Linking Oxygen to Differentiation

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Science  18 Nov 2005:
Vol. 310, Issue 5751, pp. 1093
DOI: 10.1126/science.310.5751.1093b

Cells can detect an insufficiency of oxygen and activate signaling pathways that decrease metabolic oxidative phosphorylation or increase proliferation of blood vessels. Hypoxia also causes various stem or progenitor cells to remain in an undifferentiated state. Gustafsson et al. show that this latter response to hypoxia is mediated by an interaction between the oxygen-sensing mechanisms of the cell with the Notch signaling pathway. Cells use prolyl hydroxylases to sense oxygen, and these enzymes control gene expression via the transcription factor hypoxia-inducible factor-1α (HIF-1α). The membrane protein Notch can undergo proteolytic cleavage, which allows its intracellular domain (ICD) to move into the nucleus and to interact with other proteins to regulate expression. The effects of hypoxia on differentiation of cultured mouse muscle precursor cells or primary rat neural stem cells depend on Notch signaling and were prevented by an inhibitor of the protease that generates the Notch ICD. The authors propose that HIF-1α may interact with the Notch ICD and showed that they do so in vitro. Furthermore, chromatin immunoprecipitation analyses showed that HIF-1α is recruited to the promoter regions of Notch-responsive genes in cells exposed to hypoxia, provided that Notch signaling was also activated. These results help explain the mechanisms that couple oxygen sensing to control of differentiation. — LBR

Dev. Cell 9, 617 (2005).

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