Interaction with factor inhibiting HIF-1 defines an additional mode of cross-coupling between the Notch and hypoxia signaling pathways

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 105; no. 9; pp. 3368 - 3373
• Main Authors: Zheng, Xiaofeng, Linke, Sarah, Dias, José M, Zheng, Xiaowei, Gradin, Katarina, Wallis, Tristan P, Hamilton, Brett R, Gustafsson, Maria, Ruas, Jorge L, Wilkins, Sarah, Bilton, Rebecca L, Brismar, Kerstin, Whitelaw, Murray L, Pereira, Teresa, Gorman, Jeffrey J, Ericson, Johan, Peet, Daniel J, Lendahl, Urban, Poellinger, Lorenz
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 04-03-2008; National Acad Sciences
• Subjects: Animals; Biological Sciences; Cell Line; Cell lines; Cellular biology; Chick Embryo; Genes; Humans; Hydroxylation; Hypoxia; Hypoxia - metabolism; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; International Statistical Classification of Diseases; Ligands; Medicin och hälsovetenskap; Mice; Mixed Function Oxygenases; Muscle Development; Neurons; Plasmids; Progenitor cells; Proto-Oncogene Proteins - metabolism; Receptor Cross-Talk; Receptor, Notch1 - metabolism; Receptor, Notch2 - metabolism; Receptor, Notch3; Receptor, Notch4; Receptors, Notch - metabolism; Repressor Proteins - pharmacology; Signal Transduction; Small interfering RNA; Stem cells; Transcription Factors - pharmacology; Transfection
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.0711591105

Cells 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.