Abstract
Cellular origins and genetic factors governing the genesis and maintenance of glioblastomas (GBM) are not well understood. Here, we report a pathogenetic role of the developmental regulator Id4 (inhibitor of differentiation 4) in GBM. In primary murine Ink4a/Arf(-/-) astrocytes, and human glioma cells, we provide evidence that enforced Id4 can drive malignant transformation by stimulating increased cyclin E to produce a hyperproliferative profile and by increased Jagged1 expression with Notch1 activation to drive astrocytes into a neural stem-like cell state. Thus, Id4 plays an integral role in the transformation of astrocytes via its combined actions on two-key cell cycle and differentiation regulatory molecules.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Astrocytes / cytology
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Astrocytes / physiology*
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Calcium-Binding Proteins / metabolism
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Cell Culture Techniques
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Cell Line, Tumor
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Cell Transformation, Neoplastic*
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Cells, Cultured
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Cerebral Cortex / cytology
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Cyclin E / metabolism*
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Glioblastoma / pathology
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Humans
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Inhibitor of Differentiation Proteins / metabolism*
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Intercellular Signaling Peptides and Proteins / metabolism
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Jagged-1 Protein
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Membrane Proteins / metabolism
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Mice
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Mice, Knockout
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RNA, Messenger / metabolism
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Receptor, Notch1 / genetics
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Receptor, Notch1 / metabolism*
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Serrate-Jagged Proteins
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Signal Transduction / genetics
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Signal Transduction / physiology*
Substances
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Calcium-Binding Proteins
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Cyclin E
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ID4 protein, human
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Inhibitor of Differentiation Proteins
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Intercellular Signaling Peptides and Proteins
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JAG1 protein, human
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Jag1 protein, mouse
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Jagged-1 Protein
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Membrane Proteins
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NOTCH1 protein, human
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RNA, Messenger
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Receptor, Notch1
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Serrate-Jagged Proteins