Abstract
A blood cell type termed crystal cell in Drosophila functions in clotting and wound healing and requires Notch for specification and maintenance. We report that crystal cells express elevated levels of Sima protein orthologous to mammalian hypoxia-inducible factor-α (Hif-α) even under conditions of normal oxygen availability. In these platelet-like crystal cells, Sima activates full-length Notch receptor signaling via a noncanonical, ligand-independent mechanism that promotes hemocyte survival during both normal hematopoietic development and hypoxic stress. This interaction initiates in early endosomes, is independent of Hif-β (Τangο in Drosophila), and does not activate hypoxia response targets. Studies in vertebrate myeloid cells have shown a similar up-regulation of Hif-α protein in well-oxygenated environments. This study provides a mechanistic paradigm for Hif-α/Notch interaction that may be conserved in mammals.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Aryl Hydrocarbon Receptor Nuclear Translocator / chemistry
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Aryl Hydrocarbon Receptor Nuclear Translocator / genetics
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Aryl Hydrocarbon Receptor Nuclear Translocator / metabolism
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Calcium-Binding Proteins / metabolism
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Cell Hypoxia
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Cell Survival
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Cytoplasmic Vesicles / metabolism
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DNA-Binding Proteins / chemistry
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Drosophila / cytology*
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Drosophila / genetics
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Drosophila / metabolism
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Drosophila Proteins / chemistry
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Drosophila Proteins / genetics
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Drosophila Proteins / metabolism*
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Endocytosis
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Hematopoiesis
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Hemocytes / cytology*
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Hemocytes / physiology*
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
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Intercellular Signaling Peptides and Proteins / metabolism
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Jagged-1 Protein
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Ligands
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Membrane Proteins / metabolism
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Receptors, Notch / metabolism*
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Serrate-Jagged Proteins
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Signal Transduction
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Stress, Physiological
Substances
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Calcium-Binding Proteins
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DNA-Binding Proteins
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Drosophila Proteins
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Hypoxia-Inducible Factor 1, alpha Subunit
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Intercellular Signaling Peptides and Proteins
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Jagged-1 Protein
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Ligands
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Membrane Proteins
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N protein, Drosophila
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Receptors, Notch
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Ser protein, Drosophila
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Serrate-Jagged Proteins
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Sima protein, Drosophila
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tgo protein, Drosophila
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Aryl Hydrocarbon Receptor Nuclear Translocator