Notch-regulated ankyrin-repeat protein inhibits Notch1 signaling: multiple Notch1 signaling pathways involved in T cell development.
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.
Yun
Theodore J
TJ
IDEC Pharmaceuticals, San Diego, CA 92121, USA.
Bevan
Michael J
MJ
D000818:Animals; D017089:Ankyrin Repeat / Q000235:genetics; D030161:Avian Proteins; D002352:Carrier Proteins; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D019070:Cell Lineage / Q000235:genetics; D002478:Cells, Cultured; D051858:Forkhead Transcription Factors; D005822:Genetic Vectors; D006131:Growth Inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D007424:Intracellular Fluid / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D015513:Oncogene Proteins; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D051880:Receptors, Notch; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured; D014764:Viral Proteins
D030161:Avian Proteins; D002352:Carrier Proteins; D051858:Forkhead Transcription Factors; D006131:Growth Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C497762:Notch1 protein, mouse; C499040:Nrarp protein, mouse; D015513:Oncogene Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D051880:Receptors, Notch; D014157:Transcription Factors; D014764:Viral Proteins; C409218:deltex protein, vertebrate; C490425:v-qin protein, Avian sarcoma virus 31