Hypoxia and HIF1α repress the differentiative effects of BMPs in high-grade glioma

Francesca Pistollato, Hui Ling Chen, Brian R. Rood, Hui Zhen Zhang, Domenico D'Avella, Luca Denaro, Marina Gardiman, Geertruy Te Kronnie, Philip H. Schwartz, Elena Favaro, Stefano Indraccolo, Giuseppe Basso, David M. Panchision

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)7-17
Number of pages11
JournalStem Cells
Issue number1
Publication statusPublished - Jan 2009


  • Bone morphogenetic proteins
  • Brain tumor
  • High-grade glioma
  • Hypoxia inducible factor 1α
  • Oxygen
  • Smad

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology
  • Molecular Medicine
  • Medicine(all)


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