Hypoxia and HIF1α Repress the Differentiative Effects of BMPs in High-Grade Glioma
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- Francesca Pistollato
- Hemato-Oncology Laboratory, Department of Pediatrics, University of Padova, Padova, Italy
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- Hui-Ling Chen
- Center for Neuroscience Research, Children's Research Institute, Children's National Medical Center, Washington, District of Columbia, USA
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- Brian R. Rood
- Center for Neuroscience Research, Children's Research Institute, Children's National Medical Center, Washington, District of Columbia, USA
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- Hui-Zhen Zhang
- Center for Neuroscience Research, Children's Research Institute, Children's National Medical Center, Washington, District of Columbia, USA
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- Domenico D'Avella
- Department of Neurosurgery, University of Padova, Padova, Italy
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- Luca Denaro
- Department of Neurosurgery, University of Padova, Padova, Italy
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- Marina Gardiman
- Department of Pathology, University of Padova, Padova, Italy
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- Geertruy te Kronnie
- Hemato-Oncology Laboratory, Department of Pediatrics, University of Padova, Padova, Italy
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- Philip H. Schwartz
- Children's Hospital of Orange County Research Institute, Orange, California, USA, and University of California, Irvine, Irvine, California, USA
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- Elena Favaro
- Department of Oncology and Surgical Sciences, University of Padova, Padova, Italy
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- Stefano Indraccolo
- Istituto Oncologico Veneto – IRCCS, Padova, Italy
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- Giuseppe Basso
- Hemato-Oncology Laboratory, Department of Pediatrics, University of Padova, Padova, Italy
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- David M. Panchision
- Center for Neuroscience Research, Children's Research Institute, Children's National Medical Center, Washington, District of Columbia, USA
Description
<jats:title>Abstract</jats:title> <jats:p>Hypoxia commonly occurs in solid tumors of the central nervous system (CNS) and often interferes with therapies designed to stop their growth. We found that pediatric high-grade glioma (HGG)-derived precursors showed greater expansion under lower oxygen tension, typical of solid tumors, than normal CNS precursors. Hypoxia inhibited p53 activation and subsequent astroglial differentiation of HGG precursors. Surprisingly, although HGG precursors generated endogenous bone morphogenetic protein (BMP) signaling that promoted mitotic arrest under high oxygen tension, this signaling was actively repressed by hypoxia. An acute increase in oxygen tension led to Smad activation within 30 minutes, even in the absence of exogenous BMP treatment. Treatment with BMPs further promoted astroglial differentiation or death of HGG precursors under high oxygen tension, but this effect was inhibited under hypoxic conditions. Silencing of hypoxia-inducible factor 1α (HIF1α) led to Smad activation even under hypoxic conditions, indicating that HIF1α is required for BMP repression. Conversely, BMP activation at high oxygen tension led to reciprocal degradation of HIF1α; this BMP-induced degradation was inhibited in low oxygen. These results show a novel, mutually antagonistic interaction of hypoxia-response and neural differentiation signals in HGG proliferation, and suggest differences between normal and HGG precursors that may be exploited for pediatric brain cancer therapy.</jats:p>
Journal
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- Stem Cells
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Stem Cells 27 (1), 7-17, 2009-01-01
Oxford University Press (OUP)
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Details 詳細情報について
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- CRID
- 1363951795846019840
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- ISSN
- 15494918
- 10665099
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- Web Site
- https://api.wiley.com/onlinelibrary/tdm/v1/articles/10.1634%2Fstemcells.2008-0402
- https://onlinelibrary.wiley.com/doi/pdf/10.1634/stemcells.2008-0402
- https://onlinelibrary.wiley.com/doi/full-xml/10.1634/stemcells.2008-0402
- https://academic.oup.com/stmcls/article-pdf/27/1/7/41946722/stmcls_27_1_7.pdf
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- Data Source
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- Crossref