l-685458 and Hypoxia

In the current issue of Developmental Cell, work by Gustafsson and coworkers demonstrates that hypoxia synergizes with Notch to inhibit differentiation of myogenic and neural precursor cells. This effect requires a newly described interaction between the transcriptionally active form of HIF-1alpha and the intracellular domain of Notch.

Topics: Animals; Carbamates; Cell Differentiation; Dipeptides; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Myoblasts; Receptors, Notch; Stem Cells

In addition to controlling a switch to glycolytic metabolism and induction of erythropoiesis and angiogenesis, hypoxia promotes the undifferentiated cell state in various stem and precursor cell populations. Here, we show that the latter process requires Notch signaling. Hypoxia blocks neuronal and myogenic differentiation in a Notch-dependent manner. Hypoxia activates Notch-responsive promoters and increases expression of Notch direct downstream genes. The Notch intracellular domain interacts with HIF-1alpha, a global regulator of oxygen homeostasis, and HIF-1alpha is recruited to Notch-responsive promoters upon Notch activation under hypoxic conditions. Taken together, these data provide molecular insights into how reduced oxygen levels control the cellular differentiation status and demonstrate a role for Notch in this process.

Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Carbamates; Cell Differentiation; Cell Line; Cell Line, Tumor; Dipeptides; Homeodomain Proteins; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Mice; Myoblasts; Receptor, Notch1; Receptors, Notch; Repressor Proteins; Signal Transduction; Stem Cells; Transcription Factor HES-1