrate a very quiet genome with very few nonsynonyomous single nucleotide variants or indels and a stable copy number profile. The recent advance of integrative genomics approaches from primary tumor tissue including whole-genome sequencing, RNA sequencing, whole-genome bisulfite sequencing, and ChIP sequencing for core histone marks and important transcription factors and chromatin configuration have enabled the discovery of new tumor-driving pathways and potentially druggable alterations in these cancers with quiet genomes. This knowledge after functional validation in vitro and in vivo provides critical insight in the search for the cell of origin in these tumors, the understanding of underlying pathomechanisms, and the identification of new treatment options.
    Keywords: Brain Mapping ; Histones ; Chromatin ; Pediatrics ; Landscape ; Bisulfite ; Nucleotides ; Cancer ; Copy Number ; Brain Tumors ; Enhancers ; RNA ; Transcription Factors ; Medulloblastoma ; Genomics ; Gene Mapping ; Development & Cell Cycle ; Miscellaneous Oncogenes & Growth Factors;
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 10
    Language: English
    In: Cancer Research, 04/15/2013, Vol.73(8 Supplement), pp.LB-80-LB-80
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
Close ⊗
This website uses cookies and the analysis tool Matomo. Further information can be found on the KOBV privacy pages