Notch as Link from Hypoxia to Differentiation

Science's STKE  08 Nov 2005:
Vol. 2005, Issue 309, pp. tw390
DOI: 10.1126/stke.3092005tw390

Cells sense the availability of oxygen and activate signaling pathways that promote an appropriate physiological response such as decreased metabolic oxidative phosphorylation or increased proliferation of blood vessels. Hypoxia also causes various stem or progenitor cells to remain in an undifferentiated state. Gustafsson et al. conducted experiments that 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, a well-known signaling pathway important in the control of development. Cells use prolyl hydroxylases to sense oxygen, and these enzymes control gene transcription by influencing the activity of the transcription factor HIF-1α (hypoxia-inducible factor-1α). Notch is a receptor that undergoes proteolytic cleavage to release the intracellular domain (ICD), which moves to the nucleus, where it interacts with other proteins to regulate transcription. The authors found that effects of hypoxia on differentiation of cultured mouse muscle precursor cells or primary rat neural stem cells depended on Notch signaling and was prevented by an inhibitor of the protease that generates the Notch ICD. Hypoxia also increased expression of known Notch target genes. The authors propose that HIF-1α may directly interact with the Notch ICD. Indeed, in vitro immunoprecipitation studies showed that the two proteins can physically interact. Furthermore, chromatin immunoprecipitation analyses showed that HIF-1α is recruited to promoters 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. Tumor formation is one instance in which responses to hypoxia are critical, and the authors thus suggest that it may be useful to examine whether Notch and HIF-1α also work together under these circumstances.

M. V. Gustafsson, X. Zheng, T. Pereira, K. Gradin, S. Jin, J. Lundkvist, J. L. Ruas, L. Poellinger, U. Lendahl, M. Bondesson, Hypoxia requires notch signaling to maintain the undifferentiated cell state. Dev. Cell 9, 617-628 (2005). [PubMed]