title: A Core Regulatory Circuit in Glioblastoma Stem Cells Links MAPK Activation to a Transcriptional Program of Neural Stem Cell Identity.
abstract: Glioblastoma, the most common primary malignant brain tumor, harbors a small population of tumor initiating cells (glioblastoma stem cells) that have many properties similar to neural stem cells. To investigate common regulatory networks in both neural and glioblastoma stem cells, we subjected both cell types to in-vitro differentiation conditions and measured global gene-expression changes using gene expression microarrays. Analysis of enriched transcription factor DNA-binding sites in the promoters of differentially expressed genes was used to reconstruct regulatory networks involved in differentiation. Computational predictions, which were biochemically validated, show an extensive overlap of regulatory circuitry between cell types including a network centered on the transcription factor KLF4. We further demonstrate that EGR1, a transcription factor previously shown to be downstream of the MAPK pathway, regulates KLF4 expression and that KLF4 in turn transcriptionally activates NOTCH as well as SOX2. These results demonstrate how known genomic alterations in glioma that induce constitutive activation of MAPK are transcriptionally linked to master regulators essential for neural stem cell identify.
authors.affiliation: National Cancer Institute, Neuro-Oncology Branch, Bethesda, MD, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Riddick
authors.affiliation: National Cancer Institute, Neuro-Oncology Branch, Bethesda, MD, USA.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Kotliarova
authors.affiliation: National Cancer Institute, Neuro-Oncology Branch, Bethesda, MD, USA.
authors.forename: Virginia
authors.initials: V
authors.lastname: Rodriguez
authors.affiliation: Macrogen, Seoul, Korea.
authors.forename: H S
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Weill Cornell Medical College, New York, NY, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Linkous
authors.affiliation: Weill Cornell Medical College, New York, NY, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Storaska
authors.affiliation: National Cancer Institute, Neuro-Oncology Branch, Bethesda, MD, USA.
authors.forename: Susie
authors.initials: S
authors.lastname: Ahn
authors.affiliation: National Cancer Institute, Neuro-Oncology Branch, Bethesda, MD, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Walling
authors.affiliation: National Cancer Institute, Neuro-Oncology Branch, Bethesda, MD, USA.
authors.forename: Galina
authors.initials: G
authors.lastname: Belova
authors.affiliation: Weill Cornell Medical College, New York, NY, USA.
authors.forename: Howard A
authors.initials: HA
authors.lastname: Fine
mesh_terms: D000818:Animals; D001665:Binding Sites; D015415:Biomarkers; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D019295:Computational Biology / Q000379:methods; D018450:Disease Progression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D055106:Genome-Wide Association Study; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D060787:Neoplasm Grading; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D058953:Neural Stem Cells / Q000378:metabolism*; D011485:Protein Binding; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D059467:Transcriptome
chemical_list: D015415:Biomarkers; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D014157:Transcription Factors; D020928:Mitogen-Activated Protein Kinases