Hypoxia requires notch signaling to maintain the undifferentiated cell state.
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.
Gustafsson
Maria V
MV
Department of Cell and Molecular Biology, Medical Nobel Institute, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
Zheng
Xiaowei
X
Pereira
Teresa
T
Gradin
Katarina
K
Jin
Shaobo
S
Lundkvist
Johan
J
Ruas
Jorge L
JL
Poellinger
Lorenz
L
Lendahl
Urban
U
Bondesson
Maria
M
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D002219:Carbamates / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D045744:Cell Line, Tumor; D004151:Dipeptides / Q000494:pharmacology; D018398:Homeodomain Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D051379:Mice; D032446:Myoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051881:Receptor, Notch1 / Q000378:metabolism; D051880:Receptors, Notch / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D012097:Repressor Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000072056:Transcription Factor HES-1
D051792:Basic Helix-Loop-Helix Proteins; D002219:Carbamates; D004151:Dipeptides; D018398:Homeodomain Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051881:Receptor, Notch1; D051880:Receptors, Notch; D012097:Repressor Proteins; D000072056:Transcription Factor HES-1; C489734:Hes1 protein, mouse; C485778:Hey2 protein, mouse; C410009:L 685458