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Hypoxia and HIF1α Repress the Differentiative Effects of BMPs in High-Grade Glioma
- Source :
- Stem Cells. 27:7-17
- Publication Year :
- 2009
- Publisher :
- Oxford University Press (OUP), 2009.
-
Abstract
- 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.
- Subjects :
- medicine.medical_specialty
Cellular differentiation
Bone Morphogenetic Protein 2
Down-Regulation
Mitosis
Smad Proteins
SMAD
Biology
Bone morphogenetic protein
Bone morphogenetic protein 2
Glioma
Internal medicine
medicine
Humans
Gene Silencing
Child
Cell Proliferation
Cell Differentiation
Cell Biology
Hypoxia (medical)
Hypoxia-Inducible Factor 1, alpha Subunit
medicine.disease
Cell Hypoxia
Oxygen tension
Cell biology
Oxygen
Endocrinology
Astrocytes
Neoplastic Stem Cells
Molecular Medicine
Tumor Suppressor Protein p53
medicine.symptom
Signal transduction
Signal Transduction
Developmental Biology
Subjects
Details
- ISSN :
- 15494918 and 10665099
- Volume :
- 27
- Database :
- OpenAIRE
- Journal :
- Stem Cells
- Accession number :
- edsair.doi.dedup.....a86d101696e61d668cfc393079749e00
- Full Text :
- https://doi.org/10.1634/stemcells.2008-0402