Abstract
We have characterized the function of Notch-regulated ankyrin-repeat protein (Nrarp) in mouse cell lines and in hematopoietic stem cells (HSCs). Nrarp overexpression is able to block Notch-induced activation of CBF-1. In AKR1010 thymoma cells, Nrarp overexpression blocks CBF-1-dependent transcriptional activation of Notch-responsive genes and inhibits phenotypic changes associated with Notch activation. Enforced expression of Nrarp in mouse HSCs results in a profound block in T lineage commitment and progression through early stages of thymocyte maturation. In contrast, Deltex-1 overexpression in HSCs can also block T lineage commitment but not progression through the early double negative stages of thymocyte maturation. The different effects of Deltex-1 and Nrarp overexpression suggest that alternate Notch signaling pathways mediate T vs B lineage commitment and thymocyte maturation.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Ankyrin Repeat* / genetics
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Avian Proteins*
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Carrier Proteins*
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Cell Differentiation / genetics
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Cell Differentiation / immunology
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Cell Lineage / genetics
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Cells, Cultured
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Forkhead Transcription Factors
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Genetic Vectors
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Growth Inhibitors / biosynthesis
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Growth Inhibitors / genetics
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Growth Inhibitors / physiology
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Intracellular Fluid / physiology
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Intracellular Signaling Peptides and Proteins
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Membrane Proteins / antagonists & inhibitors*
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Membrane Proteins / physiology*
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Mice
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Mice, Inbred C57BL
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Oncogene Proteins*
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Protein Biosynthesis
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Proteins / genetics
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Proteins / physiology*
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Proto-Oncogene Proteins / antagonists & inhibitors
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Proto-Oncogene Proteins / metabolism
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Receptor, Notch1
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Receptors, Cell Surface*
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Receptors, Notch
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Signal Transduction / genetics
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Signal Transduction / immunology*
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T-Lymphocyte Subsets / cytology*
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T-Lymphocyte Subsets / immunology
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T-Lymphocyte Subsets / metabolism*
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Thymus Gland / cytology
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Thymus Gland / immunology
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Thymus Gland / metabolism
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Transcription Factors*
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Transduction, Genetic
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Tumor Cells, Cultured
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Viral Proteins*
Substances
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Avian Proteins
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Carrier Proteins
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Forkhead Transcription Factors
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Growth Inhibitors
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Intracellular Signaling Peptides and Proteins
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Membrane Proteins
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Notch1 protein, mouse
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Nrarp protein, mouse
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Oncogene Proteins
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Proteins
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Proto-Oncogene Proteins
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Receptor, Notch1
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Receptors, Cell Surface
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Receptors, Notch
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Transcription Factors
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Viral Proteins
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deltex protein, vertebrate
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v-qin protein, Avian sarcoma virus 31