Zheng, X.Karttunen, S.Dias, J.Zheng, X.Gradin, K.Wallis, T.Hamilton, B.Gustafsson, M.Ruas, J.Wilkins, S.Bilton, R.Brismar, K.Whitelaw, M.Pereira, T.Gorman, J.Ericson, J.Peet, D.Lendahl, U.Poellinger, L.2008-10-012008-10-012008Proceedings of the National Academy of Sciences of USA, 2008; 105(9):3368-33730027-84241091-6490http://hdl.handle.net/2440/47890Copyright © 2008 by The National Academy of Sciences of the USACells adapt to hypoxia by a cellular response, where hypoxia-inducible factor 1α (HIF-1α) becomes stabilized and directly activates transcription of downstream genes. In addition to this “canonical” response, certain aspects of the pathway require integration with Notch signaling, i.e., HIF-1α can interact with the Notch intracellular domain (ICD) to augment the Notch downstream response. In this work, we demonstrate an additional level of complexity in this cross-talk: factor-inhibiting HIF-1 (FIH-1) regulates not only HIF activity, but also the Notch signaling output and, in addition, plays a role in how Notch signaling modulates the hypoxic response. We show that FIH-1 hydroxylates Notch ICD at two residues (N1945 and N2012) that are critical for the function of Notch ICD as a transactivator within cells and during neurogenesis and myogenesis in vivo. FIH-1 negatively regulates Notch activity and accelerates myogenic differentiation. In its modulation of the hypoxic response, Notch ICD enhances recruitment of HIF-1α to its target promoters and derepresses HIF-1α function. Addition of FIH-1, which has a higher affinity for Notch ICD than for HIF-1α, abrogates the derepression, suggesting that Notch ICD sequesters FIH-1 away from HIF-1α. In conclusion, the data reveal posttranslational modification of the activated form of the Notch receptor and an intricate mode of cross-coupling between the Notch and hypoxia signaling pathways.enCell LineChick EmbryoAnimalsHumansMiceMixed Function OxygenasesProto-Oncogene ProteinsTranscription FactorsRepressor ProteinsTransfectionSignal TransductionReceptor Cross-TalkHydroxylationMuscle DevelopmentHypoxia-Inducible Factor 1, alpha SubunitReceptors, NotchReceptor, Notch1Receptor, Notch2HypoxiaReceptor, Notch3Receptor, Notch4Journal article00200803052008100115383610.1073/pnas.07115911050002538465000362-s2.0-4214911776943721Peet, D. [0000-0002-6085-8936]