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Type: Journal article
Title: Interaction with factor inhibiting HIF-1 defines an additional mode of cross-coupling between the Notch and hypoxia signaling pathways
Author: 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.
Citation: Proceedings of the National Academy of Sciences of USA, 2008; 105(9):3368-3373
Publisher: Natl Acad Sciences
Issue Date: 2008
ISSN: 0027-8424
Statement of
Xiaofeng Zheng, Sarah Linke, José M. Dias, Xiaowei Zheng, Katarina Gradin, Tristan P. Wallis, Brett R. Hamilton, Maria Gustafsson, Jorge L. Ruas, Sarah Wilkins, Rebecca L. Bilton, Kerstin Brismar, Murray L. Whitelaw, Teresa Pereira, Jeffrey J. Gorman, Johan Ericson, Daniel J. Peet, Urban Lendahl, and Lorenz Poellinger
Abstract: 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.
Keywords: Cell Line
Chick Embryo
Mixed Function Oxygenases
Proto-Oncogene Proteins
Transcription Factors
Repressor Proteins
Signal Transduction
Receptor Cross-Talk
Muscle Development
Hypoxia-Inducible Factor 1, alpha Subunit
Receptors, Notch
Receptor, Notch1
Receptor, Notch2
Receptor, Notch3
Receptor, Notch4
Description: Copyright © 2008 by The National Academy of Sciences of the USA
Provenance: Published online before print February 25, 2008
DOI: 10.1073/pnas.0711591105
Published version:
Appears in Collections:Aurora harvest
Molecular and Biomedical Science publications

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