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Cited by 80Wnt/β-catenin signaling in development and cancerGlioma Diagnosis and TreatmentNeuroscience and Neuropharmacology Research

β-Catenin signaling initiates the activation of astrocytes and its dysregulation contributes to the pathogenesis of astrocytomas

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Yang, Chunzhang, Iyer, Rajiv R., Yu, Albert C. H., Yong, Raymund L., Park, Deric M., Weil, Robert J., Ikejiri, Barbara, Brady, Roscoe O. +2 more·2012·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1118754109PMC PMC3344971
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Abstract

Astrocytes are the most abundant cell of the CNS and demonstrate contact inhibition in which a nonproliferative, nonmotile cellular state is achieved once stable intercellular contacts are formed between mature cells. Cellular injury disrupts these intercellular contacts, causing a loss of contact inhibition and the rapid initiation of healing. Dysregulation of the molecular pathways involved in this process is thought to lead to an aggressive cellular state associated with neoplasia. We investigated whether a comparable correlation exists between the response of astrocytes to injury and the malignant phenotype of astrocytomas. We discovered that the loss of contact inhibition plays a critical role in the initiation and regulation of reactive astrocytes in the healing of wounds. In particular, injury of the astrocytes interrupts and destabilizes the cadherin-catenin complexes at the cell membrane leading to nuclear translocation of β-catenin and characteristic changes associated with the activation of astrocytes. Similar signaling pathways are found to be active—but dysregulated—in astrocytomas. Inhibition of β-catenin signaling diminished both the response of astrocytes to injury and induction of the malignant phenotype of astrocytomas. The findings shed light on a unique mechanism associated with the pathogenesis of astrocytomas and provide a model for the loss of contact inhibition that may broadly apply to understanding the mechanisms of tissue repair and tumorigenesis in the brain.

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Authors
Yang, C., Iyer, R. R., Yu, A. C. H., Yong, R. L., Park, D. M., Weil, R. J., Ikejiri, B., Brady, R. O., Lonser, R. R., & Zhuang, Z.
Affiliations
  • National Institutes of Health (US)
  • Peking University (CN)
  • University of Virginia (US)
  • Cleveland Clinic (US)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2012-04-13
Volume
109
Issue
18
Pages
6963-6968
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.1118754109
PMC
PMC3344971
OpenAlex
W2048944816
Cited by
80
References
1
Citations by year
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FWCI
3.08
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
  • Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
β-catenin signaling, astrocytes, astrocytoma, contact inhibition, reactive astrocytes, cadherin-catenin complex, astrocyte injury, wound healing, tissue repair, carcinogenesis, brain tumors, malignant phenotype
MeSH terms
Animals, Astrocytes, Astrocytoma, Cell Transformation, Neoplastic, Cells, Cultured, Models, Neurological, Phenotype, Tumor Cells, Cultured, Signal Transduction, RNA, Small Interfering, Cell Proliferation, beta Catenin, Mice, Gene Knockdown Techniques

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